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Recent developments in functionalized polymer nanoparticles for efficient drug delivery system
Nano-Structures & Nano-Objects 20 (2019) 100397
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Nano-Structures & Nano-Objects journal homepage: www.elsevier.com/locate/nanoso
Recent developments in functionalized polymer nanoparticles for efficient drug delivery system ∗
Srija Sur a , Aishwarya Rathore a , Vivek Dave a , , Kakarla Raghava Reddy b , ∗ Raghuraj Singh Chouhan c , Veera Sadhu d , a
Department of Pharmacy, Banasthali Vidyapith, Banasthali, Rajasthan 304022, India School of Chemical and Biomolecular Engineering, The University of Sydney, Sydney, NSW 2006, Australia c Department of Environmental Sciences, Jožef Stefan Institute, Ljubljana, Slovenia d School of Engineering, University of Coimbra, 3030-290 Coimbra, Portugal b
article
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Article history: Received 15 May 2019 Received in revised form 24 August 2019 Accepted 25 September 2019 Keywords: Polymeric nanoparticles Functionalization Dendrimers Polymeric micelles Functionalized polymers Drug delivery Biomedical applications
a b s t r a c t To overcome the shortcomings of conventional dosage forms, targeted and modified drug delivery system came into existence. This was the time when a novel drug delivery system was in high demand. Nanoparticles are such type of targeted drug delivery system. Nanoparticles are colloidal particles which provide site-specific delivery of drugs. There are different kinds of nanoparticles, polymeric nanoparticles are one of a kind. Polymeric nanoparticles, nowadays, is one of the most researched topics. Their major advantages include good control over size, longer clearance time, improved therapeutic efficacy and reduced toxicity. Polymer-based nanoparticles come in various forms like dendrimers, ligand-based nanoparticles, polymeric micelles, PEGylated nanoparticles, etc. This chapter includes the various advancements in polymeric nanoparticles as well as advancements in the polymers that are used in their preparation. It reveals details about functionalized nanoparticles and its types. It finally discusses the use of various polymers in the drug delivery system in order to target varied diseases, taking cancer and vaginal diseases as an example. The chapter at the end also reveals the future aspect of functionalized polymeric nanoparticles. © 2019 Elsevier B.V. All rights reserved.
Contents 1.
Introduction......................................................................................................................................................................................................................... 1.1. Background of nanotechnology and nanomedicine........................................................................................................................................... 1.2. Merits and demerits of polymeric nanoparticles............................................................................................................................................... 1.3. Polymers used and their advancements ............................................................................................................................................................. 1.3.1. PAMAM and PEGylated PAMAM .......................................................................................................................................................... 1.3.2. HPMA and HEMA ................................................................................................................................................................................... 1.3.3. Albumin ................................................................................................................................................................................................... 1.3.4. PEG transferrin ....................................................................................................................................................................................... 1.3.5. PLA ........................................................................................................................................................................................................... 1.3.6. Chitosan................................................................................................................................................................................................... 1.3.7. Alginate.................................................................................................................................................................................................... 1.3.8. Gelatin ..................................................................................................................................................................................................... 1.3.9. PLGA......................................................................................................................................................................................................... 1.3.10. PEG ........................................................................................................................................................................................................... 1.3.11. Ovomucin ................................................................................................................................................................................................ 1.3.12. PEG-PLGA ................................................................................................................................................................................................ 1.4. Synthesis methodologies of nanoparticles.......................................................................................................................................................... 1.5. Advanced methodologies of synthesis of polymeric nanoparticles ................................................................................................................. 1.5.1. Ring-opening polymerization................................................................................................................................................................ 1.5.2. Electrohydrodynamic atomization .......................................................................................................................................................
∗ Corresponding authors. E-mail addresses: [email protected] (V. Dave), [email protected] (V. Sadhu). https://doi.org/10.1016/j.nanoso.2019.100397 2352-507X/© 2019 Elsevier B.V. All rights reserved.
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1.5.3. Formation of nanoparticles by desolvation of macromolecules ....................................................................................................... 1.5.4. Self-polymerization ................................................................................................................................................................................ 1.5.5. Mussel-inspired chemistry for polymerization................................................................................................................................... 1.6. Novel polymeric nanoparticulate systems .......................................................................................................................................................... 1.6.1. Lipid polymer hybrid nanoparticles..................................................................................................................................................... 1.6.2. Solid-lipid polymer hybrid nanoparticle ............................................................................................................................................. 1.6.3. Functionalized polymeric nanoparticles .............................................................................................................................................. 1.6.4. Polysaccharide conjugated polymeric nanoparticles.......................................................................................................................... 1.6.5. Ligand-based polymeric nanoparticles ................................................................................................................................................ 1.6.6. Fluorescence polymeric nanoparticles ................................................................................................................................................. 1.7. Characterization of nanoparticles ........................................................................................................................................................................ 1.7.1. Size and morphology ............................................................................................................................................................................. 1.7.2. Percent drug loading and entrapment efficiency ............................................................................................................................... 1.7.3. Zeta potential measurement ................................................................................................................................................................. 1.7.4. Solubility determination........................................................................................................................................................................ 1.7.5. Thermal property determination.......................................................................................................................................................... 1.7.6. Raman spectroscopy .............................................................................................................................................................................. 1.7.7. In vitro drug release studies ................................................................................................................................................................. 1.7.8. Recent advancements in functionalized polymeric nanoparticles ................................................................................................... 1.8. Application of polymeric nanoparticles .............................................................................................................................................................. 1.8.1. Treatment of vaginal diseases .............................................................................................................................................................. 1.8.2. Cancer treatment.................................................................................................................................................................................... 1.9. Future prospects and challenges.......................................................................................................................................................................... 1.10. Safety issues of polymeric nanoparticles ............................................................................................................................................................ Conclusion and future aspect............................................................................................................................................................................................ Declaration of competing interest.................................................................................................................................................................................... References ...........................................................................................................................................................................................................................
1. Introduction With the alarming emergence of disease and disorders, proper targeted dosage form has gained prime importance to treat the disease and improve patient’s health. Conventional dosage form has many shortcomings like repetitive administration of the drug with a shorter half-life, decreased patient compliance, high peak, and typical peak–valley plasma concentration–time profile, etc. and due to this obtains in a steady-state drug concentration and specificity of targeting cannot be achieved. Due to these shortcomings, there was an emergence of the modified and targeted dosage form. The conventional dosage form is slowly getting substituted with their modified and targeted release dosage form. Modified and targeted drug delivery of the drugs is in high demand because of their programmed drug release, site-specificity, and increased patient compliance. For developing a modified or targeted drug delivery system, polymers are considered as the structural backbone. A biocompatible polymer because of its added advantage has seen immense growth and therefore is the heating topic of discussion. Nanoparticles are colloidal particles which provide targeted drug delivery and are in the size range of 1 to 100 nm [1]. ‘Nano’ word is derived from ‘nanos’ which is a Greek word which means extremely dwarf. Different types of nanoparticles based on the morphology and physical/ chemical property are carbon-based nanoparticles, polymeric nanoparticles metal nanoparticles, ceramic nanoparticles, semiconductor nanoparticles, lipid-based nanoparticles, etc. Out of these, polymeric nanoparticles is a widely researched topic because of its advantages over other and moreover due to advancement in polymer science and nanotechnology, as there has been immense development in polymeric nanoparticles. Some advantages of polymeric nanoparticles are its easy preparation technique, the size distribution is easy to control, good retention and protection of the drug, etc. Polymeric nanoparticles can be defined as solid colloidal particle ranging from the size range 1–100 nm and they are preferably made up of polymers obtained from natural, synthetic or semisynthetic source which may be either biodegradable or nonbiodegradable [2]. Initially, non-biodegradable polymer nanoparticles were used. The first polymeric nanoparticle was made up
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of non-biodegradable polymer e.g. polyacrylamide, polystyrene, polymethylmethacrylate, etc. But due to chronic use of these nanoparticles, many shortcomings like chronic toxicity and high immunological response against the non-biodegradable polymeric nanoparticles was observed [3]. Due to this reason, biodegradable polymeric nanoparticles gained importance. Polymeric nanoparticles can carry drug, protein or DNA material for targeting a specific organ or cell [4]. Depending on the different method of preparation, the drug or another therapeutically active compound can dissolve, attach, encapsulate or entrap to the matrix of the nanoparticles. Polymeric nanoparticles are generally nanocapsules or nonspherical in shape. Nanocapsule polymeric nanoparticles are the one in which the therapeutic component is encapsulated within a polymeric capsule shell whereas nanospheres polymeric nanoparticles are the one in which drug or other solid particles are embedded into a polymeric matrix. The pictorial representation of nanospheres and nanocapsules are as shown in Fig. 1. Increased use of polymeric nanoparticles is because of its use as a smart polymer and its target specificity and reduced side effects. Until a few years, it was difficult to treat certain disease like cancer, which required target specific action, but due to the emergence of polymeric nanoparticles, cancer treatment is no more a nightmare [5]. Polymeric nanoparticles not only deliver the drug to a particular site but also deliver the drug at a particular rate which is advantageous in treating many diseases. This review is important because a wide and a vivid knowledge about the polymers and their use in polymeric nanoparticles are immensely necessary to know about the polymeric nano-revolution in the field of medicines and nanotechnology. It has the potential to boast and modify the solutions of recent diagnostic, therapeutic and biological problems to more reliable and convincing options. This review is highly important for the polymer therapeutics include everything like proteins which have polymer conjugates, micelles of block copolymer, polymeric drugs, etc. The polymers play a very important role in the drug delivery system for the treatment of various diseases like cancer , neurodegenerative diseases, cardiovascular disorders, etc. Therefore, proper knowledge of the polymers is of utmost importance [6]. The aim and specificity of the review article lies in giving a vivid description of the
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Fig. 1. Pictorial representation of (a) nanocapsules, and (b) nanospheres.
polymers used in modern form of drug delivery system. Mainly, it focuses on the nanoparticles prepared by the use of various polymers. It also deals with the vivid description and characteristics of the polymers that can be used for nanotechnology. It has also summarized various polymeric drug delivery systems and their mode of preparation. Specifically, it gives detailed end to end information about the polymeric nanocarriers and their significance in pharmaceutical and biomedical field. There are numerous techniques for preparing nanoparticles and it basically relies on physical and chemical properties of the polymer as well as the active component. To list a few basic formulation technique — use of organic solvent, application of temperature, mechanical shaking, ultrasonication, etc. The particular technique should be used which do not degrade or affect the property of the active constituent and polymer in any way. Some example of the advancement in nanoparticles is as shown in Fig. 2. 1.1. Background of nanotechnology and nanomedicine Use of nano-sciences in the field of medicine is relatively a new concept. Nanoscience is comparatively a young science and in its infancy. Use of Nanoscience in medicines has been in research since 1990, after the invention of high tech instruments. Before the inventions of these high tech instruments, in 1900, two scientists named Albert Einstein and Max Planck proposed theoretical evidence about the presence of very tiny particles which obeyed their own laws. They, therefore, encouraged other scientists to develop certain instruments which would assist in viewing nano-sized particles. Soon after in the year 1902 structure as small as 4 nm was detected in a ruby glass with the help of ultra-microscope. Ultra-microscope was invented by two scientists named Henry Siedentopf and Richard Zsigmondy. Later in the year 1931 and thereafter many new technologies for viewing nanotechnology were invented like TEM which was developed by two scientists named Ernst Ruska and Max Knoll. Soon after TEM other instruments like an electron microscope, FIM, STM, AFM, etc. were developed which helped in viewing and working with
nano-sized particles. Norio Taniguchi in the year 1974 coined the term Nanotechnology. It was in the year 1960 when the first lipid-based nanotechnology drug delivery system was invented which was later termed a liposome. Since then many research went into finding appropriate nano-sized particles for drug delivery system. In the year 1976, the controlled drug delivery system was introduced and the emergence of this new concept shifted the attention of all the researchers towards it. The scientists even termed it as ‘magic bullet’. In late 1960 first nanoparticle was developed by Peter Paul Speiser for targeted drug delivery. Polymer nanoparticles came into the scenario in the year 1994. Many researchers started using different polymers for the preparation of nanoparticles and started witnessing the pros and cons of the same. Due to the immense advantage and safety of biodegradable polymer, biodegradable polymer nanoparticles became the topic of interest. Biodegradable have an advantage over non-biodegradable polymer nanoparticles that it is non-immunogenic, non-allergent, less toxicity, no need to remove it from the body as the polymer degrades inside the body, etc. [7,8]. The brief history of nano-medicines is as shown in Fig. 3. 1.2. Merits and demerits of polymeric nanoparticles Polymeric nanoparticle came into existence to overcome the tedious preparation technique of nanoparticles. They are a highly researched topic among the scientists because of its perks over regular nanoparticles. Polymeric nanoparticles have a larger surface area which allows for displaying a large number of surface functional groups like ligands. Their smaller size helps them to enter into smaller capillaries and thereby easily target the cell. Another advantage of this nanoparticle is its good control over size and size distribution [8]. Compared to the conventional nanoparticle, they have a longer clearance time, which means a small amount of drug is sufficient to show better therapeutic efficacy and lesser toxicity. Apart from this, they can be easily tailored and controlled. The drug loading capacity is also high and easy (without any chemical reaction). The polymeric nanoparticle
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Fig. 2. (a) Polymeric micelles side view and front view, (b) Ligand-based nanoparticles, and (c) Dendrimers, and (d) Polymeric micelles.
can be administered through various routes like oral, intra-ocular, parenteral, nasal, etc. [9–12]. Apart from having so many advantages, polymeric nanoparticles also face certain disadvantages which include toxicity due to the use of PVA as a detergent in the preparation, termination of therapy also becomes difficult in case of emergency and scaling up of these nanoparticles is difficult, expensive and require sophisticated instruments. 1.3. Polymers used and their advancements Polymers are made up of monomers or monomeric units which have large molecular masses. Polymers are a compressed form of large repeating units which are known as monomers. At present times, drug delivery assisted via nanoparticles has become a platform to enhance as well as modify various properties of drug-like a modification of solubility, Improvement of its half-life and its release characteristics thereby, enhancing the pharmacodynamic as well as pharmacokinetic parameters of the biopharmaceutical formulations. Polymeric nanoparticles hold a maximum share in it. Polymers play an important role in this regard. To prepare polymeric nanoparticles, good knowledge of polymers is very important. The stability and compatibility issue of the drug and excipients with the polymer has been a major matter of concern during the preparation of formulation. Polymers work as inert carriers in which the drugs are conjugated so that the polymer can work as a vehicle to carry the drug molecule to the targeted site. Polymers can be both synthetic as well as natural in nature. Naturally occurring polymers can be cellulose, proteins, latex, and starches whereas, on the other hand, synthetic polymers are manufactured in large scale. 1.3.1. PAMAM and PEGylated PAMAM PAMAM, also known as Poly(amidoamine) are mainly dendritic polymers which are known for its biocompatibility, water
solubility, and non-immunogenic nature. PAMAM is made up of amide and amide functionality which can encapsulate any foreign molecule mainly drug molecule because of its unique architecture. These properties of PAMAM dendrimers enable them to show their huge application in the field of biomedical and pharmaceutical sciences. But the biggest disadvantage of this type of dendrimer is its toxicity. PAMAM at its nano-size range of 1– 100 nm interacts with cellular components like mitochondria, nucleus, and endosomes. The peripheral amino groups of PAMAM dendrimer brings about toxicity depending on its concentration. Thus, modifying PAMAM becomes very important to remove their toxicity. This was the time when PEGylated PAMAM came into existence. PEGylated PAMAM was the modified version of normal PAMAM dendrimer where surface modification is done to diminish cytotoxicity and hepatic toxicity. Neutralizing or replacing the cationic groups with anionic ones is one of the important steps. PEGylation of PAMAM dendrimers improves its pharmacokinetics and biodistribution. The pharmacokinetics and bio-distribution of PEGylated PAMAM can be enhanced by decreasing their uptake by spleen, macrophage, and liver which in turn improves their systemic circulation. PEGylated PAMAM has been one of the most effective modes of drug delivery for the treatment of cancer [13]. PEGylated PAMAM has been one of the best nano-carriers for delivering anti-cancer drugs. 1.3.2. HPMA and HEMA Poly(ethylene glycol) methyl ether methacrylates (PEGMEMA) are amphiphilic molecules which are known for their biocompatibility. These molecules do not trigger the immune system thus, assuring sufficient circulation time of the nanoparticles for aiming their target site. HEMA i.e. hydroxyethyl methacrylate is one of such kind. The degradation rate of HEMA is a function of its molecular weight. These nanoparticles are prepared by an advanced method of either emulsion free radical polymerization
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Fig. 3. Historic growth of nano-medicines.
or ring-opening polymerization. Similarly, on the other hand, N-(2-hydroxypropyl) methacrylate (HPMA) is such a monomer which has nowadays been known for its non-immunogenicity and biocompatibility. HPMA is a high water-miscible monomer. PEGYlated surfmers that consists of HPMA double bond is also known as HPMA-PEG. HPMA-PEG can also behave like a surfactant as per the studies. HPMA-PEG has been prepared by N,
N′ -dicyclohexylcarbodiimide-mediated esterification of succinylated PEG with HPMA. Likewise, HPMA-LA8 is prepared by the ring-opening polymerization of HPMA and L -Lactide [14]. 1.3.3. Albumin Proteins are natural molecules that show unique properties which enable these protein molecules to be used in the numerous nanomaterials. Albumin, gelatins are some of the proteins which
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show some promising characteristics like a high degree of stability, biodegradability, non-antigenicity, etc. Protein nanoparticles have huge advantages which open up a plethora of spectrum in front of them for which they can be used for the preparation of nanoparticles. Albumin can have enhanced drug carrier activities which can encompass a large spectrum of drugs. These nanoparticles are usually stimuli-sensitive and highly bioactive substances [15]. Albumin-polymer conjugates are highly versatile that can deliver a wide variety of drugs like metal-based drugs, hydrophobic drugs, etc. 1.3.4. PEG transferrin Transferrin is iron-binding blood plasma glycoprotein that regulates and maintains the amount and level of free iron in the biological fluid. The conjugation of transferrin with PEGylated recombinant human tumor necrosis factor alpha was established to maintain the properties of PEGylation as well as also enables the formulation to target tumor cells. This conjugate is mainly preferred as it has the specificity to target tumor cells. Dexamethasone many times is delivered by this mode when Dexamethasone is transferred with solid-lipid nanoparticles where the lipid is in conjugation with transferrin. The conjugation of Tf with Dexamethasone is an excellent active targeting ligand for cell targeting [16]. 1.3.5. PLA Polylactic acid also is known as PLA, and it is biodegradable as well as biocompatible in nature. It is non-toxic in nature. The hydrophobic nature of this polymer makes it suitable for lipid polymer-based hybrid nanoparticles. PLA exhibits a large amount of mechanical strength which when used in optimized condition can produce a controlled release drug delivery system [17]. 1.3.6. Chitosan Chitosan is a deacetylated chitin derivative and is a natural polymer. Chitosan is a modified natural carbohydrate-based derivative obtained from insects, fungi, animals or other marine invertebrates. Chitosan has a large role in the biomedical field. Chitosan has been used as a polymer in many diverse fields like agriculture, biomedical, etc. It is one among the highly abundant natural polymer and can be easily processed into varied forms like threads, matrix, beads, nanoparticles, etc. Mostly chitosan is used as chitosan sponges, chitosan beads, chitosan film, chitosan nanoparticles and chitosan microbeads (microspheres) in a targeted drug delivery system. Since chitosan is a natural polymer, it is biocompatible and biodegradable as well. This property makes Chitosan a highly desired polymer. Chitosan is freely soluble in acidic solution and releases a free amino group and develop positive charge over the polymeric chain. Chitosan is had poor solubility at pH above 6.5. Generally, the chitosan nanoparticle can be formed by incorporating a polyanion like TPP (tripolyphosphate) into chitosan with constant stirring [18]. Generally, Chitosan nanoparticles can be used for drug delivery, anticancer activity, gene therapy, etc. 1.3.7. Alginate Alginate is a natural based polymer and is biodegradable and biocompatible in nature. Alginate-based nanoparticles are a highly emerging area of interest. Alginate is basically a copolymer of (1, 4) linked β -D mannuronate and α -l-glucoronate. It is watersoluble in nature and a linear polysaccharide. Mostly alginates can be used in the form of hydrogels, porous scaffolds, microparticle, and nanoparticle. Generally, alginate nanoparticle is developed by methods like ionic gelation, emulsion, covalent cross-linking, complexation method, and self-assembly method. Out of all the method of preparation, ionic gelation and complexation is a
widely used method to prepare alginate nanoparticles [19]. Alginate nanoparticles can be used for the delivery of certain drugs like an anti-tumor drug, an anticancer drug, proteins, insulin, etc. The alginate nanoparticles are controllable and are pH-sensitive. 1.3.8. Gelatin Gelatin is obtained from structural and chemical degradation of collagen. Gelatine comprises of both acidic as well as basic functional groups. Gelatin forms a triple-stranded helical structure in solution at low temperature. It is a water-soluble polymer. There are mainly two types of gelatin: Gelatin A and Gelatin B. Type A gelatin has an isoelectric point of 9.0 and is obtained from acid hydrolysis of collagen I whereas type B gelatin has an isoelectric point of 5 ad is obtained from alkaline hydrolysis of collagen I. The nanoparticle prepared using gelatin polymer is biocompatible as well as biodegradable and therefore have no adverse reactions when these nanoparticles are introduced inside the human body. Drug release from gelatin nanoparticle can be through different methods like leaching, rupture, erosion or degradation of the polymer. This would, in turn, result in the slow release of the drug [20]. 1.3.9. PLGA PLGA is the abbreviation of poly(lactic-co-glycolic acid). The advantage of using this polymer is that it is biodegradable and biocompatible. It is a synthetic polymer synthesized by ringopening co-polymerization of cyclic dimers (1, 4-dioxane-2,5diones) of glycolic acid and lactic acid. PLGA readily undergoes hydrolysis inside the body. Many studies have been done on PLGA including the toxicological studies. Toxicological studies of PLGA indicated that PLGA causes a local tissue reaction. PLGA can be dissolved in a wide variety of solvents including, tetrahydrofuran, chlorinated solvents ethyl acetate or acetone. The glass transition temperature of PLGA is above 37 ◦ C, therefore, it has glassy behavior and a fairly rigid structure. The major challenge with PLGA is the ability to reassemble into polymeric devices like nanoparticle, microcapsule, and microspheres optimal for delivery system fabrication [21]. 1.3.10. PEG PEG stands for Poly(ethylene glycol) and it is a non-ionic hydrophilic polyester which is prepared by polymerization of ethylene glycol monomer and its molecular weight ranges from 300–100,000 Da. The drawback of using PEG is that it is not biodegradable in nature and is excreted unchanged in the kidney but luckily the polymer does not accumulate in the tissues, thanks to its hydrophilic nature. Moreover because of its hydrophilic nature PEG can be used to stabilize the nanoparticle especially in aqueous media, avoid aggregation due to steric hindrance in production, storage, as well as the application also PEG, increases solubility. Another advantage of PEG is that it does not involve ionic moiety and therefore no problem occurs when PEG is in contact with any charged molecule like DNA. Moreover, PEG suppresses opsonization and therefore is not readily detected by the immune system as a foreign substance and undergoes slower uptake by RES in spleen and liver [22,23]. 1.3.11. Ovomucin Ovomucin is a highly glycosylated protein with a molecular weight between 5500–8300 kDa depending on the isolation method followed and environmental condition. Ovomucin is mainly composed of two basic subunits namely α -ovomucin and β -ovomucin. It is a naturally obtained polymer obtained from the egg white. Ovomucin is a macromolecular protein which is viscous in nature. The drawback of using ovomucin as a polymer in the nanoparticle is that it may be an allergen to some patients and hence it is a less preferred polymer [24]. Ovomucin also has a biological function like antiviral nature, macrophage activation, etc.
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Fig. 4. Conventional methods of preparation of polymeric nanoparticles.
1.3.12. PEG-PLGA PEG-PLGA is an example of the block copolymer. It is a synthetic polymeric block synthesized by COOH-PEG-NH2 and PLGACOOH conjugation. This polymer is biodegradable in nature and it readily self arrange itself into nanometric micelle and entrap drug within itself and release it in a time-dependent manner. PEG PLGA is an emerging polymer system because it can be easily synthesized and is better than single PLGA. PEG-PLGA is an amphiphilic substance and therefore it orients in such a way that hydrophobic PLGA remains inside and hydrophilic PEG is outside the micelle and act as a stabilizing shell. The drug can be easily entrapped in this polymeric block. Another advantage of PEGylated PLGA nanoparticle is that even hydrophilic drug can be entrapped [25]. 1.4. Synthesis methodologies of nanoparticles The preparation of Nanoparticles needs optimization of the various preparation parameters depending on the various applications for which the polymeric nanoparticles are to be used. The selection of the drug and the polymer is very important, in a similar way, the method of preparation also plays a vital role in acquiring the properties of interest. A wide range of polymers is used for the preparation of polymeric nanoparticles. The combination of the different polymeric systems with the nanostructures has helped to develop a sustained release drug delivery system. There are various ways of preparation of Polymeric Nanoparticles. The conventional method of polymeric nanoparticles is as shown in Figs. 4 and 5. Nanoprecipitation is one such method of preparation of polymeric nanoparticles which can be on the other hand known as interfacial deposition or solvent displacement method. This technique was first introduced by Fessi. This is mainly an encapsulation technique which involves precipitation of polymers followed by their solidification. The solidification of polymers occurs due to the interfacial disposition of the polymers. The interfacial disposition of polymers takes place by displacement of a semi-polar solvent miscible with water, which was initially present in a lipophilic solution.
In this preparation process, first, a suitable organic solvent is selected. The organic solvent should be water-miscible by nature. The desired drug and the polymer should be dissolved in the organic solvent. Then, finally, the aqueous phase which contains a stabilizer is added with continuously stirring. Due to a decrease in the interfacial tension between the aqueous phase and the organic phase, the diffusion of organic solvent into the aqueous phase takes place very rapidly. This rapid diffusion and the flow of solvent forms and characterizes well-defined droplets of nanoparticles. Then finally the nanosuspension is obtained after freeze-drying the suspension with the help of 5% mannitol as cryoprotectant [26,27]. For example, from ancient times, the polymersome system has been prepared largely. The copolymer nanoparticles system had been a common nanoparticles system mainly with two polymers namely 2-methacryloyloxyethyl phosphorylcholine (MPC) and 2-(diisopropylamine)ethyl methacrylate (DPA). But the recent advancement in the preparation of nanoparticle system by nanosuspension method is the micellar system of nanoparticles. The micellar system of nanoparticles has been recently explored and has been prepared by the nanosuspension method. This unexplored fact about the micellar formation by nanoprecipitation method has helped to investigate how this method influences the effect of solvent and the choice of buffer upon the micellar size. MPC100 -DPA100 copolymer has been used in the preparation of solutions with the help of methanol and ethanol. Solvent evaporation is one the most common technique of preparation of polymeric nanoparticles. Mainly, in this technique of preparation of polymeric nanoparticles, such as an organic solvent is selected into which drug will get dissolved and dispersed. Then, in this solution of an organic solvent which contains the dispersed drug, the polymer is also dissolved. Then, the resultant organic phase which contains the drug and the polymer is then added to the aqueous phase. The aqueous phase contains surfactant like poloxamer 188, Polysorbate 80, PVA, etc. The organic phase and the aqueous phase are mixed by highspeed homogenization, which results in the formation of a stable emulsion. After the emulsion is formed, the emulsion is converted
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Fig. 5. Overview of conventional methods of preparation of polymeric nanoparticles.
to nanoparticle suspension. Under highly increased temperature and reduced pressure, the evaporation of the solvent takes place. In general practice, mainly single emulsions or double emulsions are prepared by ultra-sonication or high-speed homogenization. Finally, ultracentrifugation is carried out to get the solidified nanoparticles [28]. Salting out is nothing but the modification of solvent diffusion or emulsification. It is the modified version of the emulsion process. In this process, drug and polymer are dissolved in an organic solvent which is miscible in water. Then, the resulting solution formed is mixed with the aqueous counterpart of the solution which already had the salting-out agent in it. Thus, the organic phase which already contained the surfactant is mixed with the aqueous solution which contained the salting-out agent and the stabilizer, by continuous stirring. The salting-out agents, like magnesium and calcium chloride mainly prevents the miscibility of the aqueous phase with the organic phase resulting in the formation of an emulsion. When the emulsion is diluted, a reverse salting-out effect is observed which results in the precipitation of the polymer. The precipitated polymer matrix contains the encapsulated drug leading to the formation of nanoparticles [29]. Supercritical fluid technology avoids the use of organic solvents for the preparation of polymeric nanoparticles. Drug and polymer are dissolved in an environmentally friendly solvent which potential enough in producing polymeric nanoparticles. The drug and polymer together are converted to a solution with the supercritical fluid. This solution expands rapidly across the capillary nozzle into the ambient air. A high degree of supersaturation accompanied by the fast expansion of the solution leads to the homogeneous nucleation and finely dispersed nanoparticles [30–32]. Dialysis is a technique similar to the nanoprecipitation technique. But the only difference is that the polymers with the
drug dissolved in the water-miscible organic solvent are placed inside a dialysis membrane. The organic phase comes into the aqueous phase by diffusing out through the dialysis tube. The diffusion reduces the interfacial tension between the two phases. Subsequently, inside the membrane, there is displacement of the solvent. This event is followed by loss solubility of the polymer which leads to the progressive aggregation of the polymer [33]. Polymerization is basically a technique where there is the polymerization of two monomers. When the two monomers are present in two different interfaces, then the technique is known as an interfacial polymerization. When a single or multiple emulsions are used for the encapsulation of drugs, then the technique is single/ double emulsion technique. Polymeric micelles are often formed by the technique of polymerization. The basic principle behind all these processes is nothing but the polymerization of the monomeric units. There could be intermolecular cross-linking established by the polymerization reaction. The disadvantage of the polymerization technique is that there could be unreacted monomers, toxic substances may be generated from the chemical reactions, unreacted toxic by-products may also originate from monomeric reactions, etc. [34,35]. The brief description with the advancement in the technique is as mentioned in Table 1. 1.5. Advanced methodologies of synthesis of polymeric nanoparticles There have been various advancements in the method of preparation of nanoparticles. Many new advanced and revolutionary techniques have come up in recent years for the preparation of polymeric nanoparticles. Drug loading in the polymer is mainly achieved by two modes: First, when the drug is absorbed in the polymeric nanoparticles after it is being formed and secondly, instilling the drug in the nanoparticles right at its time of preparation. The advanced techniques include Ringopening polymerization, Electrohydrodynamic atomization, and Desolvation of macromolecules.
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Table 1 Conventional methods of preparation of polymeric nanoparticles. Technique
Summary
Specific Agents required
Reference
Nanoprecipitation
Formation of the particle is based on precipitation and subsequent solidification of polymers due to the interfacial deposition of polymer
Non-solvent for the polymer required.
[26,27]
Solvent Evaporation
After the formation of a stable emulsion of the organic phase (containing polymer and drug) and the aqueous phase (containing surfactant) the organic solvent is evaporated out under increased temperature and reduced pressure.
Surfactant required
[28]
Salting out
The salting out agents prevents the miscibility of organic
Salting out agent required.
[29]
Supercritical fluid technology
Without the use of organic solvent, the solution is formed by dissolving the polymers and the drug in the supercritical fluid. After this, across the orifice of the capillary, the solution is rapidly expanded into ambient air which in turn, results in rapid pressure reduction accompanied by high super saturation. This forms homogeneous nucleation and uniform-sized nanoparticles.
Supercritical fluid and a capillary nozzle required
[30–32]
Dialysis
Here the organic phase diffuses out through the dialysis tube into the aqueous phase, forming a homogeneous suspension of nanoparticles.
No surfactant required, dialysis membrane or dialysis tube is required.
[33]
1.5.1. Ring-opening polymerization Ring-opening polymerization is a technique where the growth of the chain takes place. In this process, the terminal end of the polymer acts as the reactive center for the chain opening reaction of cyclic monomer. It is a process of end-chain activation, electrophilic monomer activation and can also be the process of nucleophilic monomer activation. Caprolactone is taken as an example for the ring-opening polymerization technique. 6-Marcapto −1-hexanol, DPP and toluene were already stored in an ampule. The reaction is proceeded by the mixing of eCaprolactone at a temperature of 50 ◦ C. Triethylamine in the added to the aliquot. The polymerization reaction usually comes to an end by the addition of cold methanol. The product obtained is thus filtered out and dried at vacuum [36,37]. 1.5.2. Electrohydrodynamic atomization This process was initially developed with PLGA solution and acetonitrile. In this process, there is diffusion of the fluid which leads to the formation of polymeric nanoparticles with narrow size distribution and reduced size. This method was declared to be a dynamic method where fine droplets are prepared from conical meniscus of a liquid under the influence of electrostatic stress [38,39]. The process or electro-hydrodynamic polymerization was first developed by Xie et al. 1.5.3. Formation of nanoparticles by desolvation of macromolecules Polysaccharide can be desolvated by pH or temperature change by the addition of an appropriate amount of counterion. The main technology behind the desolvation method is nothing but the addition of a desolvating agent. This method does not require high temperature, therefore, thermolabile drug substances or thermolabile molecules can be treated with this method of preparation. For example, BSA nanoparticles had been prepared by desolvation technique where acetone was used as a desolvating agent [40,41]. 1.5.4. Self-polymerization Polydopamine, being a naturally occurring pigment contains melanin in it. Therefore, it shows some highlighting properties of presence of melanin in electricity, magnetics, and optics. Moreover, it has excellent biocompatibility. In addition to its biocompatibility, functional groups such as catechol, imine as well as amine can be incorporated in the chemical structure of Polydopamine. This is the reason, polydopamine have some wide applications in the field of biology and biomedicine. The best property of Dopamine is that it is a monomer can self-polymerize itself under alkaline conditions. The self-polymerization property of dopamine is a very simple process when the dopamine
monomers polymerize instantly when added into an alkaline solution by changing the color from pale brown to deep brown. This Polydopamine has immense use in polymer coating and is known to formulate a smart functional drug delivery system [42]. Molybdenum disulfide (MoS2 ), when treated with Gold Nanocomposites modified with polydopamine, shows an amazing anti-bacterial activity when tested against S.aureus [43]. Fluorescent nanoparticles are now-a-day considered to be the most trending research interest. Fluorescent nanoparticles show remarkable optical properties when compared with organic dyes and this is the main reason they have immense applications in the field of drug delivery and bioimaging. Biological imaging can be used as an important tool of monitoring the biological processes like studying the development of infectious diseases, monitoring tumor growth and metastasis, etc. Fluorescent materials are mainly of three broad types which includes organic, inorganic and traditional fluorescent materials. Traditional fluorescent materials have several disadvantages like poor membrane permeability, highly expensive and so on. On the other hand, inorganic fluorescent materials have high toxicity. Therefore, organic fluorescent materials are preferred over these two fluorescent materials because their high biocompatibility [44]. Moreover, when Polydopamine is used to modify the fluorescence organic nanoparticles they show great properties for cell-imaging and many more [45]. Moreover, there are many researches which have developed nanocomposites. The nanocomposites are the conjugation of carbontubes and polydopamine functionalized with chitosan. Apart from its application in the medical field, it has been used for copper ion removal [46]. Similarly, SiO2-PDA-PAPTCl is another such nanocomposites which have excellent adsorption properties where PAPTI, namely poly((3-Acrylamidopropyl)trimethylammonium chloride) is a cationic polymer [47]. Self-polymerization property of dopamine with polyethyleneimine has excellent properties of biological imaging. They have enhanced property of biocompatibility and biodegradability as well [48]. Therefore, from the above examples it can be assumed that polydopamine by it self-polymerization property has huge applications in the field of thermal therapy, bio-imaging and drug delivery system as well [49]. 1.5.5. Mussel-inspired chemistry for polymerization Mussel inspired chemistry is a type of chemistry where synthetic polymers are used to mimic the excellent polymeric coating properties of naturally derived substances. Huang et al. 2018 synthesized a polyacrylamide-immobilized molybdenum disulfide composites with the help of mussel-inspired chemistry. Polyacrylamide was immobilized onto nanosheets of MoS2 . Molybdenum disulfide nanosheets were first modified by polydopamine.
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Polydopamine was obtained from dopamine by the oxidative polymerization in the alkaline solution. After MoS2 nanosheets are modified with polydopamine, polyacrylamide was incorporated by surface-initiated polymerization method. This prepared solution is mainly used for adsorption of heavy metals like copper [50]. This type of chemistry is one of the most promising chemical technologies which are used as a surface modification tool. MoS2 nanosheets are surface modified by copolymerization technique. Mussel inspired chemistry are declared to be one of the most convincing chemistry for the surface modification of the nano-technologically derived drug delivery system [51]. In inclusion with the above applications, mussel-inspired chemistry has lot of implications in the field of environmental science as well. This includes oil-in-water separation, catalysis, and adsorption for purification in nature [52]. 1.6. Novel polymeric nanoparticulate systems 1.6.1. Lipid polymer hybrid nanoparticles Nanoparticles made from solid lipids are gaining a lot of importance nowadays. Solid lipid nanoparticles are one of the advanced modes to drug delivery where the particles are in submicron range these particles act as colloidal carriers which are made up of lipids dispersed in an aqueous surfactant solution. These solid lipid nanoparticles generally come in the form of lipid-polymer hybrid nanoparticles. The main advantage of this type of drug delivery system is that they bear the advantage of both the solid phase and the liquid phase. The lipid-polymer hybrid nanoparticulate system shows various advantages like good tolerability, protection of incorporated drugs as well as controlled release of the drug from the dosage form. The existence of polymer and lipid together gives them a unique characteristic where the hydrophilic and lipophilic characters coexist in the same platform. The coexistence of these two characters leads to a large variety of dosage form which can encapsulate a large variety of drugs. The lipid-polymer hybrid nanoparticles are basically composed of three layers which when arranged from inside to outside includes (1) hydrophobic core where a large amount of hydrophobic drug can be incorporated, (2) interfacial layer of lipid is present which behave like a biocompatible and flexible shell and finally the outermost layer i.e. (3) the hydrophilic layer which is basically an outermost polymer stealth that can improve the stability of the nanoparticles as well as the circulation time of the delivery system. But on the other hand, a lipid-polymer hybrid nanoparticle, under gastric conditions, has poor colloidal stability and thus, they have decreased bioavailability by oral delivery systems. Another biggest disadvantage of lipid-polymer hybrid nanoparticles is that drying them is very difficult and reverse aggregation can also take place in them before drying them. To overcome all these disadvantages and to cope up with the growing demand to have a stable nanoparticle that can be delivered by oral route solid-lipid polymer hybrid nanoparticles came into existence [53,54]. 1.6.2. Solid-lipid polymer hybrid nanoparticle Solid lipid polymeric nanoparticle is nothing but an advanced version of lipid polymeric hybrid nanoparticles with just a different design. They are formed by a core–shell structure where solid lipid nanoparticles are coated with polymer shell. This type of drug delivery system ensures higher encapsulation efficiency of mainly hydrophilic drugs which are water-soluble by nature. They can be prepared by from various biomaterials like pectin, bovine serum albumin, etc., therefore, biocompatibility is not an issue. The polymeric shell of solid lipid-polymer hybrid nanoparticles plays the role of maintaining colloidal integrity and stability while on the other hand, the solid-lipid core ensures encapsulation efficiency [55].
1.6.3. Functionalized polymeric nanoparticles Polymeric nanoparticles become functionalized when the polymer is modified by some means or the other. This improves their bio-distribution and also protects the nanoparticles from phagocytosis by RES. When the nanoparticles are protected from being destroyed, there is an increased level of drug in the blood. Suppose take an example of PEGylated nanoparticles where PEG is used as the coating material at the surface of the nanoparticles. As per reports it has been found that there is an increased concentration of PEG-coated nanoparticles in CNS. Based on the properties that have been modified, functionalized polymeric nanoparticles are mainly of four generations. The first generation includes long stealth nanoparticles which are followed by the second generation that includes lectin-based polymerized nanoparticles. Then, in the third generation, polysaccharide-based nanoparticulate system emerged which was finally followed by ligand-based nanoparticles in the fourth generation [56]. The first two generations of functionalized nanoparticles mainly include long stealth nanoparticles and lectin-based nanoparticles. In long stealth or long circulatory nanoparticles, the nanoparticles are produced in such a sterically protected way that their circulation time has been prolonged. The sterically protected nanoparticles are produced mainly by protein adsorption and suppression of surface opsonization. On the other hand, lectin-based polymeric nanoparticles use lectin. Lectins are fundamental to many cells and they show specific interaction with carbohydrate non-covalently. Many times lectins are tagged with fluorescent polymeric substances which work as biomarkers and thus, can be used for detection purpose. 1.6.4. Polysaccharide conjugated polymeric nanoparticles This is an important class of functionalized polymeric nanoparticles where polysaccharides are incorporated into the surface of the nanoparticles by some means or the other. During the preparation of polymeric nanoparticles polysaccharides are mainly adsorbed at the surface of the nanoparticles. Polyesters which are hydrophobic in nature like PLA, PLGA, etc. are covalently incorporated with a polysaccharide skeleton comprising of chitosan, dextran and hyaluronic acid. This is considered to be one of the most biocompatible drug delivery system [57]. 1.6.5. Ligand-based polymeric nanoparticles Ligand-based polymeric nanoparticles are the most recent type of drug delivery system which is known as magic bullets. They are designed such that they can deliver bioactive substances at specific sites. The sensing of biological materials can be acquired by the presence of nanoparticles at the very surface of the nanoparticles. For example, the Green fluorescent protein is used for the sensing of cancerous cells. Sometimes even a slight change in the head of the ligands improves the property of cell affinity in this type of drug delivery system. Ligand-based nanoparticles is a highly advanced method which can be used for disease diagnosis as well as intracellular delivery of drug [58]. 1.6.6. Fluorescence polymeric nanoparticles Aggregation-induced emission (AIE) radiates strong effect of fluorescence due to aggregation or accumulation of fluorophores while on the other hand, there are very weak or almost no emission when there is accumulation in dilute solutions. AIE has brought about great advancements when it came to biomedical applications of AIE-active polymeric probes. Science has developed polymeric nanoparticles of luminescent nature. In this type of formulation, various fluorescent compounds are used such as fluorescent proteins, luminescent polymers which have coordination with metal substances, etc. The fluorescence intensity of this type of formulation is extremely weak and also causes
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fluorescence quenching when they are in highly aggregated stage. Aggregation-induced emission (AIE) is just a very good solution to this problem [59]. These AIE active molecules can be used as bio as well as chemosensors [60] Fluorescent organic nanoparticles are those nanoparticles which have unique properties of Aggregationinduced emission (AIE). It has been found experimentally that water-dispersible fluorescent organic nanoparticles have excellent emission properties. Many scientists through synthetic techniques have conjugated AIE active dyes with polymers or block co-polymers and together they give rise to excellent fluorescent organic materials which can function for bio-imaging as well as therapeutic purpose. There are a lot of researches which has used tandem polymerization technique to combine with various AIE properties. But this technique has a lot of disadvantages like poor solubility, strict stoichiometric balance, etc. Therefore, to modify the technique, one-pot three-component tandem polymerization with the aromatic dyes came into existence. The polymers obtained from this technique are of good water solubility, can form film and also has high thermal stability. Similarly, there are many onepot polymerization techniques such as MALI reaction, tandem polymerization, and its modified version and so on. The polymers prepared by this technique have a high level of biocompatibility and causes very less disturbances to cellular activities. This is the main reason that the polymers prepared by this technique have huge amount of applications in the field of biomedical research and drug delivery system [61]. Many new researchers have nowadays synthesized blockcopolymers which has luminescent property. In other words, present research is more focused on the preparing nanoparticles which can serve the dual purpose of bio-imaging as well as drug delivery. PEGMA-PhE FPNs nanoparticle was prepared which has the bio-luminescent property because it has been prepared by the use of fluorescent organic polymeric nanoparticles [62]. Similarly, AIE-active-salicyaldehyde-poly(PEG-co-vinylaniline) was prepared whose was aimed to serve the dual purpose [63]. Above all, this block copolymers as well as luminescent polymeric nanoparticles are prepared by the one-pot multicomponent reaction. This reaction mechanism is highly efficient and effective process on synthesizing luminescent nanoparticles as it serves various advantages. Due to these advantages, researchers have also tried ultrasound technique for the ultrafast delivery of various cross-linked copolymers which have the property of aggregation-induced emission. Poly(PEGMA-AEMA) with AIEgen having a termination of aldehyde is one such example [64]. Moreover, nanodiamonds are one of the most emerging concepts of fluorescent nanotechnology nowadays. The research interest is towards to conjugation of the nanodiamonds which is with hyperbranched functionalized polymer. They are proved to be one of the most important controlled release drug delivery systems for the treatment of cancer. This type of modern drug delivery system has drawn the attention towards itself as far as biomedical research is concerned. biomedical research [65]. Last but not least, these AIE aggregates have high cellular uptake capability. A prominent example is functionalized glutamate conjugated into a prominent luminescent nanoparticle [66]. 1.7. Characterization of nanoparticles
11
determination of chemical characteristics for example presence of a conjugated molecule or bonded ligands and zeta potential. The physical characterization is done with the help of SEM, TEM, UV spectroscopy, X-ray diffraction, Differential Centrifugal Sedimentation, Dynamic Light Scattering, etc. whereas chemical characterization is done with the help of techniques like NMR, FTIR, Raman spectroscopy, Gel electrophoresis, inductively coupled plasma mass spectrometry, etc. [67–74]. Different characterization technique of polymeric nanoparticles is as shown in Fig. 6. 1.7.1. Size and morphology Particle size determination is of prime importance in nanoparticle characterization. The particle size of the nanoparticle highly depends on the excipients, polymer and preparation technique. Particle size is also important because many secondary properties like surface area, toxicity, degradation, targeting, uptake mechanism, etc. are linked with the particle size. The two main techniques used to determine the particle size distribution are photon correlation spectroscopy, electron microscopy. Electron microscopy includes TEM, SEM, freeze-fracture technique. The electron microscopy technique measures individual particle size and particle size distribution. It is a relatively faster process. TEM i.e. Transmission electron microscopy is a technique in which the size of the particle can be measured by transmission of the electron beam through a sample. The transmitted beam shows variation in amplitude and phase which provides imaging contrast that is a function of sample size, thickness, material, etc. The image formed when the electrons are transmitted through the specimen is magnified and focused with the help of an objective lens and the image appears on an imaging screen. TEM has comparatively a higher resolution than light-based imaging technique [69–71]. SEM (scanning electron microscopy) can also be used to determine the nanoparticle size. In this technique, the electron microscope images the surface view of the particle with the help of high energy electron beam. The electron beam strikes the sample surface and thereby interact with sample’s atom and signals in the form of secondary electrons. The backscattered secondary electrons and also the characteristic X-ray generated would depict information about composition, surface characteristics, and topography of the nanoparticles [64]. Other techniques may include Atomic force microscopy, mercury porosimetry, etc. In Atomic force microscopy (AFM) visualization of the nanostructure is possible and in mercury porosimetry, the freeze-dried nanoparticles are filled in a dilatometer under vacuum and later are measured with mercury pressure porositometer. Morphology refers to physical shape and surface topography. Morphology or direct visualization can be done by SEM, TEM, AFM, sorptometer, etc. [67–71]. 1.7.2. Percent drug loading and entrapment efficiency Percent drug loading and entrapment efficiency are essential to be calculated. It tells how much amount of drug is entrapped inside the nanoparticle successfully. The entrapment efficiency and loading capacity depend on the procedure followed and how efficiently the experiment was performed. It is expressed in percentage. Encapsulation efficiency
Characterization is important to determine the shape, size, specific surface area, structure, etc. Characterization of nanoparticles can be broadly divided into two domains. The first classification is one which deals with physical properties determination of nanoparticles. For example shape, size, crystal structure or mono-dispersity and the other classification involves the
=
total amount of drug added − free non entrapped amount of drug total amount of drug added
× 100 Loading capacity =
amount of total entrapped drug total nanoparticle weight
× 100
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Fig. 6. Instrumentation of RAMAN Spectroscopy.
For calculating the Entrapment and drug loading efficiency a specified amount of drug-loaded nanoparticle is dissolved in particular solvent by centrifugation or sonication for an hour. The sample so obtained is then filtered using the membrane filtration technique. The concentration of the sample is in mg/ml and it is analyzed using UV/vis spectroscopy technique or other analytical technique [67–72]. 1.7.3. Zeta potential measurement Zeta potential measures the effective charge on the surface of the nanoparticle. The nanoparticle has a certain surface charge which can be screened by the concentration of opposite charge and this layer moves along with the nanoparticle and together the two layers of charges around the nanoparticle are termed as an electrical double layer. Zeta potential is the difference between the potential between the electric double layer. The magnitude of zeta potential also determines the stability of the particle. The charge of the nanoparticle also depends on the pH of the solution. Zeta potential is measured with the help of a cell containing gold electrodes. The nanoparticle-containing solution is poured in the cell and the voltage is applied between the electrodes. The particles will move in the direction of their opposite charge electrode. A Doppler technique measures the particle voltage. The laser beam passes through the cell and fluctuation in the intensity of the laser determines the particle speed at multiple voltages and this helps in calculation of zeta potential. The Zeta potential value can be measured using a Zeta-sizer equipped with HeNe laser [67–72]. 1.7.4. Solubility determination Solubility can be determined by solubilizing the nanoparticle in distilled water. Excess of the pure drug is dissolved in a predetermined amount of distilled water in a conical flask. The conical flask is placed on an orbital shaker for a day. This would ensure saturation of the drug. The solution is then filtered and diluted adequately and the concentration is determined using appropriate spectroscopically [67–70]. 1.7.5. Thermal property determination 1.7.5.1. DSC. To know about the thermal properties of the polymers is one of the most essential things for the processing of materials and also predicting the shelf life of the final product. Differential Scanning Calorimetry is one of the most powerful
techniques for analyzing the thermal properties of the polymer. The thermal properties help us to judge the nature and characteristics of the polymer-based products. In heat-flux DSC, when heat is flown, the temperature difference between the sample and the reference is measured and compared. When heat evolves out from the sample, the graph in the DSC plot shows exothermic reaction but on the other hand, when the sample absorbs heat in the thermal process, then the graph becomes indicative of endothermic reaction. 1.7.5.2. TGA. TGA is known as Thermogravimetric analysis. It provides a transparent idea regarding the weight loss of the sample that is to be analyzed with respect to temperature increase. In this process, the change in the sample mass is measured which occurs during various thermally assisted events like sublimation, desorption, oxidation, etc. During the whole process of analyzing the sample is subjected to a program which helps in increasing the temperature [73]. 1.7.5.3. DTA. DTA is known as Differential Thermal Analysis. In this process, the sample and the reference are subjected to identical heat treatments. The temperature difference shown by the sample and the inert reference is measured and the analysis is carried out accordingly. Change in specific heat or any change in enthalpy of transition is detected by the method of DTA [73]. 1.7.6. Raman spectroscopy Raman spectroscopy is a spectroscopic technique which helps in observing the rotational, vibrational and other modes of frequency in the given nanoparticles. It provides a structural fingerprint of the given nanoparticle. This method quantitatively and qualitatively analyzes the covalent bond and differentiates between different materials and also helps us to find the strain in the given molecule [58]. Brief instrumentation is as mentioned in Fig. 6. 1.7.7. In vitro drug release studies For finding the in vitro drug release, place the sample in a dialysis bag and place it in the dissolution medium. The study is continued using USP dissolution apparatus, at a particular time interval a certain amount of sample solution is withdrawn and filtered and analyzed spectroscopically. Recently ultrafiltration technique is also used to find them in vitro drug release.
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13
Fig. 7. Characterization of nanoparticles.
Fig. 8. PEGylated nanoparticles used for the treatment of skin tumor.
1.7.8. Recent advancements in functionalized polymeric nanoparticles 1. Stimuli-responsive nanoparticles are the part of smart technological advancements that brought about a revolution in the field of smart delivery of therapeutic agents for the
treatment of solid tumors. The stimuli developed nanoparticles are inactive when it is present in the bloodstream. It gets activated in the presence of stimuli like pH, temperature, enzymatic scale-up [74–76]. 2. Cancer cells have pH less than normal cells that means the pH in normal cells is much higher than cancer or tumor
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Fig. 9. Ligand-based nanoparticles targeted through active targeting.
cells. Thus, the new advancements of nanocarriers made up by pH-responsive polymers have become a revolutionary approach for the diagnosis of cancer and its treatment. pHresponsive nanocarriers with programmable size changes with a change in pH and thus works as targeted release dosage form [67–69,76–78]. 3. Combination Chemotherapy has widely been used for the treatment of cancer. It is effective against overcoming the drug resistance and also achieving a synergistic effect against cancer in the clinic. Methotrexate and pemetrexed with chitosan polymer have been prepared. The above synergistic formulation has been prepared by modifying mPEG (methoxy poly(ethylene glycol) where PEGylated chitosan particles are prepared to be used as Stealth nanocarriers. The technology has been carried out to target human lung adenocarcinoma epithelial [69]. Fig. 7 shows how PEGylated nanoparticles treat tumor cells. 4. The concept of nanogel as nano-sized nanoparticles has significantly been used in the treatment of cancer by the mode of gene delivery. The most valid advantage of nanogel over conventional dosage form is that it does not show any destabilization even in highly dilute conditions. Narian et al. have been credited to formulate a nanogel with the cationic core. The unique characteristics of nano preparation in that it is temperature as well as pressure-sensitive. The thermosensitive polymer used was PNIPAM, but Poly (N-vinylcaprolactam) (PVCL) is preferred more for its excellent compatibility with the biological system. Nanogels prepared with PVCL depicts a volume phase transition temperature at 32 ◦ C–38 ◦ C in water, which is very close to the physiological conditions. And for preparation of pHsensitive nanogels, Poly(2-diethylaminoethyl)methacrylate is used as a polymer [70]. 5. Magnetic nanocarriers have one of the recent approaches for the treatment of multimodal cancer therapy. The anticancer drug doxorubicin is conjugated with pH and thermoresponsive magnetic nanocomposites. The formulation is developed by linking the magnetic composites with doxorubicin through acid-cleavable imine linkage which offers
the formulation an advanced feature of targeted drug delivery of the drug molecules. The dual characteristics of temperature and pH-sensitive nature give control over the release of doxorubicin [71]. 6. Ligand-based nanoparticles show programmed selectivity and affinity for a specific target site which gives a depth of understanding of molecular recognition and tissue recognition [79]. This ability of molecular as well as tissue recognition implicates that it is one of the most effective technique for detection of metabolites, biomarker for cancer, etc. Fig. 8 shows ligand-based targeting. 7. Dendrimers are nothing but polymeric architectures that are known for their versatile use in the drug delivery and drug targeting. This nano-structured molecule is basically starred shaped with three compartments including the core, dendritic structures that is, the branches and finally the exterior structure with a functional group in the surface, These dendrimers are an important tool of targeted drug delivery [80–82] (see Fig. 9). The advancements came up with a lot of revolutions in the field of drug delivery through nanotechnology. The various new advanced polymeric nanostructures have brought about a lot of new patents in the field of nanotechnology. The Tables 2–4 represent a brief description of the patents related to the polymeric nanoparticles. 1.8. Application of polymeric nanoparticles 1.8.1. Treatment of vaginal diseases The vagina is the main route of administration to obtain local effect or systemic effect and this route can also bypass the hepatic first-pass metabolism. This route can also be used to treat the sexually transmitted disease or infections. But administering the drug through vaginal route is not easy and has many shortcomings. The abundant mucus produced by the vagina is the major barrier for the conventional dosage form and because of this conventional drug does not show sustained and targeted action. It is because of these shortcomings that modified release dosage
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Table 2 Recent patented polymer-based NPs for drug delivery. Formulation
Patent number
Nanocarrier
Therapeutic uses
Tumor-targeting drug-loaded particles
CN102697737 A
Gelatin and PLGA
Cancer treatment
Functional PLA-PEG copolymers, the nanoparticles thereof, their preparation and use for targeted drug delivery and imaging Functional PLA-PEG copolymers, the nanoparticles thereof, their preparation and use for targeted drug delivery and imaging
WO2013127949 A1
PLA-PEG copolymers
Cancer treatment and imaging
Human recombinant epidermal growth factor (hrEGF)-modified cisplatin-loaded polymeric nanoparticles and preparation method and application thereof
CN102793671 A
mPEG-PLGA-PLL
Cancer treatment
Cellulose-based nanoparticles for drug delivery
WO2012103634 A1
CMC-Ac-PEG
Cancer treatment
Contrast media for cancer diagnosis containing amphiphilic hyaluronic acid complex nanoparticle and drug carrier for treating cancer
KR1020100037494
HA
Cancer diagnosis and treatment
Compound epirubicin hydrochloride polylactic-co-glycolic acid (PLGA) nanoparticles and preparation method thereof
PLGA
Anti-tumor combined medicament
CN102697795 A
PLGA
Cancer treatment
Nanoparticle composition and methods to make and use the same
US20130209566 A1
POE
Eye-related diseases, cancer, arthritis, etc.
Polymer-nanoparticle magnetic resonance contrast agent and preparing method thereof
CN101612407 B
PLA-PEG-DTPA-Gd
Magnetic resonance
Nanoparticle carrier systems based on human serum albumin for photodynamic therapy
WO2011071968 A3
Albumin
Photodynamic therapy
A high-loading nanoparticle-based formulation for water-insoluble steroids
WO2013063279 A1
PEG-b-PLA
Steroids deficit treatment
Injectable biomaterial
US20120195826 A1
HPMA-HMA and HPMA-TBA
Occluding normal or malformation of blood vessels; necrosating tumors
Nanoparticles comprising rapamycin and albumin as an anticancer agent
US20130280336 A1
Albumin
Treating, stabilizing, preventing, and/or delaying cancer
Drug loaded polymeric nanoparticles and methods of making and using same
EP2309990 B1
PLA-PEG
Cancer treatment
Functional biodegradable polymers
WO2012015481 A1
PLA, PLGA or PGA
Delivery of a therapeutic agent
Polymer formulations for delivery of bioactive materials
US8114883 B2
PLGA
Delivery of therapeutic agents
Biodegradable drug-polymer delivery system
US8128954 B2
Cyclodextrin
Delivery of therapeutic agents or ocular diseases treatment
Injectable cross-linked polymeric preparations and uses thereof
US8110561
Polysaccharide gels
Body tissue treatment
Table 3 Recent patented formulations regarding dendrimer-based nanoparticles for drug delivery. Formulation
Patent number
Nanocarrier
Therapeutic uses
Hydroxyl-terminated dendrimers
WO2011053618 A3
Hydroxyl-terminated PAMAM
Cancer treatment and diagnosis
Carbosilane dendrimers and the use thereof as antiviral agents
EP2537880 A2
Carbosilane
Antiviral, antibacterial or antifungal treatment
Injectable dendrimer hydrogel nanoparticles
EP2552458 A1
PAMAM
Therapeutic treatment and diagnosis
Dendrimer compositions and methods of synthesis
EP2488172 A2
PAMAM
Cancer treatment and diagnosis
Targeted dendrimer-drug conjugates
WO2011072290 A3
PEGylated PAMAM
Liver-specific delivery of therapeutic agents
Interior functionalized hyperbranched dendron-conjugated nanoparticles and uses thereof
WO2012018383 A2
Cystamine core PAMAM
Cancer treatment
Compositions and methods for delivering nucleic acid molecules and treating cancer
WO2012024396 A3
PPI
Cancer treatment
form for vagina was introduced. The polymeric nanoparticles have been introduced to overcome the physiological barrier and has certain advantages like mucoadhesiveness, easy penetration to mucosa as well as a sustained and targeted release of the drug. Both biodegradable and non-biodegradable polymer of natural and synthetic origin has gained immense interest [82].
Both natural and synthetic polymeric nanoparticle can be used but generally natural polymers such as proteins and polysaccharides are used at relatively lesser degree because of variation in different sources, the problem in the preparation process, uncertainty of the source, antigenic to some patient, etc. Therefore biodegradable synthetic polymeric nanoparticles are highly
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S. Sur, A. Rathore, V. Dave et al. / Nano-Structures & Nano-Objects 20 (2019) 100397 Table 4 Nanoparticle drug delivery systems undergoing clinical investigation. Name
API
Polymers
Use
Clinical trial phase
BIND-014 CALAA-01 CRLX101 OpaxioTM ProLindacTM CT-2103 NK911 MTX-HSA SPI049C NK105 Paclical R VivaGel⃝
Docetaxel Anti-RRM2 siRNA Camptothecin Paclitaxel Oxaliplatin Camptothecin Doxorubicin Methotrexate Doxorubicin Paclitaxel Paclitaxel SPL7013
PEG-PLA Cyclodextrin-PEGtranferrin Cyclodextrin-PEG Poliglutamic acid HPMA-DACH Polyglutamic acid PEG-PAA micelle HAS P-glycoprotein micelle PEG-PAA micelle Polymeric micelle Dendrimer
Solid tumors Solid tumors Several types of cancers Lung and ovarian cancer Solid tumors Ovarian cancer Solid tumors Kidney cancer Several types of cancers Gastric cancer Ovarian cancer HIV infections
I I II III II III III II III II III II/III
Table 5 Polymeric nanoparticles for the treatment of vaginal diseases. Drug name
Nature of the drug
Polymer used
Size
Technique
MOA
Uses/target
Ref.
Ascorbic acid
Hydrophilic
Chitosan
170 nm-
Ionotropic gelation
Antioxidant and reduces free radical; boost immunity
Cervical Cancer
[82]
Insulin
Hydrophilic
Chitosan
265–279 nm
Ionotropic gelation
Binds to glycoprotein receptor and maintain the glucose level
Model for peptides delivery
[83]
Silver saccharinate
Hydrophilic
Alginate
100–250 nm
Reverse emulsification
Interaction with a thiol group and act as antimicrobial
HSV-2 and Neisseria gonorrhoeae inhibition
[19]
Tenofovir
Hydrophilic
Gelatin
294.7–445 nm
PLGA 50:50
118 nm
Inhibits the activity of HIV reverse transcriptase by competing with deoxyadenosine 5′ -triphosphate
Sexual transmission of HIV in women
[20]
Hydrophilic
Desolvation method Double emulsion-solvent evaporation
Ciprofloxacin
Hydrophilic
Ovomucin
235 nm
Nano-precipitation
Broad-spectrum antibiotic and inhibit DNA gyrase, type II topoisomerase, topoisomerase IV, necessary to thereby inhibit cell division.
Treat bacterial infection
[24]
Riboflavin
Hydrophilic
Ovomucin
52–235 nm
Nano-precipitation
Antioxidant as riboflavin is a precursor of flavin adenine dinucleotide
Treat vaginal lesion
[24]
Acyclovir
Hydrophobic
PVPK30-EC
403 nm
Nano-precipitation
PVPK30-ERSPO
99 nm
Nano-precipitation
Inhibitor of herpesvirus DNA polymerase and other viral DNA polymerase
Efavirenz
Lipophilic
PLGA 50:50
275 nm
Emulsion-solvent evaporation
Inhibit reverse transcriptase enzyme (RNA-directed DNA polymerase)
Sexual transmission of HIV in women
[86]
Dapivirine
Lipophilic
PLGA 50:50
168 nm
[86]
poly (ε -caprolactone)
182–194 nm
Inhibit reverse transcriptase enzyme
Treat HIV-1 infection
Lipophilic
Emulsion-solvent evaporation Solvent displacement method
Clotrimazole
Lipophilic
PLGA 50:50
492 nm
Emulsificationdiffusion
Inhibits ergosterol synthesis by interacting with yeast 14-α demethylase
Treat Vaginal infection like a vaginal yeast infection, itching, discharge, etc.
[88]
Paclitaxel
hydrophobic
PLGA 50:50
245 nm
Solvent diffusion/nanoprecipitation
Interfere with microtubule growth
Treat the genital disease, cancer, HIV
[89]
Elvitegravir (EVG)
Lipophilic
PLA conjugated with HPG
131–135 nm
Nano-emulsion protocol
Inhibits HIV-1 integrase and prevent HIV 1 DNA integration with human genome DNA
Treat HIV and other viral and fungal infection.
[90]
Imiquimod
Lipophilic
poly (ε -caprolactone)
199 nm for uncoating and 213 nm chitosan coated
Interfacial deposition
Improve immune response by activating toll like receptor 7 (TLR7), stimulates apoptosis
Treat genital warts in female, antiviral, antitumor
[91]
Antiviral
[84]
[85]
[85]
[87]
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Table 6 Different natural and synthetic polymeric nanoparticles used in cancer drug delivery. Drug name
Nature of the drug
Polymer used/ Polymer formulation
Technique
Mechanism of action
Uses/targets
Status
Product name
Ref
Paclitaxel
Highly water-insoluble
PEG-PLA
Block co-polymerization (nanoprecipitation) Nanoprecipitation
Inhibitor of microtubule; binds to tubulin, prevents the assembly of microtubules thus, resulting in inhibition of cell division. Interacts with DNA by intercalation and inhibition of macromolecular biosynthesis.
Breast cancer, pancreatic cancer
Clinically approved
[22, 23]
Ovarian cancer
Phase III
Genexol (approved in south Korea) Paclical
Advanced adenocarcinoma
Clinically approved
Doxil
[25]
Polymeric micelle
Doxorubicin
Hydrophilic
PLGA-PEG block copolymers (with folic acid)
Double emulsion solvent evaporation, single emulsion solvent evaporation, and dialysis method
Vincristine
Poor water solubility but readily dissolve in an organic solvent (alkaloid)
PLGA
o/w single emulsion solvent evaporation process
Partially works on binding with tubulin protein which does not allow the tubulin dimer to polymerize.
Acute lymphoblastic leukemia
Phase III
Marqibo
[21]
Amphotericin B
Polyene by nature; soluble in acidic water (pH-2) or basic water (pH-11); soluble in methanol
PLGA
Emulsion solvent evaporation method
Acts by binding on the sterol component of the cell membrane, and thus disrupts the cell.
Invasive fungal disease
Phase III
Ambisome
[92]
siRNA
Nucleic acid
PEG-CCP/CaP
Double-emulsion solvent evaporation technique
Suppress the expression of the carcinogenic gene by targeting the mRNA expression
Pancreatic tumors
Phase I
NCT01437007
[93]
Cisplatin
Platinum-based compound
PEG-P(Glu)
Dialysis
Bind to DNA thereby interfere with repair mechanism of the DNA leading to cell death
Colon adenocarcinoma cells
Phase III
Nanoplatin
[93]
Ascorbic acid
Hydrophilic
Chitosan
Ionic gelation method
The level of C-reactive protein decreases and also there is a decrease in proinflammatory cytokines It stops metastasis and also hinders the growth of the tumor and encourages encapsulation of tumor. Anti-apoptotic activity with the help of Bcl-2 Modulation of markers for cancer proliferation By preventing the expression of cyclin D1
Pancreas, breast, kidney, liver, lymphoma, prostate, colon and stomach
Clinical (phase exactly not known)
No product name as such
Breast cancer in mice
Non-clinical
Cells from renal carcinoma
Non-clinical
Cells from cervical cancer
Non-clinical
Lung cancer in ferrets
Non-clinical
used for vaginal drug delivery system. The polymeric nanoparticle should meet certain requirements like stable at vaginal pH, mucoadhesive, easily permeate into the mucous, etc. The polymeric nanoparticle for vaginal drug delivery is divided into 4 generations. The first generation nanoparticle is the one which gets captured in the liver by RES (reticuloendothelial system); the second generation comprises of stealth nanoparticles which are coated by polymers which are water-soluble e.g. PEG. This
[18]
increases the systemic circulation of the nanoparticle and passive targeting; the third generation nanoparticle comprises of ligandbased targeting and the-ligand specifically targets the particular receptor. Finally, the fourth generation nanoparticle comprises of multifunctional nanoparticles. This nanoparticle comprises the diagnostic agents, the therapeutic agent and a therapeutic efficacy reporter in the same system. The polymeric nanoparticle obtained from natural or synthetic sources for vaginal treatment
18
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Fig. 10. Different cancers and diseases treated by polymeric nanoparticles.
is as mentioned in the table. Natural polymers like alginate and chitosan are widely used for the preparation of nanoparticle for vaginal drug delivery formulation. Chitosan polymer when used in vaginal drug delivery system act as mucoadhesive and subsequently increase the retention time enhancing the activity of the drug. Synthetic polymer include poly(DL-lactic acid), polycaprolactone, poly(lactic-co-glycolic acid), polyacrylates, PLGA etc. [82, 83]. Table 5 gives a detailed account of the different natural and synthetic nanoparticles used in vaginal drug delivery. 1.8.2. Cancer treatment Cancer is one of the gravest diseases nowadays. Cancer is in its alarming stage and has become one of the deadliest diseases worldwide. Chemotherapy and surgical techniques were the only methods of treatment of cancer in earlier times. The concept of encapsulation of the drug came into existence for effective targeting as well as treatment of cancer cells. The biggest disadvantage of the conventional method is that chemotherapy and other modes of radiation cannot distinguish between the self and non-self cells. This inability of discrimination of self and non-self cells causes a huge and extensive amount of side-effects, thereby causing harm to even healthy cells. The concept of encapsulation of drug came into existence for systematic, specific and targeted delivery of drug with reduced side-effects. The nature of the polymer also determines a lot of things related to the formulation. Like PEG-PLGA is preferred other amphiphilic block copolymers because PEG-PLGA has superior biocompatibility, non-crystalline nature and glass transition temperature which is above the room temperature. PEG-PLA has also been in trend for its superiority in many physical and chemical properties [67,68,76–78] (see Fig. 10 and Table 6). 1.9. Future prospects and challenges Almost all nanoparticles have increased extravasation into the tumor interstitium. Moreover, the polymeric nanoparticles have a very efficient ability to modify it with various ligands and targeting agents that can target to required site. The polymers have high potential to act as a drug delivery system. Nowadays, modern technology aims to modify polymeric nanocarriers in such a way that it can serve the dual function of bio-imaging as
well as therapeutic diagnostics. A day may come when polymers might be modified in such a way that polymers will be able to assess the genotypic phenotype of the patient as hence, the treatment can be provided accordingly. The biggest challenge of the polymeric nanoparticles is that they sometimes have toxic degradation when the residual material associated with them is toxic. Sometimes extensive accumulation of the polymers can also lead to huge toxicity. Polymeric nanostructures are extensively used in four broad areas covering the most important aspects of biomedical and pharmaceutical fields. It can serve the purpose of analytical and imaging tool can be used in theranostics and targeted drug delivery system. It also plays a vital role in tissue engineering. Therefore, it can be stated that polymeric nanocarriers have a highly promising future in field of medicine and biomedical application. A day might come when the polymeric nanoparticles should be functionalized in such a way that they can use in stem cell technology. Presently, these polymers already do have extension application in gene therapy and in those drug delivery systems which deliver nucleic acid as a treatment regime. Preparation of the polymeric drug delivery system can be challenging at times since there can be some biocompatibility and biodegradability issues but because of its extensive application, polymers are thought to bring about revolution in the science, medicine, and biomedical applications. 1.10. Safety issues of polymeric nanoparticles Wide varieties of the polymer can be used in the preparation of polymeric nanoparticle which includes a biodegradable and non-biodegradable polymer. Biodegradable polymers are comparatively safer than non-biodegradable polymer. The polymer used should be preferably biocompatible and biodegradable. Accumulation of the polymer inside the body can pose a safety concern. At present only a few polymers are approved and are guaranteed to be safe by the FDA. The most commonly used polymer in CNS is PACA and till now its safety poses a big question and this polymer is not approved by the FDA till date. On the other hand polymers like PLGA, PLA, etc. are proved to be safe for human use. They are biocompatible and biodegradable and are also approved by US-FDA.
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Generally, natural polymers are preferred over synthetic polymers since they are of natural origin and are biocompatible and biodegradable. Due to shortcomings like lack of uniformity in the source, difficulty in manufacturing, season based procurement of polymer, easy contamination by the microorganism, etc., synthetic polymer came into the picture. The polymers’ property should be studied thoroughly before using in the nanoparticle preparation. One should ensure its safety, non-toxicity before manufacturing of a particular nanoparticle. There is also a high risk involved during the manufacturing of polymeric nanoparticles. The major risk involved during the manufacturing of dry powdered polymeric nanoparticles. Handling of such powders is difficult and poses a high exposure to the workers through inhalation into the pulmonary system, absorption through the dermal system and through ingestion through the GI system. These occupational hazards can be overcome by following good personal hygiene as well as basic safety rules and wearing personal protective equipment. Apart from the above-mentioned risk, polymeric nanoparticle also poses certain environmental hazards. Certain nanoparticles can be toxic to living species and environment. For example, a polymeric nanoparticle can be highly hazardous to the microorganism and may also contaminate the groundwater owing to big-time threat to the ecosystem. The nanoparticle can also enter the food chain and affect the environment adversely. For example deposition of polymeric nanoparticle in crops, fishes or other living species may affect the food chain and environment adversely. To avoid such environmental hazards certain guidelines should be laid down to avoid contamination of the environment. The waste material from the production plant of polymeric nanoparticles should also be properly disposed [80–82]. 2. Conclusion and future aspect The functionalized polymeric nanoparticle is a smart drug delivery system. Wide varieties of the polymer have been studied for its safety and effective drug delivery to a specific site. The functionalized polymeric nanoparticle has a wide variety of application ranging from drug delivery in the vagina, brain, cancer treatment, gene therapy and many more. In last few decades, several advancements have taken place in the field of functionalized nanoparticle which includes the release of the drug based on external stimuli, target-specific drug release, magnetic nanocarriers, ligand-based polymeric nanoparticles, nanogels and many more. Many functionalized polymeric nanoparticles have entered the market whereas many are in different phases of clinical trials. These nanoparticles effectively load the drug and target the specific site and thereby decrease side effects. The future of nanomedicine especially the functionalized polymeric nanoparticles will improve and further advancement would help in treating deadly diseases like cancer with lesser side effects. The continuous ongoing research on functionalized nanoparticle would improve the diagnosis, treatment, and prevention against diseases techniques. Research should be reconsidered to develop a simple, efficient, straightforward manufacturing technique and easy scaling up technique. Certain regulatory guidelines should be laid down to improve the safety of the nanoparticle towards human and the ecosystem. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Contents lists available at ScienceDirect
Nano-Structures & Nano-Objects journal homepage: www.elsevier.com/locate/nanoso
Recent developments in functionalized polymer nanoparticles for efficient drug delivery system ∗
Srija Sur a , Aishwarya Rathore a , Vivek Dave a , , Kakarla Raghava Reddy b , ∗ Raghuraj Singh Chouhan c , Veera Sadhu d , a
Department of Pharmacy, Banasthali Vidyapith, Banasthali, Rajasthan 304022, India School of Chemical and Biomolecular Engineering, The University of Sydney, Sydney, NSW 2006, Australia c Department of Environmental Sciences, Jožef Stefan Institute, Ljubljana, Slovenia d School of Engineering, University of Coimbra, 3030-290 Coimbra, Portugal b
article
info
Article history: Received 15 May 2019 Received in revised form 24 August 2019 Accepted 25 September 2019 Keywords: Polymeric nanoparticles Functionalization Dendrimers Polymeric micelles Functionalized polymers Drug delivery Biomedical applications
a b s t r a c t To overcome the shortcomings of conventional dosage forms, targeted and modified drug delivery system came into existence. This was the time when a novel drug delivery system was in high demand. Nanoparticles are such type of targeted drug delivery system. Nanoparticles are colloidal particles which provide site-specific delivery of drugs. There are different kinds of nanoparticles, polymeric nanoparticles are one of a kind. Polymeric nanoparticles, nowadays, is one of the most researched topics. Their major advantages include good control over size, longer clearance time, improved therapeutic efficacy and reduced toxicity. Polymer-based nanoparticles come in various forms like dendrimers, ligand-based nanoparticles, polymeric micelles, PEGylated nanoparticles, etc. This chapter includes the various advancements in polymeric nanoparticles as well as advancements in the polymers that are used in their preparation. It reveals details about functionalized nanoparticles and its types. It finally discusses the use of various polymers in the drug delivery system in order to target varied diseases, taking cancer and vaginal diseases as an example. The chapter at the end also reveals the future aspect of functionalized polymeric nanoparticles. © 2019 Elsevier B.V. All rights reserved.
Contents 1.
Introduction......................................................................................................................................................................................................................... 1.1. Background of nanotechnology and nanomedicine........................................................................................................................................... 1.2. Merits and demerits of polymeric nanoparticles............................................................................................................................................... 1.3. Polymers used and their advancements ............................................................................................................................................................. 1.3.1. PAMAM and PEGylated PAMAM .......................................................................................................................................................... 1.3.2. HPMA and HEMA ................................................................................................................................................................................... 1.3.3. Albumin ................................................................................................................................................................................................... 1.3.4. PEG transferrin ....................................................................................................................................................................................... 1.3.5. PLA ........................................................................................................................................................................................................... 1.3.6. Chitosan................................................................................................................................................................................................... 1.3.7. Alginate.................................................................................................................................................................................................... 1.3.8. Gelatin ..................................................................................................................................................................................................... 1.3.9. PLGA......................................................................................................................................................................................................... 1.3.10. PEG ........................................................................................................................................................................................................... 1.3.11. Ovomucin ................................................................................................................................................................................................ 1.3.12. PEG-PLGA ................................................................................................................................................................................................ 1.4. Synthesis methodologies of nanoparticles.......................................................................................................................................................... 1.5. Advanced methodologies of synthesis of polymeric nanoparticles ................................................................................................................. 1.5.1. Ring-opening polymerization................................................................................................................................................................ 1.5.2. Electrohydrodynamic atomization .......................................................................................................................................................
∗ Corresponding authors. E-mail addresses: [email protected] (V. Dave), [email protected] (V. Sadhu). https://doi.org/10.1016/j.nanoso.2019.100397 2352-507X/© 2019 Elsevier B.V. All rights reserved.
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1.5.3. Formation of nanoparticles by desolvation of macromolecules ....................................................................................................... 1.5.4. Self-polymerization ................................................................................................................................................................................ 1.5.5. Mussel-inspired chemistry for polymerization................................................................................................................................... 1.6. Novel polymeric nanoparticulate systems .......................................................................................................................................................... 1.6.1. Lipid polymer hybrid nanoparticles..................................................................................................................................................... 1.6.2. Solid-lipid polymer hybrid nanoparticle ............................................................................................................................................. 1.6.3. Functionalized polymeric nanoparticles .............................................................................................................................................. 1.6.4. Polysaccharide conjugated polymeric nanoparticles.......................................................................................................................... 1.6.5. Ligand-based polymeric nanoparticles ................................................................................................................................................ 1.6.6. Fluorescence polymeric nanoparticles ................................................................................................................................................. 1.7. Characterization of nanoparticles ........................................................................................................................................................................ 1.7.1. Size and morphology ............................................................................................................................................................................. 1.7.2. Percent drug loading and entrapment efficiency ............................................................................................................................... 1.7.3. Zeta potential measurement ................................................................................................................................................................. 1.7.4. Solubility determination........................................................................................................................................................................ 1.7.5. Thermal property determination.......................................................................................................................................................... 1.7.6. Raman spectroscopy .............................................................................................................................................................................. 1.7.7. In vitro drug release studies ................................................................................................................................................................. 1.7.8. Recent advancements in functionalized polymeric nanoparticles ................................................................................................... 1.8. Application of polymeric nanoparticles .............................................................................................................................................................. 1.8.1. Treatment of vaginal diseases .............................................................................................................................................................. 1.8.2. Cancer treatment.................................................................................................................................................................................... 1.9. Future prospects and challenges.......................................................................................................................................................................... 1.10. Safety issues of polymeric nanoparticles ............................................................................................................................................................ Conclusion and future aspect............................................................................................................................................................................................ Declaration of competing interest.................................................................................................................................................................................... References ...........................................................................................................................................................................................................................
1. Introduction With the alarming emergence of disease and disorders, proper targeted dosage form has gained prime importance to treat the disease and improve patient’s health. Conventional dosage form has many shortcomings like repetitive administration of the drug with a shorter half-life, decreased patient compliance, high peak, and typical peak–valley plasma concentration–time profile, etc. and due to this obtains in a steady-state drug concentration and specificity of targeting cannot be achieved. Due to these shortcomings, there was an emergence of the modified and targeted dosage form. The conventional dosage form is slowly getting substituted with their modified and targeted release dosage form. Modified and targeted drug delivery of the drugs is in high demand because of their programmed drug release, site-specificity, and increased patient compliance. For developing a modified or targeted drug delivery system, polymers are considered as the structural backbone. A biocompatible polymer because of its added advantage has seen immense growth and therefore is the heating topic of discussion. Nanoparticles are colloidal particles which provide targeted drug delivery and are in the size range of 1 to 100 nm [1]. ‘Nano’ word is derived from ‘nanos’ which is a Greek word which means extremely dwarf. Different types of nanoparticles based on the morphology and physical/ chemical property are carbon-based nanoparticles, polymeric nanoparticles metal nanoparticles, ceramic nanoparticles, semiconductor nanoparticles, lipid-based nanoparticles, etc. Out of these, polymeric nanoparticles is a widely researched topic because of its advantages over other and moreover due to advancement in polymer science and nanotechnology, as there has been immense development in polymeric nanoparticles. Some advantages of polymeric nanoparticles are its easy preparation technique, the size distribution is easy to control, good retention and protection of the drug, etc. Polymeric nanoparticles can be defined as solid colloidal particle ranging from the size range 1–100 nm and they are preferably made up of polymers obtained from natural, synthetic or semisynthetic source which may be either biodegradable or nonbiodegradable [2]. Initially, non-biodegradable polymer nanoparticles were used. The first polymeric nanoparticle was made up
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of non-biodegradable polymer e.g. polyacrylamide, polystyrene, polymethylmethacrylate, etc. But due to chronic use of these nanoparticles, many shortcomings like chronic toxicity and high immunological response against the non-biodegradable polymeric nanoparticles was observed [3]. Due to this reason, biodegradable polymeric nanoparticles gained importance. Polymeric nanoparticles can carry drug, protein or DNA material for targeting a specific organ or cell [4]. Depending on the different method of preparation, the drug or another therapeutically active compound can dissolve, attach, encapsulate or entrap to the matrix of the nanoparticles. Polymeric nanoparticles are generally nanocapsules or nonspherical in shape. Nanocapsule polymeric nanoparticles are the one in which the therapeutic component is encapsulated within a polymeric capsule shell whereas nanospheres polymeric nanoparticles are the one in which drug or other solid particles are embedded into a polymeric matrix. The pictorial representation of nanospheres and nanocapsules are as shown in Fig. 1. Increased use of polymeric nanoparticles is because of its use as a smart polymer and its target specificity and reduced side effects. Until a few years, it was difficult to treat certain disease like cancer, which required target specific action, but due to the emergence of polymeric nanoparticles, cancer treatment is no more a nightmare [5]. Polymeric nanoparticles not only deliver the drug to a particular site but also deliver the drug at a particular rate which is advantageous in treating many diseases. This review is important because a wide and a vivid knowledge about the polymers and their use in polymeric nanoparticles are immensely necessary to know about the polymeric nano-revolution in the field of medicines and nanotechnology. It has the potential to boast and modify the solutions of recent diagnostic, therapeutic and biological problems to more reliable and convincing options. This review is highly important for the polymer therapeutics include everything like proteins which have polymer conjugates, micelles of block copolymer, polymeric drugs, etc. The polymers play a very important role in the drug delivery system for the treatment of various diseases like cancer , neurodegenerative diseases, cardiovascular disorders, etc. Therefore, proper knowledge of the polymers is of utmost importance [6]. The aim and specificity of the review article lies in giving a vivid description of the
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Fig. 1. Pictorial representation of (a) nanocapsules, and (b) nanospheres.
polymers used in modern form of drug delivery system. Mainly, it focuses on the nanoparticles prepared by the use of various polymers. It also deals with the vivid description and characteristics of the polymers that can be used for nanotechnology. It has also summarized various polymeric drug delivery systems and their mode of preparation. Specifically, it gives detailed end to end information about the polymeric nanocarriers and their significance in pharmaceutical and biomedical field. There are numerous techniques for preparing nanoparticles and it basically relies on physical and chemical properties of the polymer as well as the active component. To list a few basic formulation technique — use of organic solvent, application of temperature, mechanical shaking, ultrasonication, etc. The particular technique should be used which do not degrade or affect the property of the active constituent and polymer in any way. Some example of the advancement in nanoparticles is as shown in Fig. 2. 1.1. Background of nanotechnology and nanomedicine Use of nano-sciences in the field of medicine is relatively a new concept. Nanoscience is comparatively a young science and in its infancy. Use of Nanoscience in medicines has been in research since 1990, after the invention of high tech instruments. Before the inventions of these high tech instruments, in 1900, two scientists named Albert Einstein and Max Planck proposed theoretical evidence about the presence of very tiny particles which obeyed their own laws. They, therefore, encouraged other scientists to develop certain instruments which would assist in viewing nano-sized particles. Soon after in the year 1902 structure as small as 4 nm was detected in a ruby glass with the help of ultra-microscope. Ultra-microscope was invented by two scientists named Henry Siedentopf and Richard Zsigmondy. Later in the year 1931 and thereafter many new technologies for viewing nanotechnology were invented like TEM which was developed by two scientists named Ernst Ruska and Max Knoll. Soon after TEM other instruments like an electron microscope, FIM, STM, AFM, etc. were developed which helped in viewing and working with
nano-sized particles. Norio Taniguchi in the year 1974 coined the term Nanotechnology. It was in the year 1960 when the first lipid-based nanotechnology drug delivery system was invented which was later termed a liposome. Since then many research went into finding appropriate nano-sized particles for drug delivery system. In the year 1976, the controlled drug delivery system was introduced and the emergence of this new concept shifted the attention of all the researchers towards it. The scientists even termed it as ‘magic bullet’. In late 1960 first nanoparticle was developed by Peter Paul Speiser for targeted drug delivery. Polymer nanoparticles came into the scenario in the year 1994. Many researchers started using different polymers for the preparation of nanoparticles and started witnessing the pros and cons of the same. Due to the immense advantage and safety of biodegradable polymer, biodegradable polymer nanoparticles became the topic of interest. Biodegradable have an advantage over non-biodegradable polymer nanoparticles that it is non-immunogenic, non-allergent, less toxicity, no need to remove it from the body as the polymer degrades inside the body, etc. [7,8]. The brief history of nano-medicines is as shown in Fig. 3. 1.2. Merits and demerits of polymeric nanoparticles Polymeric nanoparticle came into existence to overcome the tedious preparation technique of nanoparticles. They are a highly researched topic among the scientists because of its perks over regular nanoparticles. Polymeric nanoparticles have a larger surface area which allows for displaying a large number of surface functional groups like ligands. Their smaller size helps them to enter into smaller capillaries and thereby easily target the cell. Another advantage of this nanoparticle is its good control over size and size distribution [8]. Compared to the conventional nanoparticle, they have a longer clearance time, which means a small amount of drug is sufficient to show better therapeutic efficacy and lesser toxicity. Apart from this, they can be easily tailored and controlled. The drug loading capacity is also high and easy (without any chemical reaction). The polymeric nanoparticle
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Fig. 2. (a) Polymeric micelles side view and front view, (b) Ligand-based nanoparticles, and (c) Dendrimers, and (d) Polymeric micelles.
can be administered through various routes like oral, intra-ocular, parenteral, nasal, etc. [9–12]. Apart from having so many advantages, polymeric nanoparticles also face certain disadvantages which include toxicity due to the use of PVA as a detergent in the preparation, termination of therapy also becomes difficult in case of emergency and scaling up of these nanoparticles is difficult, expensive and require sophisticated instruments. 1.3. Polymers used and their advancements Polymers are made up of monomers or monomeric units which have large molecular masses. Polymers are a compressed form of large repeating units which are known as monomers. At present times, drug delivery assisted via nanoparticles has become a platform to enhance as well as modify various properties of drug-like a modification of solubility, Improvement of its half-life and its release characteristics thereby, enhancing the pharmacodynamic as well as pharmacokinetic parameters of the biopharmaceutical formulations. Polymeric nanoparticles hold a maximum share in it. Polymers play an important role in this regard. To prepare polymeric nanoparticles, good knowledge of polymers is very important. The stability and compatibility issue of the drug and excipients with the polymer has been a major matter of concern during the preparation of formulation. Polymers work as inert carriers in which the drugs are conjugated so that the polymer can work as a vehicle to carry the drug molecule to the targeted site. Polymers can be both synthetic as well as natural in nature. Naturally occurring polymers can be cellulose, proteins, latex, and starches whereas, on the other hand, synthetic polymers are manufactured in large scale. 1.3.1. PAMAM and PEGylated PAMAM PAMAM, also known as Poly(amidoamine) are mainly dendritic polymers which are known for its biocompatibility, water
solubility, and non-immunogenic nature. PAMAM is made up of amide and amide functionality which can encapsulate any foreign molecule mainly drug molecule because of its unique architecture. These properties of PAMAM dendrimers enable them to show their huge application in the field of biomedical and pharmaceutical sciences. But the biggest disadvantage of this type of dendrimer is its toxicity. PAMAM at its nano-size range of 1– 100 nm interacts with cellular components like mitochondria, nucleus, and endosomes. The peripheral amino groups of PAMAM dendrimer brings about toxicity depending on its concentration. Thus, modifying PAMAM becomes very important to remove their toxicity. This was the time when PEGylated PAMAM came into existence. PEGylated PAMAM was the modified version of normal PAMAM dendrimer where surface modification is done to diminish cytotoxicity and hepatic toxicity. Neutralizing or replacing the cationic groups with anionic ones is one of the important steps. PEGylation of PAMAM dendrimers improves its pharmacokinetics and biodistribution. The pharmacokinetics and bio-distribution of PEGylated PAMAM can be enhanced by decreasing their uptake by spleen, macrophage, and liver which in turn improves their systemic circulation. PEGylated PAMAM has been one of the most effective modes of drug delivery for the treatment of cancer [13]. PEGylated PAMAM has been one of the best nano-carriers for delivering anti-cancer drugs. 1.3.2. HPMA and HEMA Poly(ethylene glycol) methyl ether methacrylates (PEGMEMA) are amphiphilic molecules which are known for their biocompatibility. These molecules do not trigger the immune system thus, assuring sufficient circulation time of the nanoparticles for aiming their target site. HEMA i.e. hydroxyethyl methacrylate is one of such kind. The degradation rate of HEMA is a function of its molecular weight. These nanoparticles are prepared by an advanced method of either emulsion free radical polymerization
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Fig. 3. Historic growth of nano-medicines.
or ring-opening polymerization. Similarly, on the other hand, N-(2-hydroxypropyl) methacrylate (HPMA) is such a monomer which has nowadays been known for its non-immunogenicity and biocompatibility. HPMA is a high water-miscible monomer. PEGYlated surfmers that consists of HPMA double bond is also known as HPMA-PEG. HPMA-PEG can also behave like a surfactant as per the studies. HPMA-PEG has been prepared by N,
N′ -dicyclohexylcarbodiimide-mediated esterification of succinylated PEG with HPMA. Likewise, HPMA-LA8 is prepared by the ring-opening polymerization of HPMA and L -Lactide [14]. 1.3.3. Albumin Proteins are natural molecules that show unique properties which enable these protein molecules to be used in the numerous nanomaterials. Albumin, gelatins are some of the proteins which
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show some promising characteristics like a high degree of stability, biodegradability, non-antigenicity, etc. Protein nanoparticles have huge advantages which open up a plethora of spectrum in front of them for which they can be used for the preparation of nanoparticles. Albumin can have enhanced drug carrier activities which can encompass a large spectrum of drugs. These nanoparticles are usually stimuli-sensitive and highly bioactive substances [15]. Albumin-polymer conjugates are highly versatile that can deliver a wide variety of drugs like metal-based drugs, hydrophobic drugs, etc. 1.3.4. PEG transferrin Transferrin is iron-binding blood plasma glycoprotein that regulates and maintains the amount and level of free iron in the biological fluid. The conjugation of transferrin with PEGylated recombinant human tumor necrosis factor alpha was established to maintain the properties of PEGylation as well as also enables the formulation to target tumor cells. This conjugate is mainly preferred as it has the specificity to target tumor cells. Dexamethasone many times is delivered by this mode when Dexamethasone is transferred with solid-lipid nanoparticles where the lipid is in conjugation with transferrin. The conjugation of Tf with Dexamethasone is an excellent active targeting ligand for cell targeting [16]. 1.3.5. PLA Polylactic acid also is known as PLA, and it is biodegradable as well as biocompatible in nature. It is non-toxic in nature. The hydrophobic nature of this polymer makes it suitable for lipid polymer-based hybrid nanoparticles. PLA exhibits a large amount of mechanical strength which when used in optimized condition can produce a controlled release drug delivery system [17]. 1.3.6. Chitosan Chitosan is a deacetylated chitin derivative and is a natural polymer. Chitosan is a modified natural carbohydrate-based derivative obtained from insects, fungi, animals or other marine invertebrates. Chitosan has a large role in the biomedical field. Chitosan has been used as a polymer in many diverse fields like agriculture, biomedical, etc. It is one among the highly abundant natural polymer and can be easily processed into varied forms like threads, matrix, beads, nanoparticles, etc. Mostly chitosan is used as chitosan sponges, chitosan beads, chitosan film, chitosan nanoparticles and chitosan microbeads (microspheres) in a targeted drug delivery system. Since chitosan is a natural polymer, it is biocompatible and biodegradable as well. This property makes Chitosan a highly desired polymer. Chitosan is freely soluble in acidic solution and releases a free amino group and develop positive charge over the polymeric chain. Chitosan is had poor solubility at pH above 6.5. Generally, the chitosan nanoparticle can be formed by incorporating a polyanion like TPP (tripolyphosphate) into chitosan with constant stirring [18]. Generally, Chitosan nanoparticles can be used for drug delivery, anticancer activity, gene therapy, etc. 1.3.7. Alginate Alginate is a natural based polymer and is biodegradable and biocompatible in nature. Alginate-based nanoparticles are a highly emerging area of interest. Alginate is basically a copolymer of (1, 4) linked β -D mannuronate and α -l-glucoronate. It is watersoluble in nature and a linear polysaccharide. Mostly alginates can be used in the form of hydrogels, porous scaffolds, microparticle, and nanoparticle. Generally, alginate nanoparticle is developed by methods like ionic gelation, emulsion, covalent cross-linking, complexation method, and self-assembly method. Out of all the method of preparation, ionic gelation and complexation is a
widely used method to prepare alginate nanoparticles [19]. Alginate nanoparticles can be used for the delivery of certain drugs like an anti-tumor drug, an anticancer drug, proteins, insulin, etc. The alginate nanoparticles are controllable and are pH-sensitive. 1.3.8. Gelatin Gelatin is obtained from structural and chemical degradation of collagen. Gelatine comprises of both acidic as well as basic functional groups. Gelatin forms a triple-stranded helical structure in solution at low temperature. It is a water-soluble polymer. There are mainly two types of gelatin: Gelatin A and Gelatin B. Type A gelatin has an isoelectric point of 9.0 and is obtained from acid hydrolysis of collagen I whereas type B gelatin has an isoelectric point of 5 ad is obtained from alkaline hydrolysis of collagen I. The nanoparticle prepared using gelatin polymer is biocompatible as well as biodegradable and therefore have no adverse reactions when these nanoparticles are introduced inside the human body. Drug release from gelatin nanoparticle can be through different methods like leaching, rupture, erosion or degradation of the polymer. This would, in turn, result in the slow release of the drug [20]. 1.3.9. PLGA PLGA is the abbreviation of poly(lactic-co-glycolic acid). The advantage of using this polymer is that it is biodegradable and biocompatible. It is a synthetic polymer synthesized by ringopening co-polymerization of cyclic dimers (1, 4-dioxane-2,5diones) of glycolic acid and lactic acid. PLGA readily undergoes hydrolysis inside the body. Many studies have been done on PLGA including the toxicological studies. Toxicological studies of PLGA indicated that PLGA causes a local tissue reaction. PLGA can be dissolved in a wide variety of solvents including, tetrahydrofuran, chlorinated solvents ethyl acetate or acetone. The glass transition temperature of PLGA is above 37 ◦ C, therefore, it has glassy behavior and a fairly rigid structure. The major challenge with PLGA is the ability to reassemble into polymeric devices like nanoparticle, microcapsule, and microspheres optimal for delivery system fabrication [21]. 1.3.10. PEG PEG stands for Poly(ethylene glycol) and it is a non-ionic hydrophilic polyester which is prepared by polymerization of ethylene glycol monomer and its molecular weight ranges from 300–100,000 Da. The drawback of using PEG is that it is not biodegradable in nature and is excreted unchanged in the kidney but luckily the polymer does not accumulate in the tissues, thanks to its hydrophilic nature. Moreover because of its hydrophilic nature PEG can be used to stabilize the nanoparticle especially in aqueous media, avoid aggregation due to steric hindrance in production, storage, as well as the application also PEG, increases solubility. Another advantage of PEG is that it does not involve ionic moiety and therefore no problem occurs when PEG is in contact with any charged molecule like DNA. Moreover, PEG suppresses opsonization and therefore is not readily detected by the immune system as a foreign substance and undergoes slower uptake by RES in spleen and liver [22,23]. 1.3.11. Ovomucin Ovomucin is a highly glycosylated protein with a molecular weight between 5500–8300 kDa depending on the isolation method followed and environmental condition. Ovomucin is mainly composed of two basic subunits namely α -ovomucin and β -ovomucin. It is a naturally obtained polymer obtained from the egg white. Ovomucin is a macromolecular protein which is viscous in nature. The drawback of using ovomucin as a polymer in the nanoparticle is that it may be an allergen to some patients and hence it is a less preferred polymer [24]. Ovomucin also has a biological function like antiviral nature, macrophage activation, etc.
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Fig. 4. Conventional methods of preparation of polymeric nanoparticles.
1.3.12. PEG-PLGA PEG-PLGA is an example of the block copolymer. It is a synthetic polymeric block synthesized by COOH-PEG-NH2 and PLGACOOH conjugation. This polymer is biodegradable in nature and it readily self arrange itself into nanometric micelle and entrap drug within itself and release it in a time-dependent manner. PEG PLGA is an emerging polymer system because it can be easily synthesized and is better than single PLGA. PEG-PLGA is an amphiphilic substance and therefore it orients in such a way that hydrophobic PLGA remains inside and hydrophilic PEG is outside the micelle and act as a stabilizing shell. The drug can be easily entrapped in this polymeric block. Another advantage of PEGylated PLGA nanoparticle is that even hydrophilic drug can be entrapped [25]. 1.4. Synthesis methodologies of nanoparticles The preparation of Nanoparticles needs optimization of the various preparation parameters depending on the various applications for which the polymeric nanoparticles are to be used. The selection of the drug and the polymer is very important, in a similar way, the method of preparation also plays a vital role in acquiring the properties of interest. A wide range of polymers is used for the preparation of polymeric nanoparticles. The combination of the different polymeric systems with the nanostructures has helped to develop a sustained release drug delivery system. There are various ways of preparation of Polymeric Nanoparticles. The conventional method of polymeric nanoparticles is as shown in Figs. 4 and 5. Nanoprecipitation is one such method of preparation of polymeric nanoparticles which can be on the other hand known as interfacial deposition or solvent displacement method. This technique was first introduced by Fessi. This is mainly an encapsulation technique which involves precipitation of polymers followed by their solidification. The solidification of polymers occurs due to the interfacial disposition of the polymers. The interfacial disposition of polymers takes place by displacement of a semi-polar solvent miscible with water, which was initially present in a lipophilic solution.
In this preparation process, first, a suitable organic solvent is selected. The organic solvent should be water-miscible by nature. The desired drug and the polymer should be dissolved in the organic solvent. Then, finally, the aqueous phase which contains a stabilizer is added with continuously stirring. Due to a decrease in the interfacial tension between the aqueous phase and the organic phase, the diffusion of organic solvent into the aqueous phase takes place very rapidly. This rapid diffusion and the flow of solvent forms and characterizes well-defined droplets of nanoparticles. Then finally the nanosuspension is obtained after freeze-drying the suspension with the help of 5% mannitol as cryoprotectant [26,27]. For example, from ancient times, the polymersome system has been prepared largely. The copolymer nanoparticles system had been a common nanoparticles system mainly with two polymers namely 2-methacryloyloxyethyl phosphorylcholine (MPC) and 2-(diisopropylamine)ethyl methacrylate (DPA). But the recent advancement in the preparation of nanoparticle system by nanosuspension method is the micellar system of nanoparticles. The micellar system of nanoparticles has been recently explored and has been prepared by the nanosuspension method. This unexplored fact about the micellar formation by nanoprecipitation method has helped to investigate how this method influences the effect of solvent and the choice of buffer upon the micellar size. MPC100 -DPA100 copolymer has been used in the preparation of solutions with the help of methanol and ethanol. Solvent evaporation is one the most common technique of preparation of polymeric nanoparticles. Mainly, in this technique of preparation of polymeric nanoparticles, such as an organic solvent is selected into which drug will get dissolved and dispersed. Then, in this solution of an organic solvent which contains the dispersed drug, the polymer is also dissolved. Then, the resultant organic phase which contains the drug and the polymer is then added to the aqueous phase. The aqueous phase contains surfactant like poloxamer 188, Polysorbate 80, PVA, etc. The organic phase and the aqueous phase are mixed by highspeed homogenization, which results in the formation of a stable emulsion. After the emulsion is formed, the emulsion is converted
8
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Fig. 5. Overview of conventional methods of preparation of polymeric nanoparticles.
to nanoparticle suspension. Under highly increased temperature and reduced pressure, the evaporation of the solvent takes place. In general practice, mainly single emulsions or double emulsions are prepared by ultra-sonication or high-speed homogenization. Finally, ultracentrifugation is carried out to get the solidified nanoparticles [28]. Salting out is nothing but the modification of solvent diffusion or emulsification. It is the modified version of the emulsion process. In this process, drug and polymer are dissolved in an organic solvent which is miscible in water. Then, the resulting solution formed is mixed with the aqueous counterpart of the solution which already had the salting-out agent in it. Thus, the organic phase which already contained the surfactant is mixed with the aqueous solution which contained the salting-out agent and the stabilizer, by continuous stirring. The salting-out agents, like magnesium and calcium chloride mainly prevents the miscibility of the aqueous phase with the organic phase resulting in the formation of an emulsion. When the emulsion is diluted, a reverse salting-out effect is observed which results in the precipitation of the polymer. The precipitated polymer matrix contains the encapsulated drug leading to the formation of nanoparticles [29]. Supercritical fluid technology avoids the use of organic solvents for the preparation of polymeric nanoparticles. Drug and polymer are dissolved in an environmentally friendly solvent which potential enough in producing polymeric nanoparticles. The drug and polymer together are converted to a solution with the supercritical fluid. This solution expands rapidly across the capillary nozzle into the ambient air. A high degree of supersaturation accompanied by the fast expansion of the solution leads to the homogeneous nucleation and finely dispersed nanoparticles [30–32]. Dialysis is a technique similar to the nanoprecipitation technique. But the only difference is that the polymers with the
drug dissolved in the water-miscible organic solvent are placed inside a dialysis membrane. The organic phase comes into the aqueous phase by diffusing out through the dialysis tube. The diffusion reduces the interfacial tension between the two phases. Subsequently, inside the membrane, there is displacement of the solvent. This event is followed by loss solubility of the polymer which leads to the progressive aggregation of the polymer [33]. Polymerization is basically a technique where there is the polymerization of two monomers. When the two monomers are present in two different interfaces, then the technique is known as an interfacial polymerization. When a single or multiple emulsions are used for the encapsulation of drugs, then the technique is single/ double emulsion technique. Polymeric micelles are often formed by the technique of polymerization. The basic principle behind all these processes is nothing but the polymerization of the monomeric units. There could be intermolecular cross-linking established by the polymerization reaction. The disadvantage of the polymerization technique is that there could be unreacted monomers, toxic substances may be generated from the chemical reactions, unreacted toxic by-products may also originate from monomeric reactions, etc. [34,35]. The brief description with the advancement in the technique is as mentioned in Table 1. 1.5. Advanced methodologies of synthesis of polymeric nanoparticles There have been various advancements in the method of preparation of nanoparticles. Many new advanced and revolutionary techniques have come up in recent years for the preparation of polymeric nanoparticles. Drug loading in the polymer is mainly achieved by two modes: First, when the drug is absorbed in the polymeric nanoparticles after it is being formed and secondly, instilling the drug in the nanoparticles right at its time of preparation. The advanced techniques include Ringopening polymerization, Electrohydrodynamic atomization, and Desolvation of macromolecules.
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Table 1 Conventional methods of preparation of polymeric nanoparticles. Technique
Summary
Specific Agents required
Reference
Nanoprecipitation
Formation of the particle is based on precipitation and subsequent solidification of polymers due to the interfacial deposition of polymer
Non-solvent for the polymer required.
[26,27]
Solvent Evaporation
After the formation of a stable emulsion of the organic phase (containing polymer and drug) and the aqueous phase (containing surfactant) the organic solvent is evaporated out under increased temperature and reduced pressure.
Surfactant required
[28]
Salting out
The salting out agents prevents the miscibility of organic
Salting out agent required.
[29]
Supercritical fluid technology
Without the use of organic solvent, the solution is formed by dissolving the polymers and the drug in the supercritical fluid. After this, across the orifice of the capillary, the solution is rapidly expanded into ambient air which in turn, results in rapid pressure reduction accompanied by high super saturation. This forms homogeneous nucleation and uniform-sized nanoparticles.
Supercritical fluid and a capillary nozzle required
[30–32]
Dialysis
Here the organic phase diffuses out through the dialysis tube into the aqueous phase, forming a homogeneous suspension of nanoparticles.
No surfactant required, dialysis membrane or dialysis tube is required.
[33]
1.5.1. Ring-opening polymerization Ring-opening polymerization is a technique where the growth of the chain takes place. In this process, the terminal end of the polymer acts as the reactive center for the chain opening reaction of cyclic monomer. It is a process of end-chain activation, electrophilic monomer activation and can also be the process of nucleophilic monomer activation. Caprolactone is taken as an example for the ring-opening polymerization technique. 6-Marcapto −1-hexanol, DPP and toluene were already stored in an ampule. The reaction is proceeded by the mixing of eCaprolactone at a temperature of 50 ◦ C. Triethylamine in the added to the aliquot. The polymerization reaction usually comes to an end by the addition of cold methanol. The product obtained is thus filtered out and dried at vacuum [36,37]. 1.5.2. Electrohydrodynamic atomization This process was initially developed with PLGA solution and acetonitrile. In this process, there is diffusion of the fluid which leads to the formation of polymeric nanoparticles with narrow size distribution and reduced size. This method was declared to be a dynamic method where fine droplets are prepared from conical meniscus of a liquid under the influence of electrostatic stress [38,39]. The process or electro-hydrodynamic polymerization was first developed by Xie et al. 1.5.3. Formation of nanoparticles by desolvation of macromolecules Polysaccharide can be desolvated by pH or temperature change by the addition of an appropriate amount of counterion. The main technology behind the desolvation method is nothing but the addition of a desolvating agent. This method does not require high temperature, therefore, thermolabile drug substances or thermolabile molecules can be treated with this method of preparation. For example, BSA nanoparticles had been prepared by desolvation technique where acetone was used as a desolvating agent [40,41]. 1.5.4. Self-polymerization Polydopamine, being a naturally occurring pigment contains melanin in it. Therefore, it shows some highlighting properties of presence of melanin in electricity, magnetics, and optics. Moreover, it has excellent biocompatibility. In addition to its biocompatibility, functional groups such as catechol, imine as well as amine can be incorporated in the chemical structure of Polydopamine. This is the reason, polydopamine have some wide applications in the field of biology and biomedicine. The best property of Dopamine is that it is a monomer can self-polymerize itself under alkaline conditions. The self-polymerization property of dopamine is a very simple process when the dopamine
monomers polymerize instantly when added into an alkaline solution by changing the color from pale brown to deep brown. This Polydopamine has immense use in polymer coating and is known to formulate a smart functional drug delivery system [42]. Molybdenum disulfide (MoS2 ), when treated with Gold Nanocomposites modified with polydopamine, shows an amazing anti-bacterial activity when tested against S.aureus [43]. Fluorescent nanoparticles are now-a-day considered to be the most trending research interest. Fluorescent nanoparticles show remarkable optical properties when compared with organic dyes and this is the main reason they have immense applications in the field of drug delivery and bioimaging. Biological imaging can be used as an important tool of monitoring the biological processes like studying the development of infectious diseases, monitoring tumor growth and metastasis, etc. Fluorescent materials are mainly of three broad types which includes organic, inorganic and traditional fluorescent materials. Traditional fluorescent materials have several disadvantages like poor membrane permeability, highly expensive and so on. On the other hand, inorganic fluorescent materials have high toxicity. Therefore, organic fluorescent materials are preferred over these two fluorescent materials because their high biocompatibility [44]. Moreover, when Polydopamine is used to modify the fluorescence organic nanoparticles they show great properties for cell-imaging and many more [45]. Moreover, there are many researches which have developed nanocomposites. The nanocomposites are the conjugation of carbontubes and polydopamine functionalized with chitosan. Apart from its application in the medical field, it has been used for copper ion removal [46]. Similarly, SiO2-PDA-PAPTCl is another such nanocomposites which have excellent adsorption properties where PAPTI, namely poly((3-Acrylamidopropyl)trimethylammonium chloride) is a cationic polymer [47]. Self-polymerization property of dopamine with polyethyleneimine has excellent properties of biological imaging. They have enhanced property of biocompatibility and biodegradability as well [48]. Therefore, from the above examples it can be assumed that polydopamine by it self-polymerization property has huge applications in the field of thermal therapy, bio-imaging and drug delivery system as well [49]. 1.5.5. Mussel-inspired chemistry for polymerization Mussel inspired chemistry is a type of chemistry where synthetic polymers are used to mimic the excellent polymeric coating properties of naturally derived substances. Huang et al. 2018 synthesized a polyacrylamide-immobilized molybdenum disulfide composites with the help of mussel-inspired chemistry. Polyacrylamide was immobilized onto nanosheets of MoS2 . Molybdenum disulfide nanosheets were first modified by polydopamine.
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Polydopamine was obtained from dopamine by the oxidative polymerization in the alkaline solution. After MoS2 nanosheets are modified with polydopamine, polyacrylamide was incorporated by surface-initiated polymerization method. This prepared solution is mainly used for adsorption of heavy metals like copper [50]. This type of chemistry is one of the most promising chemical technologies which are used as a surface modification tool. MoS2 nanosheets are surface modified by copolymerization technique. Mussel inspired chemistry are declared to be one of the most convincing chemistry for the surface modification of the nano-technologically derived drug delivery system [51]. In inclusion with the above applications, mussel-inspired chemistry has lot of implications in the field of environmental science as well. This includes oil-in-water separation, catalysis, and adsorption for purification in nature [52]. 1.6. Novel polymeric nanoparticulate systems 1.6.1. Lipid polymer hybrid nanoparticles Nanoparticles made from solid lipids are gaining a lot of importance nowadays. Solid lipid nanoparticles are one of the advanced modes to drug delivery where the particles are in submicron range these particles act as colloidal carriers which are made up of lipids dispersed in an aqueous surfactant solution. These solid lipid nanoparticles generally come in the form of lipid-polymer hybrid nanoparticles. The main advantage of this type of drug delivery system is that they bear the advantage of both the solid phase and the liquid phase. The lipid-polymer hybrid nanoparticulate system shows various advantages like good tolerability, protection of incorporated drugs as well as controlled release of the drug from the dosage form. The existence of polymer and lipid together gives them a unique characteristic where the hydrophilic and lipophilic characters coexist in the same platform. The coexistence of these two characters leads to a large variety of dosage form which can encapsulate a large variety of drugs. The lipid-polymer hybrid nanoparticles are basically composed of three layers which when arranged from inside to outside includes (1) hydrophobic core where a large amount of hydrophobic drug can be incorporated, (2) interfacial layer of lipid is present which behave like a biocompatible and flexible shell and finally the outermost layer i.e. (3) the hydrophilic layer which is basically an outermost polymer stealth that can improve the stability of the nanoparticles as well as the circulation time of the delivery system. But on the other hand, a lipid-polymer hybrid nanoparticle, under gastric conditions, has poor colloidal stability and thus, they have decreased bioavailability by oral delivery systems. Another biggest disadvantage of lipid-polymer hybrid nanoparticles is that drying them is very difficult and reverse aggregation can also take place in them before drying them. To overcome all these disadvantages and to cope up with the growing demand to have a stable nanoparticle that can be delivered by oral route solid-lipid polymer hybrid nanoparticles came into existence [53,54]. 1.6.2. Solid-lipid polymer hybrid nanoparticle Solid lipid polymeric nanoparticle is nothing but an advanced version of lipid polymeric hybrid nanoparticles with just a different design. They are formed by a core–shell structure where solid lipid nanoparticles are coated with polymer shell. This type of drug delivery system ensures higher encapsulation efficiency of mainly hydrophilic drugs which are water-soluble by nature. They can be prepared by from various biomaterials like pectin, bovine serum albumin, etc., therefore, biocompatibility is not an issue. The polymeric shell of solid lipid-polymer hybrid nanoparticles plays the role of maintaining colloidal integrity and stability while on the other hand, the solid-lipid core ensures encapsulation efficiency [55].
1.6.3. Functionalized polymeric nanoparticles Polymeric nanoparticles become functionalized when the polymer is modified by some means or the other. This improves their bio-distribution and also protects the nanoparticles from phagocytosis by RES. When the nanoparticles are protected from being destroyed, there is an increased level of drug in the blood. Suppose take an example of PEGylated nanoparticles where PEG is used as the coating material at the surface of the nanoparticles. As per reports it has been found that there is an increased concentration of PEG-coated nanoparticles in CNS. Based on the properties that have been modified, functionalized polymeric nanoparticles are mainly of four generations. The first generation includes long stealth nanoparticles which are followed by the second generation that includes lectin-based polymerized nanoparticles. Then, in the third generation, polysaccharide-based nanoparticulate system emerged which was finally followed by ligand-based nanoparticles in the fourth generation [56]. The first two generations of functionalized nanoparticles mainly include long stealth nanoparticles and lectin-based nanoparticles. In long stealth or long circulatory nanoparticles, the nanoparticles are produced in such a sterically protected way that their circulation time has been prolonged. The sterically protected nanoparticles are produced mainly by protein adsorption and suppression of surface opsonization. On the other hand, lectin-based polymeric nanoparticles use lectin. Lectins are fundamental to many cells and they show specific interaction with carbohydrate non-covalently. Many times lectins are tagged with fluorescent polymeric substances which work as biomarkers and thus, can be used for detection purpose. 1.6.4. Polysaccharide conjugated polymeric nanoparticles This is an important class of functionalized polymeric nanoparticles where polysaccharides are incorporated into the surface of the nanoparticles by some means or the other. During the preparation of polymeric nanoparticles polysaccharides are mainly adsorbed at the surface of the nanoparticles. Polyesters which are hydrophobic in nature like PLA, PLGA, etc. are covalently incorporated with a polysaccharide skeleton comprising of chitosan, dextran and hyaluronic acid. This is considered to be one of the most biocompatible drug delivery system [57]. 1.6.5. Ligand-based polymeric nanoparticles Ligand-based polymeric nanoparticles are the most recent type of drug delivery system which is known as magic bullets. They are designed such that they can deliver bioactive substances at specific sites. The sensing of biological materials can be acquired by the presence of nanoparticles at the very surface of the nanoparticles. For example, the Green fluorescent protein is used for the sensing of cancerous cells. Sometimes even a slight change in the head of the ligands improves the property of cell affinity in this type of drug delivery system. Ligand-based nanoparticles is a highly advanced method which can be used for disease diagnosis as well as intracellular delivery of drug [58]. 1.6.6. Fluorescence polymeric nanoparticles Aggregation-induced emission (AIE) radiates strong effect of fluorescence due to aggregation or accumulation of fluorophores while on the other hand, there are very weak or almost no emission when there is accumulation in dilute solutions. AIE has brought about great advancements when it came to biomedical applications of AIE-active polymeric probes. Science has developed polymeric nanoparticles of luminescent nature. In this type of formulation, various fluorescent compounds are used such as fluorescent proteins, luminescent polymers which have coordination with metal substances, etc. The fluorescence intensity of this type of formulation is extremely weak and also causes
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fluorescence quenching when they are in highly aggregated stage. Aggregation-induced emission (AIE) is just a very good solution to this problem [59]. These AIE active molecules can be used as bio as well as chemosensors [60] Fluorescent organic nanoparticles are those nanoparticles which have unique properties of Aggregationinduced emission (AIE). It has been found experimentally that water-dispersible fluorescent organic nanoparticles have excellent emission properties. Many scientists through synthetic techniques have conjugated AIE active dyes with polymers or block co-polymers and together they give rise to excellent fluorescent organic materials which can function for bio-imaging as well as therapeutic purpose. There are a lot of researches which has used tandem polymerization technique to combine with various AIE properties. But this technique has a lot of disadvantages like poor solubility, strict stoichiometric balance, etc. Therefore, to modify the technique, one-pot three-component tandem polymerization with the aromatic dyes came into existence. The polymers obtained from this technique are of good water solubility, can form film and also has high thermal stability. Similarly, there are many onepot polymerization techniques such as MALI reaction, tandem polymerization, and its modified version and so on. The polymers prepared by this technique have a high level of biocompatibility and causes very less disturbances to cellular activities. This is the main reason that the polymers prepared by this technique have huge amount of applications in the field of biomedical research and drug delivery system [61]. Many new researchers have nowadays synthesized blockcopolymers which has luminescent property. In other words, present research is more focused on the preparing nanoparticles which can serve the dual purpose of bio-imaging as well as drug delivery. PEGMA-PhE FPNs nanoparticle was prepared which has the bio-luminescent property because it has been prepared by the use of fluorescent organic polymeric nanoparticles [62]. Similarly, AIE-active-salicyaldehyde-poly(PEG-co-vinylaniline) was prepared whose was aimed to serve the dual purpose [63]. Above all, this block copolymers as well as luminescent polymeric nanoparticles are prepared by the one-pot multicomponent reaction. This reaction mechanism is highly efficient and effective process on synthesizing luminescent nanoparticles as it serves various advantages. Due to these advantages, researchers have also tried ultrasound technique for the ultrafast delivery of various cross-linked copolymers which have the property of aggregation-induced emission. Poly(PEGMA-AEMA) with AIEgen having a termination of aldehyde is one such example [64]. Moreover, nanodiamonds are one of the most emerging concepts of fluorescent nanotechnology nowadays. The research interest is towards to conjugation of the nanodiamonds which is with hyperbranched functionalized polymer. They are proved to be one of the most important controlled release drug delivery systems for the treatment of cancer. This type of modern drug delivery system has drawn the attention towards itself as far as biomedical research is concerned. biomedical research [65]. Last but not least, these AIE aggregates have high cellular uptake capability. A prominent example is functionalized glutamate conjugated into a prominent luminescent nanoparticle [66]. 1.7. Characterization of nanoparticles
11
determination of chemical characteristics for example presence of a conjugated molecule or bonded ligands and zeta potential. The physical characterization is done with the help of SEM, TEM, UV spectroscopy, X-ray diffraction, Differential Centrifugal Sedimentation, Dynamic Light Scattering, etc. whereas chemical characterization is done with the help of techniques like NMR, FTIR, Raman spectroscopy, Gel electrophoresis, inductively coupled plasma mass spectrometry, etc. [67–74]. Different characterization technique of polymeric nanoparticles is as shown in Fig. 6. 1.7.1. Size and morphology Particle size determination is of prime importance in nanoparticle characterization. The particle size of the nanoparticle highly depends on the excipients, polymer and preparation technique. Particle size is also important because many secondary properties like surface area, toxicity, degradation, targeting, uptake mechanism, etc. are linked with the particle size. The two main techniques used to determine the particle size distribution are photon correlation spectroscopy, electron microscopy. Electron microscopy includes TEM, SEM, freeze-fracture technique. The electron microscopy technique measures individual particle size and particle size distribution. It is a relatively faster process. TEM i.e. Transmission electron microscopy is a technique in which the size of the particle can be measured by transmission of the electron beam through a sample. The transmitted beam shows variation in amplitude and phase which provides imaging contrast that is a function of sample size, thickness, material, etc. The image formed when the electrons are transmitted through the specimen is magnified and focused with the help of an objective lens and the image appears on an imaging screen. TEM has comparatively a higher resolution than light-based imaging technique [69–71]. SEM (scanning electron microscopy) can also be used to determine the nanoparticle size. In this technique, the electron microscope images the surface view of the particle with the help of high energy electron beam. The electron beam strikes the sample surface and thereby interact with sample’s atom and signals in the form of secondary electrons. The backscattered secondary electrons and also the characteristic X-ray generated would depict information about composition, surface characteristics, and topography of the nanoparticles [64]. Other techniques may include Atomic force microscopy, mercury porosimetry, etc. In Atomic force microscopy (AFM) visualization of the nanostructure is possible and in mercury porosimetry, the freeze-dried nanoparticles are filled in a dilatometer under vacuum and later are measured with mercury pressure porositometer. Morphology refers to physical shape and surface topography. Morphology or direct visualization can be done by SEM, TEM, AFM, sorptometer, etc. [67–71]. 1.7.2. Percent drug loading and entrapment efficiency Percent drug loading and entrapment efficiency are essential to be calculated. It tells how much amount of drug is entrapped inside the nanoparticle successfully. The entrapment efficiency and loading capacity depend on the procedure followed and how efficiently the experiment was performed. It is expressed in percentage. Encapsulation efficiency
Characterization is important to determine the shape, size, specific surface area, structure, etc. Characterization of nanoparticles can be broadly divided into two domains. The first classification is one which deals with physical properties determination of nanoparticles. For example shape, size, crystal structure or mono-dispersity and the other classification involves the
=
total amount of drug added − free non entrapped amount of drug total amount of drug added
× 100 Loading capacity =
amount of total entrapped drug total nanoparticle weight
× 100
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Fig. 6. Instrumentation of RAMAN Spectroscopy.
For calculating the Entrapment and drug loading efficiency a specified amount of drug-loaded nanoparticle is dissolved in particular solvent by centrifugation or sonication for an hour. The sample so obtained is then filtered using the membrane filtration technique. The concentration of the sample is in mg/ml and it is analyzed using UV/vis spectroscopy technique or other analytical technique [67–72]. 1.7.3. Zeta potential measurement Zeta potential measures the effective charge on the surface of the nanoparticle. The nanoparticle has a certain surface charge which can be screened by the concentration of opposite charge and this layer moves along with the nanoparticle and together the two layers of charges around the nanoparticle are termed as an electrical double layer. Zeta potential is the difference between the potential between the electric double layer. The magnitude of zeta potential also determines the stability of the particle. The charge of the nanoparticle also depends on the pH of the solution. Zeta potential is measured with the help of a cell containing gold electrodes. The nanoparticle-containing solution is poured in the cell and the voltage is applied between the electrodes. The particles will move in the direction of their opposite charge electrode. A Doppler technique measures the particle voltage. The laser beam passes through the cell and fluctuation in the intensity of the laser determines the particle speed at multiple voltages and this helps in calculation of zeta potential. The Zeta potential value can be measured using a Zeta-sizer equipped with HeNe laser [67–72]. 1.7.4. Solubility determination Solubility can be determined by solubilizing the nanoparticle in distilled water. Excess of the pure drug is dissolved in a predetermined amount of distilled water in a conical flask. The conical flask is placed on an orbital shaker for a day. This would ensure saturation of the drug. The solution is then filtered and diluted adequately and the concentration is determined using appropriate spectroscopically [67–70]. 1.7.5. Thermal property determination 1.7.5.1. DSC. To know about the thermal properties of the polymers is one of the most essential things for the processing of materials and also predicting the shelf life of the final product. Differential Scanning Calorimetry is one of the most powerful
techniques for analyzing the thermal properties of the polymer. The thermal properties help us to judge the nature and characteristics of the polymer-based products. In heat-flux DSC, when heat is flown, the temperature difference between the sample and the reference is measured and compared. When heat evolves out from the sample, the graph in the DSC plot shows exothermic reaction but on the other hand, when the sample absorbs heat in the thermal process, then the graph becomes indicative of endothermic reaction. 1.7.5.2. TGA. TGA is known as Thermogravimetric analysis. It provides a transparent idea regarding the weight loss of the sample that is to be analyzed with respect to temperature increase. In this process, the change in the sample mass is measured which occurs during various thermally assisted events like sublimation, desorption, oxidation, etc. During the whole process of analyzing the sample is subjected to a program which helps in increasing the temperature [73]. 1.7.5.3. DTA. DTA is known as Differential Thermal Analysis. In this process, the sample and the reference are subjected to identical heat treatments. The temperature difference shown by the sample and the inert reference is measured and the analysis is carried out accordingly. Change in specific heat or any change in enthalpy of transition is detected by the method of DTA [73]. 1.7.6. Raman spectroscopy Raman spectroscopy is a spectroscopic technique which helps in observing the rotational, vibrational and other modes of frequency in the given nanoparticles. It provides a structural fingerprint of the given nanoparticle. This method quantitatively and qualitatively analyzes the covalent bond and differentiates between different materials and also helps us to find the strain in the given molecule [58]. Brief instrumentation is as mentioned in Fig. 6. 1.7.7. In vitro drug release studies For finding the in vitro drug release, place the sample in a dialysis bag and place it in the dissolution medium. The study is continued using USP dissolution apparatus, at a particular time interval a certain amount of sample solution is withdrawn and filtered and analyzed spectroscopically. Recently ultrafiltration technique is also used to find them in vitro drug release.
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Fig. 7. Characterization of nanoparticles.
Fig. 8. PEGylated nanoparticles used for the treatment of skin tumor.
1.7.8. Recent advancements in functionalized polymeric nanoparticles 1. Stimuli-responsive nanoparticles are the part of smart technological advancements that brought about a revolution in the field of smart delivery of therapeutic agents for the
treatment of solid tumors. The stimuli developed nanoparticles are inactive when it is present in the bloodstream. It gets activated in the presence of stimuli like pH, temperature, enzymatic scale-up [74–76]. 2. Cancer cells have pH less than normal cells that means the pH in normal cells is much higher than cancer or tumor
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Fig. 9. Ligand-based nanoparticles targeted through active targeting.
cells. Thus, the new advancements of nanocarriers made up by pH-responsive polymers have become a revolutionary approach for the diagnosis of cancer and its treatment. pHresponsive nanocarriers with programmable size changes with a change in pH and thus works as targeted release dosage form [67–69,76–78]. 3. Combination Chemotherapy has widely been used for the treatment of cancer. It is effective against overcoming the drug resistance and also achieving a synergistic effect against cancer in the clinic. Methotrexate and pemetrexed with chitosan polymer have been prepared. The above synergistic formulation has been prepared by modifying mPEG (methoxy poly(ethylene glycol) where PEGylated chitosan particles are prepared to be used as Stealth nanocarriers. The technology has been carried out to target human lung adenocarcinoma epithelial [69]. Fig. 7 shows how PEGylated nanoparticles treat tumor cells. 4. The concept of nanogel as nano-sized nanoparticles has significantly been used in the treatment of cancer by the mode of gene delivery. The most valid advantage of nanogel over conventional dosage form is that it does not show any destabilization even in highly dilute conditions. Narian et al. have been credited to formulate a nanogel with the cationic core. The unique characteristics of nano preparation in that it is temperature as well as pressure-sensitive. The thermosensitive polymer used was PNIPAM, but Poly (N-vinylcaprolactam) (PVCL) is preferred more for its excellent compatibility with the biological system. Nanogels prepared with PVCL depicts a volume phase transition temperature at 32 ◦ C–38 ◦ C in water, which is very close to the physiological conditions. And for preparation of pHsensitive nanogels, Poly(2-diethylaminoethyl)methacrylate is used as a polymer [70]. 5. Magnetic nanocarriers have one of the recent approaches for the treatment of multimodal cancer therapy. The anticancer drug doxorubicin is conjugated with pH and thermoresponsive magnetic nanocomposites. The formulation is developed by linking the magnetic composites with doxorubicin through acid-cleavable imine linkage which offers
the formulation an advanced feature of targeted drug delivery of the drug molecules. The dual characteristics of temperature and pH-sensitive nature give control over the release of doxorubicin [71]. 6. Ligand-based nanoparticles show programmed selectivity and affinity for a specific target site which gives a depth of understanding of molecular recognition and tissue recognition [79]. This ability of molecular as well as tissue recognition implicates that it is one of the most effective technique for detection of metabolites, biomarker for cancer, etc. Fig. 8 shows ligand-based targeting. 7. Dendrimers are nothing but polymeric architectures that are known for their versatile use in the drug delivery and drug targeting. This nano-structured molecule is basically starred shaped with three compartments including the core, dendritic structures that is, the branches and finally the exterior structure with a functional group in the surface, These dendrimers are an important tool of targeted drug delivery [80–82] (see Fig. 9). The advancements came up with a lot of revolutions in the field of drug delivery through nanotechnology. The various new advanced polymeric nanostructures have brought about a lot of new patents in the field of nanotechnology. The Tables 2–4 represent a brief description of the patents related to the polymeric nanoparticles. 1.8. Application of polymeric nanoparticles 1.8.1. Treatment of vaginal diseases The vagina is the main route of administration to obtain local effect or systemic effect and this route can also bypass the hepatic first-pass metabolism. This route can also be used to treat the sexually transmitted disease or infections. But administering the drug through vaginal route is not easy and has many shortcomings. The abundant mucus produced by the vagina is the major barrier for the conventional dosage form and because of this conventional drug does not show sustained and targeted action. It is because of these shortcomings that modified release dosage
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Table 2 Recent patented polymer-based NPs for drug delivery. Formulation
Patent number
Nanocarrier
Therapeutic uses
Tumor-targeting drug-loaded particles
CN102697737 A
Gelatin and PLGA
Cancer treatment
Functional PLA-PEG copolymers, the nanoparticles thereof, their preparation and use for targeted drug delivery and imaging Functional PLA-PEG copolymers, the nanoparticles thereof, their preparation and use for targeted drug delivery and imaging
WO2013127949 A1
PLA-PEG copolymers
Cancer treatment and imaging
Human recombinant epidermal growth factor (hrEGF)-modified cisplatin-loaded polymeric nanoparticles and preparation method and application thereof
CN102793671 A
mPEG-PLGA-PLL
Cancer treatment
Cellulose-based nanoparticles for drug delivery
WO2012103634 A1
CMC-Ac-PEG
Cancer treatment
Contrast media for cancer diagnosis containing amphiphilic hyaluronic acid complex nanoparticle and drug carrier for treating cancer
KR1020100037494
HA
Cancer diagnosis and treatment
Compound epirubicin hydrochloride polylactic-co-glycolic acid (PLGA) nanoparticles and preparation method thereof
PLGA
Anti-tumor combined medicament
CN102697795 A
PLGA
Cancer treatment
Nanoparticle composition and methods to make and use the same
US20130209566 A1
POE
Eye-related diseases, cancer, arthritis, etc.
Polymer-nanoparticle magnetic resonance contrast agent and preparing method thereof
CN101612407 B
PLA-PEG-DTPA-Gd
Magnetic resonance
Nanoparticle carrier systems based on human serum albumin for photodynamic therapy
WO2011071968 A3
Albumin
Photodynamic therapy
A high-loading nanoparticle-based formulation for water-insoluble steroids
WO2013063279 A1
PEG-b-PLA
Steroids deficit treatment
Injectable biomaterial
US20120195826 A1
HPMA-HMA and HPMA-TBA
Occluding normal or malformation of blood vessels; necrosating tumors
Nanoparticles comprising rapamycin and albumin as an anticancer agent
US20130280336 A1
Albumin
Treating, stabilizing, preventing, and/or delaying cancer
Drug loaded polymeric nanoparticles and methods of making and using same
EP2309990 B1
PLA-PEG
Cancer treatment
Functional biodegradable polymers
WO2012015481 A1
PLA, PLGA or PGA
Delivery of a therapeutic agent
Polymer formulations for delivery of bioactive materials
US8114883 B2
PLGA
Delivery of therapeutic agents
Biodegradable drug-polymer delivery system
US8128954 B2
Cyclodextrin
Delivery of therapeutic agents or ocular diseases treatment
Injectable cross-linked polymeric preparations and uses thereof
US8110561
Polysaccharide gels
Body tissue treatment
Table 3 Recent patented formulations regarding dendrimer-based nanoparticles for drug delivery. Formulation
Patent number
Nanocarrier
Therapeutic uses
Hydroxyl-terminated dendrimers
WO2011053618 A3
Hydroxyl-terminated PAMAM
Cancer treatment and diagnosis
Carbosilane dendrimers and the use thereof as antiviral agents
EP2537880 A2
Carbosilane
Antiviral, antibacterial or antifungal treatment
Injectable dendrimer hydrogel nanoparticles
EP2552458 A1
PAMAM
Therapeutic treatment and diagnosis
Dendrimer compositions and methods of synthesis
EP2488172 A2
PAMAM
Cancer treatment and diagnosis
Targeted dendrimer-drug conjugates
WO2011072290 A3
PEGylated PAMAM
Liver-specific delivery of therapeutic agents
Interior functionalized hyperbranched dendron-conjugated nanoparticles and uses thereof
WO2012018383 A2
Cystamine core PAMAM
Cancer treatment
Compositions and methods for delivering nucleic acid molecules and treating cancer
WO2012024396 A3
PPI
Cancer treatment
form for vagina was introduced. The polymeric nanoparticles have been introduced to overcome the physiological barrier and has certain advantages like mucoadhesiveness, easy penetration to mucosa as well as a sustained and targeted release of the drug. Both biodegradable and non-biodegradable polymer of natural and synthetic origin has gained immense interest [82].
Both natural and synthetic polymeric nanoparticle can be used but generally natural polymers such as proteins and polysaccharides are used at relatively lesser degree because of variation in different sources, the problem in the preparation process, uncertainty of the source, antigenic to some patient, etc. Therefore biodegradable synthetic polymeric nanoparticles are highly
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S. Sur, A. Rathore, V. Dave et al. / Nano-Structures & Nano-Objects 20 (2019) 100397 Table 4 Nanoparticle drug delivery systems undergoing clinical investigation. Name
API
Polymers
Use
Clinical trial phase
BIND-014 CALAA-01 CRLX101 OpaxioTM ProLindacTM CT-2103 NK911 MTX-HSA SPI049C NK105 Paclical R VivaGel⃝
Docetaxel Anti-RRM2 siRNA Camptothecin Paclitaxel Oxaliplatin Camptothecin Doxorubicin Methotrexate Doxorubicin Paclitaxel Paclitaxel SPL7013
PEG-PLA Cyclodextrin-PEGtranferrin Cyclodextrin-PEG Poliglutamic acid HPMA-DACH Polyglutamic acid PEG-PAA micelle HAS P-glycoprotein micelle PEG-PAA micelle Polymeric micelle Dendrimer
Solid tumors Solid tumors Several types of cancers Lung and ovarian cancer Solid tumors Ovarian cancer Solid tumors Kidney cancer Several types of cancers Gastric cancer Ovarian cancer HIV infections
I I II III II III III II III II III II/III
Table 5 Polymeric nanoparticles for the treatment of vaginal diseases. Drug name
Nature of the drug
Polymer used
Size
Technique
MOA
Uses/target
Ref.
Ascorbic acid
Hydrophilic
Chitosan
170 nm-
Ionotropic gelation
Antioxidant and reduces free radical; boost immunity
Cervical Cancer
[82]
Insulin
Hydrophilic
Chitosan
265–279 nm
Ionotropic gelation
Binds to glycoprotein receptor and maintain the glucose level
Model for peptides delivery
[83]
Silver saccharinate
Hydrophilic
Alginate
100–250 nm
Reverse emulsification
Interaction with a thiol group and act as antimicrobial
HSV-2 and Neisseria gonorrhoeae inhibition
[19]
Tenofovir
Hydrophilic
Gelatin
294.7–445 nm
PLGA 50:50
118 nm
Inhibits the activity of HIV reverse transcriptase by competing with deoxyadenosine 5′ -triphosphate
Sexual transmission of HIV in women
[20]
Hydrophilic
Desolvation method Double emulsion-solvent evaporation
Ciprofloxacin
Hydrophilic
Ovomucin
235 nm
Nano-precipitation
Broad-spectrum antibiotic and inhibit DNA gyrase, type II topoisomerase, topoisomerase IV, necessary to thereby inhibit cell division.
Treat bacterial infection
[24]
Riboflavin
Hydrophilic
Ovomucin
52–235 nm
Nano-precipitation
Antioxidant as riboflavin is a precursor of flavin adenine dinucleotide
Treat vaginal lesion
[24]
Acyclovir
Hydrophobic
PVPK30-EC
403 nm
Nano-precipitation
PVPK30-ERSPO
99 nm
Nano-precipitation
Inhibitor of herpesvirus DNA polymerase and other viral DNA polymerase
Efavirenz
Lipophilic
PLGA 50:50
275 nm
Emulsion-solvent evaporation
Inhibit reverse transcriptase enzyme (RNA-directed DNA polymerase)
Sexual transmission of HIV in women
[86]
Dapivirine
Lipophilic
PLGA 50:50
168 nm
[86]
poly (ε -caprolactone)
182–194 nm
Inhibit reverse transcriptase enzyme
Treat HIV-1 infection
Lipophilic
Emulsion-solvent evaporation Solvent displacement method
Clotrimazole
Lipophilic
PLGA 50:50
492 nm
Emulsificationdiffusion
Inhibits ergosterol synthesis by interacting with yeast 14-α demethylase
Treat Vaginal infection like a vaginal yeast infection, itching, discharge, etc.
[88]
Paclitaxel
hydrophobic
PLGA 50:50
245 nm
Solvent diffusion/nanoprecipitation
Interfere with microtubule growth
Treat the genital disease, cancer, HIV
[89]
Elvitegravir (EVG)
Lipophilic
PLA conjugated with HPG
131–135 nm
Nano-emulsion protocol
Inhibits HIV-1 integrase and prevent HIV 1 DNA integration with human genome DNA
Treat HIV and other viral and fungal infection.
[90]
Imiquimod
Lipophilic
poly (ε -caprolactone)
199 nm for uncoating and 213 nm chitosan coated
Interfacial deposition
Improve immune response by activating toll like receptor 7 (TLR7), stimulates apoptosis
Treat genital warts in female, antiviral, antitumor
[91]
Antiviral
[84]
[85]
[85]
[87]
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Table 6 Different natural and synthetic polymeric nanoparticles used in cancer drug delivery. Drug name
Nature of the drug
Polymer used/ Polymer formulation
Technique
Mechanism of action
Uses/targets
Status
Product name
Ref
Paclitaxel
Highly water-insoluble
PEG-PLA
Block co-polymerization (nanoprecipitation) Nanoprecipitation
Inhibitor of microtubule; binds to tubulin, prevents the assembly of microtubules thus, resulting in inhibition of cell division. Interacts with DNA by intercalation and inhibition of macromolecular biosynthesis.
Breast cancer, pancreatic cancer
Clinically approved
[22, 23]
Ovarian cancer
Phase III
Genexol (approved in south Korea) Paclical
Advanced adenocarcinoma
Clinically approved
Doxil
[25]
Polymeric micelle
Doxorubicin
Hydrophilic
PLGA-PEG block copolymers (with folic acid)
Double emulsion solvent evaporation, single emulsion solvent evaporation, and dialysis method
Vincristine
Poor water solubility but readily dissolve in an organic solvent (alkaloid)
PLGA
o/w single emulsion solvent evaporation process
Partially works on binding with tubulin protein which does not allow the tubulin dimer to polymerize.
Acute lymphoblastic leukemia
Phase III
Marqibo
[21]
Amphotericin B
Polyene by nature; soluble in acidic water (pH-2) or basic water (pH-11); soluble in methanol
PLGA
Emulsion solvent evaporation method
Acts by binding on the sterol component of the cell membrane, and thus disrupts the cell.
Invasive fungal disease
Phase III
Ambisome
[92]
siRNA
Nucleic acid
PEG-CCP/CaP
Double-emulsion solvent evaporation technique
Suppress the expression of the carcinogenic gene by targeting the mRNA expression
Pancreatic tumors
Phase I
NCT01437007
[93]
Cisplatin
Platinum-based compound
PEG-P(Glu)
Dialysis
Bind to DNA thereby interfere with repair mechanism of the DNA leading to cell death
Colon adenocarcinoma cells
Phase III
Nanoplatin
[93]
Ascorbic acid
Hydrophilic
Chitosan
Ionic gelation method
The level of C-reactive protein decreases and also there is a decrease in proinflammatory cytokines It stops metastasis and also hinders the growth of the tumor and encourages encapsulation of tumor. Anti-apoptotic activity with the help of Bcl-2 Modulation of markers for cancer proliferation By preventing the expression of cyclin D1
Pancreas, breast, kidney, liver, lymphoma, prostate, colon and stomach
Clinical (phase exactly not known)
No product name as such
Breast cancer in mice
Non-clinical
Cells from renal carcinoma
Non-clinical
Cells from cervical cancer
Non-clinical
Lung cancer in ferrets
Non-clinical
used for vaginal drug delivery system. The polymeric nanoparticle should meet certain requirements like stable at vaginal pH, mucoadhesive, easily permeate into the mucous, etc. The polymeric nanoparticle for vaginal drug delivery is divided into 4 generations. The first generation nanoparticle is the one which gets captured in the liver by RES (reticuloendothelial system); the second generation comprises of stealth nanoparticles which are coated by polymers which are water-soluble e.g. PEG. This
[18]
increases the systemic circulation of the nanoparticle and passive targeting; the third generation nanoparticle comprises of ligandbased targeting and the-ligand specifically targets the particular receptor. Finally, the fourth generation nanoparticle comprises of multifunctional nanoparticles. This nanoparticle comprises the diagnostic agents, the therapeutic agent and a therapeutic efficacy reporter in the same system. The polymeric nanoparticle obtained from natural or synthetic sources for vaginal treatment
18
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Fig. 10. Different cancers and diseases treated by polymeric nanoparticles.
is as mentioned in the table. Natural polymers like alginate and chitosan are widely used for the preparation of nanoparticle for vaginal drug delivery formulation. Chitosan polymer when used in vaginal drug delivery system act as mucoadhesive and subsequently increase the retention time enhancing the activity of the drug. Synthetic polymer include poly(DL-lactic acid), polycaprolactone, poly(lactic-co-glycolic acid), polyacrylates, PLGA etc. [82, 83]. Table 5 gives a detailed account of the different natural and synthetic nanoparticles used in vaginal drug delivery. 1.8.2. Cancer treatment Cancer is one of the gravest diseases nowadays. Cancer is in its alarming stage and has become one of the deadliest diseases worldwide. Chemotherapy and surgical techniques were the only methods of treatment of cancer in earlier times. The concept of encapsulation of the drug came into existence for effective targeting as well as treatment of cancer cells. The biggest disadvantage of the conventional method is that chemotherapy and other modes of radiation cannot distinguish between the self and non-self cells. This inability of discrimination of self and non-self cells causes a huge and extensive amount of side-effects, thereby causing harm to even healthy cells. The concept of encapsulation of drug came into existence for systematic, specific and targeted delivery of drug with reduced side-effects. The nature of the polymer also determines a lot of things related to the formulation. Like PEG-PLGA is preferred other amphiphilic block copolymers because PEG-PLGA has superior biocompatibility, non-crystalline nature and glass transition temperature which is above the room temperature. PEG-PLA has also been in trend for its superiority in many physical and chemical properties [67,68,76–78] (see Fig. 10 and Table 6). 1.9. Future prospects and challenges Almost all nanoparticles have increased extravasation into the tumor interstitium. Moreover, the polymeric nanoparticles have a very efficient ability to modify it with various ligands and targeting agents that can target to required site. The polymers have high potential to act as a drug delivery system. Nowadays, modern technology aims to modify polymeric nanocarriers in such a way that it can serve the dual function of bio-imaging as
well as therapeutic diagnostics. A day may come when polymers might be modified in such a way that polymers will be able to assess the genotypic phenotype of the patient as hence, the treatment can be provided accordingly. The biggest challenge of the polymeric nanoparticles is that they sometimes have toxic degradation when the residual material associated with them is toxic. Sometimes extensive accumulation of the polymers can also lead to huge toxicity. Polymeric nanostructures are extensively used in four broad areas covering the most important aspects of biomedical and pharmaceutical fields. It can serve the purpose of analytical and imaging tool can be used in theranostics and targeted drug delivery system. It also plays a vital role in tissue engineering. Therefore, it can be stated that polymeric nanocarriers have a highly promising future in field of medicine and biomedical application. A day might come when the polymeric nanoparticles should be functionalized in such a way that they can use in stem cell technology. Presently, these polymers already do have extension application in gene therapy and in those drug delivery systems which deliver nucleic acid as a treatment regime. Preparation of the polymeric drug delivery system can be challenging at times since there can be some biocompatibility and biodegradability issues but because of its extensive application, polymers are thought to bring about revolution in the science, medicine, and biomedical applications. 1.10. Safety issues of polymeric nanoparticles Wide varieties of the polymer can be used in the preparation of polymeric nanoparticle which includes a biodegradable and non-biodegradable polymer. Biodegradable polymers are comparatively safer than non-biodegradable polymer. The polymer used should be preferably biocompatible and biodegradable. Accumulation of the polymer inside the body can pose a safety concern. At present only a few polymers are approved and are guaranteed to be safe by the FDA. The most commonly used polymer in CNS is PACA and till now its safety poses a big question and this polymer is not approved by the FDA till date. On the other hand polymers like PLGA, PLA, etc. are proved to be safe for human use. They are biocompatible and biodegradable and are also approved by US-FDA.
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Generally, natural polymers are preferred over synthetic polymers since they are of natural origin and are biocompatible and biodegradable. Due to shortcomings like lack of uniformity in the source, difficulty in manufacturing, season based procurement of polymer, easy contamination by the microorganism, etc., synthetic polymer came into the picture. The polymers’ property should be studied thoroughly before using in the nanoparticle preparation. One should ensure its safety, non-toxicity before manufacturing of a particular nanoparticle. There is also a high risk involved during the manufacturing of polymeric nanoparticles. The major risk involved during the manufacturing of dry powdered polymeric nanoparticles. Handling of such powders is difficult and poses a high exposure to the workers through inhalation into the pulmonary system, absorption through the dermal system and through ingestion through the GI system. These occupational hazards can be overcome by following good personal hygiene as well as basic safety rules and wearing personal protective equipment. Apart from the above-mentioned risk, polymeric nanoparticle also poses certain environmental hazards. Certain nanoparticles can be toxic to living species and environment. For example, a polymeric nanoparticle can be highly hazardous to the microorganism and may also contaminate the groundwater owing to big-time threat to the ecosystem. The nanoparticle can also enter the food chain and affect the environment adversely. For example deposition of polymeric nanoparticle in crops, fishes or other living species may affect the food chain and environment adversely. To avoid such environmental hazards certain guidelines should be laid down to avoid contamination of the environment. The waste material from the production plant of polymeric nanoparticles should also be properly disposed [80–82]. 2. Conclusion and future aspect The functionalized polymeric nanoparticle is a smart drug delivery system. Wide varieties of the polymer have been studied for its safety and effective drug delivery to a specific site. The functionalized polymeric nanoparticle has a wide variety of application ranging from drug delivery in the vagina, brain, cancer treatment, gene therapy and many more. In last few decades, several advancements have taken place in the field of functionalized nanoparticle which includes the release of the drug based on external stimuli, target-specific drug release, magnetic nanocarriers, ligand-based polymeric nanoparticles, nanogels and many more. Many functionalized polymeric nanoparticles have entered the market whereas many are in different phases of clinical trials. These nanoparticles effectively load the drug and target the specific site and thereby decrease side effects. The future of nanomedicine especially the functionalized polymeric nanoparticles will improve and further advancement would help in treating deadly diseases like cancer with lesser side effects. The continuous ongoing research on functionalized nanoparticle would improve the diagnosis, treatment, and prevention against diseases techniques. Research should be reconsidered to develop a simple, efficient, straightforward manufacturing technique and easy scaling up technique. Certain regulatory guidelines should be laid down to improve the safety of the nanoparticle towards human and the ecosystem. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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