Polymer-based nanocontainers for drug delivery

Chapter 16

Polymer-based nanocontainers for drug delivery Francesca Froiioa,b, Narimane Lammaria,c, Mohamad Tarhinia, Munther Alomarid, Wahida Louaerc, Abdeslam Hassen Meniaic, Donatella Paolinob, Hatem Fessia and Abdelhamid Elaissaria a

Univ. Lyon, University Claude Bernard Lyon-1, CNRS, LAGEP-UMR, Lyon, France, b Department of Experimental and Clinical Medicine, University

“Magna Græcia” of Catanzaro, Catanzaro, Italy, c Environmental Process Engineering Laboratory, University Constantine 3, Salah Boubnider, Constantine, Algeria, d Department of Stem Cell Biology, Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia

1 Introduction Nature is an everlasting source of active molecules that can be used for an indefinite number of known diseases and body malfunction. This availability of therapeutic active compounds was a known fact early in history. And with the evolution of science and analytical methods, more natural active molecules are being continuously discovered. Molecules such as morphine, digitoxin, and quinine that were all derived from plants were proven to have an analgesic, cardiac, and antipyretic effects, respectively [1]. Moreover, nature-provided molecules also have anticancer effects, such as Herceptin, paclitaxel, and curcumin [2, 3]. However, limitations often exist that can prevent certain natural drugs from achieving their maximal potential when it comes to in vivo administration. Poor solubility, undesirable toxicity, and the difficulty to bypass certain body barriers are factors that render most of the natural molecules less efficient, risky, and in some cases impractical [4, 5]. To solve these problems, many approaches were applied. While it’s difficult to synthesize natural products due to their complexity, their structure modification proved to be a great approach to increase their solubility and activity or even to reduce side effects. For instance, oleanolic acid is an abundant natural product with a large variety of therapeutic effects such as anticancer, antidiabetes, and hepatoprotective. On the other hand, oleanolic acid has a poor water solubility, and if administrated with high doses, it can induce cholestasis and hepatotoxicity [6]. Thus, chemical modification of oleanolic acid drew some attention. Suh et al. were able to produce 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oic acid that is more effective as an antiinflammatory agent than its parent compound oleanolic acid [7]. In addition, other derivatives for this compounds such as carbenoxolone showed a more potent antiulcer effect, all with lower toxicity than oleanolic acid [8]. Another popular approach is to use encapsulation technology, a strategy in which a vehicle is created to carry the drug during its circulation to its desired target. These vehicles are usually nano- or microscaled particles, and it can be composed from phospholipids, proteins, metals, polymers, etc. [9–12]. However, nanoparticles have several advantages compared with microparticles. Microparticles have the tendency to stay longer at the location in which they were placed, while nanoparticles have the swiftest clearance at the same time frame [13]. In addition, nanoparticles, because of their small size, have the tendency to cross difficult biological barriers in which microparticles are unlikely to cross [14]. Nanoparticles are nanosized structures that can be synthetized from several materials, and their efficacy as drug carriers and delivery system was demonstrated in the last decades [15, 16]. By incorporating a drug inside a nanoparticulate system, the stability of the drug increases, its blood circulation becomes easier, and its activity can be focused from targeting the whole system into a specific location that by its turn reduce the side effect of the molecule in question [17]. Moreover, nanoparticles were employed as a strategy to overcome the poor water solubility of hydrophobic drugs [18]. For examples, paclitaxel, a recognized drug for the treatment of ovarian, breast, and nonsmall cell lung cancer, suffers from a high hydrophobicity. Its low water solubility hinders its clinical applications [19]. Nevertheless, using hydrotropic polymer micelles as nanocarriers for paclitaxel, its concentration in an aqueous medium upsurges dramatically by a factor of 1000, on top of the high drug-loading capacity and the long-term stability of the particles [20]. Apart from that, the hydrophilic drug also suffers from poor cellular uptake, low bioavailability, and poor stability against hydrolytic degradation [18]. These Smart Nanocontainers. https://doi.org/10.1016/B978-0-12-816770-0.00016-2 Copyright © 2020 Elsevier Inc. All rights reserved.

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challenges can also be overcome by nanoparticle technology. Li et al. demonstrated that the water-soluble bovine serum albumin when encapsulated within PEGylated poly(lactic-co-glycolic acid) nanoparticles, its half-life prolonged from 13 min to 4.5 h. In addition, it significantly changes its biodistribution in rats [21]. Different polymers were used as building blocks for nanoparticles, among which are biocompatible or biodegradable. Particles were built from proteins, dextran, PLGA, Eudragit, chitosan, MPEG-PLA, etc. [22]. Likewise, many methods were used to prepare such particles. Literature heavily cited nanoprecipitation, emulsification, spray-drying, ionic gelation, etc. [22, 23]. The choice of the preparation method depends on the type of polymer and the desired end product [24]. In this review, polymeric nanocarriers were discussed, major preparation methods were explained, and the ability of using these carriers as drug carriers was examined from different angles.

2 Drug encapsulation processes This chapter explains the preparation methods of polymeric nanoparticles. However, we only covered the scenarios of already performed polymers. Also, cases of only hydrophobic drugs were mentioned with a little highlight on the difficulty of encapsulating hydrophilic drugs. Various pharmaceutical techniques were discussed such as emulsification and nanoprecipitation. The effect of their experimental parameters on the particles was highlighted, and the feasibility of using polymeric nanoparticles as a safe drug carrier was heavily mentioned. Finally, particle characteristics, surface modification, release profiles, and future perspective were discussed.

2.1

Nanoprecipitation

The nanoprecipitation technique is a good option for instantaneous development of either nanocapsules or nanospheres. This method was first described by Fessi et al. (1989) [25]; having many benefits, it is simple, fast, and reproducible, and it consumes a low amount of energy and raw materials [26]. The nanoprecipitation process consists on the addition of water-miscible organic phase, under magnetic stirring, into an aqueous phase triggering a displacement of the organic solvent that leads to polymer interfacial deposition. Basically the organic phase consists of an organic solvent in which the polymer is dissolved. Likewise the aqueous phase may comprise a mixture of nonsolvents and surfactants [27]. Acetone and ethanol are widely used as organic solvents. Additionally a mixture of solvents such as mixture of acetone with water or ethanol has been used in the literature. Furthermore, some oils could be added to enhance the dissolution of hydrophobic active [28]. Among the biodegradable polymers, polyesters, especially PCL, PLA, and PLGA, were widely used [27]. Lince et al. (2008) stated that the mechanism of nanoparticle formation includes three steps: particle nucleation, molecular growth, and aggregation. The supersaturation is the driving force of all these steps; it is mainly influenced by fluid dynamics and mixing. Indeed, high stirring rate leads to high nucleation rates, whereas lower mixing rate induces low nucleation rates [29]. Several operating process could affect the physicochemical properties of the nanoparticles; they comprise the solventto-nonsolvent volume ratio, the amount of the encapsulated drug, and the type and amount of polymer and stabilizer. Several work studies highlighted the remarkable effect of polymer amount on particle size; as the polymer amount increases, the viscosity of the organic phase increases, which may hinder solvent diffusion to water, and thus the particle size increases [30–33]. Similar results were obtained when the polymer molecular weight was increased [34]. The effect of organic-to-aqueous volume ratio on particle size has been largely studied. Dong and Feng (2004) found that an increase in water volume decreases particle size [32]. Budhian et al. (2007) attributed this fact to the increase of the solvent diffusion of water, which leads to more rapid precipitation of polymer and the formation of small nanoparticles [35]. However, the opposite phenomenon happened in other work studies [33]. Regarding the effect of stabilizer amount, a decrease in particle size has been assessed at higher amount [36]. However, it did not exhibit significant effect in other work studies [32]. An increase of the stirring speed generates a decrease in the particles’ size, which is attributed to the highest efficient shear mixing and, hence, more rapid diffusion of the solvent to the nonsolvent [33]. In addition to encapsulate both hydrophilic and hydrophobic drugs [37–39], the nanoprecipitation method could also encapsulate natural compounds like plant extracts [40–43] and essential oils [44–47]. To scale-up the nanoprecipitation method and to enhance reproducibility, several approaches have been currently developed such as membrane contactor and microfluidic technology [48, 49]. Table 1 summarizes some examples of using the nanoprecipitation method in drug delivery during the last years.

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TABLE 1 Preparation methods of different polymeric nanoparticles. Method

Polymer

Encapsulated molecule

SIZE (NM)

ZETA (MV)

Aim

References

Nanoprecipitation

PLGA

Carvacol

210

19

Antibiofilm activity

[46]

Cytarabine

125

21

Leukemia treatment

[102]

Ropivacaine

162

11

Antiinflammatory

[103]

Vitamin E

165

16

Antioxidant

[48]

Gatifloxacin

184


32

Antibiotic

[104]

PLGA

Doxorubicin

174


40

Systematic evaluation

[53]

PCL

Nilotinib Mesylate

216


7

Leukemia treatment

[54]

PLA-PEG

Plasmid DNA

130


30

Systematic evaluation

[105]

PHB

Rifampicin

Antituberculosis

[106]

PLA-PEG

Oxytocin

<200

34

Improve oral delivery

[59]

PLGA

Paclitaxel Paclitaxel

250 190

–
7

Systematic evaluation Cancer chemotherapy

[58] [60]

PLGA

Insulin

300


20

Blood glucose control

[63]

Daunorubicin

138


25

Drug resistance in cancer cells

[64]

PDLLA

Letrozole

348


30

Systematic evaluation

[107]

PCL

Pantoprazole

450,000

–

Inhibits gastric acid secretion

[82]

PLGA

Heparin

2500


28

Inflammation treatment

[108]

RS30D

Theophylline

<60,000

–

Asthma

[109]

PCL

Fish oil

73

–

Cardiovascular diseases

[110]

PLGA

Hydrocortisone acetate

1000

–

Antiinflammatory

[111]

PLA

5-Fluorouracil

220

–

Anticancer

[112]

Chitosan

L-Ascorbic

acid Thymoquinone

140

–

Antioxidant

[113]

Pectin

Flaxseed oil

862,000

Source of omega-3

[114]

Alginate

Articaine hydrochloride

340

Local anesthetic

[115]

PCL

Emulsion diffusion

Simple emulsion evaporation

Double emulsion evaporation

Spray-drying

Supercritical fluid technology

Ionic gelation

2.2


22

Emulsion diffusion

Emulsion diffusion (ESD) is an efficient method for the encapsulation of lipophilic molecules. It was first developed by Quintanar-Guerrero et al. for the preparation of PLA nanospheres [50]. In this technique the polymer and the hydrophobic drug must be dissolved in an organic phase that is partially miscible with an aqueous phase containing a stabilizing agent. These two phases are then mixed together upon high-speed homogenization, allowing a mutual saturation of both phases. Subsequently the saturated solvent phase is emulsified in an excess of water leading to the diffusion of the organic solvent from the dispersed phase that initiate the precipitation of the polymer in the form of particles [51].

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The experimental parameters of this method can actually affect the colloidal properties of the produced particles. Hong et al. evaluated the effect of mixing velocity on the size of PLA particles. It was found that by increasing the speed from 10 to 50 m/s, particle size decreases from approximately 400 to <100 nm. However, increasing the temperature leads to agglomeration of smaller particles to form microsized ones [52]. The use of ESD to construct biodegradable polymeric particles as drug carriers was also investigated. The anticancer drug doxorubicin was encapsulated within PLGA nanoparticles. Particles with a size of 170 nm and zeta potential of
40 mV were obtained. In addition, the drug loading using this ESD was 6.6-mg drug/mg nanoparticles, and the loading efficiency was 44%. These values were higher than the other two methods used in this study (nanoprecipitation and double emulsion). However, the in vitro drug release profile was similar for the three methods [53]. In another study, PCL nanoparticles were prepared as carriers of both nilotinib (Nil) and mesylate (IM) as a therapeutic agent against chronic myeloid leukemia. High encapsulation efficiency was obtained for both drugs, 55% for Nil and 95% for IM. Moreover, the IC50 for both drugs on leukemia cells was reduced compared with free drugs, while the constant release of the drugs leads to an extensive effectiveness time. In addition, the obtained nanoparticles showed more therapeutic efficiency at a lower dose by maximizing the cytotoxicity and minimizing the chances of cell resistance to drugs [54]. ESD have several advantages: particles produced with this method usually possess a narrow size distribution, while the drug retains high encapsulation efficiency. In addition, it is not energy-consuming and reproducible. However, the need to remove a high water volume from the suspension can be considered as a disadvantage. Plus, in the case of hydrophilic drugs, this can cause a leakage into the saturated aqueous external phase and reduce the encapsulation efficiency. For this reason, ESD is considered suitable for hydrophobic drugs [50, 51, 55].

2.3

Simple emulsion evaporation

Opposing to ESD, simple emulsion evaporation (SEE) does not require water excess as a dilution solvent. This method, first developed by Vanderhoff et al. [22], does require an organic phase and an aqueous phase. SEE involve two steps: The first is the emulsification of one phase into the other. The second step is the evaporation of the solvent in which the polymer is dissolved, which leads to the precipitation of the polymer in the form of particle. This method can produce oil-in-water (o/w) emulsion or water-in-oil (w/o) emulsion to encapsulate hydrophobic and hydrophilic drugs, respectively. In principle the polymer and drug must be dissolved in the phase that is destined to be evaporated, while the other phase should contain a stabilizer. SEE uses high-speed homogenization or ultrasonication, and the evaporation can be done by simple stirring at room temperature or at high temperature and low-pressure conditions [56, 57]. Similar to ESD the properties of particles made by SEE can be affected by the variation of the experimental parameters. Paclitaxel-loaded PLGA nanoparticles were prepared by SEE with various experimental parameters. It was found that the diameter of the particles can be affected by various factors such as drug concentration, aqueous-/organic-phase volume ratio, initial concentration of the polymer, sonication time, and the stabilizer concentration [58]. In another study, oxytocin-loaded PLA-PEG nanoparticles were prepared by SEE. Equally, it was found that the same parameters could affect the properties of the particles, in addition to the nature surfactant, the presence of a viscosifying agent, and the time of sonication. Using SEE, particles with a size of 200 nm were obtained and with a drug loading of 3.3% [59]. The use of polymeric nanoparticles prepared by SEE for cancer chemotherapy was investigated before. Paclitaxelloaded PLGA nanoparticles were synthetized, and their activity in vitro was compared with other commercial products (Taxol and Cremophor EL) [60]. It was found that loaded particles were more cytotoxic on HeLa cells than Taxol, while in contrast to Cremophor, no cytotoxicity of the polymer was observed. In addition, Paclitaxel-loaded nanoparticles exhibited an inconspicuous antitumor efficacy and enhanced survival rates, providing once again the viability of using polymeric nanoparticles as drug carriers [60].

2.4

Double emulsion evaporation

Although SEE can be used for the encapsulation of hydrophilic drugs, the drug loading using this method is often very low. Therefore another approach must be adapted for the encapsulation of such drugs. This can be solved by using double emulsion evaporation (DEE) method [61]. It is constituted of two-step emulsifications in which the first results in a W/O emulsion by dispersing and aqueous phase in a nonmiscible organic solvent under high shear homogenization or low power sonication. The second step is dispersing the obtained W/O emulsion in another aqueous phase containing a hydrophilic emulsifier under homogenization or sonication. However, when using sonication, it must be at low power and short time in order not to break the first emulsion. This allows the obtaining of a water-in-oil-in-water (W/O/W) double emulsion [62].

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Finally an evaporation of organic solvent step is done at room temperature or by rotary evaporator. It is also possible to obtain different combinations of double emulsions such as W/O/O or O/W/O [22]. The experimental parameters in this method such as drug concentration, stabilizer concentration, polymer concentration, and volume ratios of the different phases can govern the colloidal properties and drug loading and release behavior of the particles. Insulin-loaded PLGA nanoparticles were prepared by DEE method. It was found that the size of the particles increases by increasing the initial drug concentration while the surface charge stayed constant. On the other hand, increasing the stabilizer concentration leads to a decrease in particle size, while the absence of a stabilizer increases drug loading. In addition, it was found in this study that homogenization is more suitable than sonication. Finally, loaded particles showed a controlled release for 168 h in both in vitro and in vivo cases [63]. PLGA nanoparticles were used in another study to encapsulate daunorubicin in an attempt to overcome drug resistance. Particles were prepared with DEE and had a spherical shape, a size of 140 nm, and a zeta potential of
25 mV. The total drug content of the drug was 2.8% mass, and the inclusion rate was 73.1%. The cytotoxicity of these particles was proven in vitro against human erythroblastic leukemia К562 cells and human breast adenocarcinoma MCF-7 cells. It was found that the cytotoxicity of the particles against the resistant cell lines is higher than that of the free drug. Loaded particles were 1.14 times more efficient than the free drug. These particles were able to inhibit the tumor growth while decreasing the nonspecific toxicity of the drug [64]. This method has the advantage of encapsulating both hydrophobic and hydrophilic drugs. However, some details can be considered as drawbacks. First the fact that it is a two emulsification step process makes it relatively time-consuming and difficult to scale-up. In addition, the use of high shear homogenization can damage the used biomolecule and cause a reduction in activity [65].

2.5

Spray-drying

Spray-drying, a relatively simple and continuous processing technique, has been used for decades to encapsulate volatile compounds into micro- and nanoparticles [66, 67]. This method consists of atomizing a polymer containing drug solution with a nozzle in a chamber supplied with hot air, which evaporates the solvent instantaneously due to the enormous surface area between droplets and the drying gas. The polymer precipitates subsequently and leads to the encapsulation of the drug within the resulted particulate carriers [68]. Spray-drying is commonly used for the encapsulation of heat-sensitive ingredients, such as essential oil [69, 70], enzymes [71], and flavors [72], due to the short time of contact between hot air and raw material; generally the evaporation occurs between 15 and 30 s and takes place at the surface of the particle; thus the materials never reach the inlet temperature of drying gas [73]. Vegetable oils have also been encapsulated by this technique [74]. To achieve high encapsulation efficiency and desirable particle size, several parameters should be optimized like the spray rate and mechanism; the composition of the feeding solution [75]; and the drying air temperature, rate, and humidity [76]. Among the several biodegradable polymers, PLA [77, 78], PLGA [79, 80], PCL [81, 82], and chitosan [83, 84] are widely used. Table 1 illustrates some examples of the application of spray-drying process.

2.6

Supercritical fluid technology

The main drawback of the spray-drying technique is the development of coarse particles with broad particle size distribution, which is crucial in determining the bioavailability of pharmaceuticals presented in a solid formulation, and the possible degradation of the product due to mechanical or thermal stresses [85, 86]. The supercritical fluid-based process has gained great attention since 1990 to solve the mentioned problems [87, 88]. This process uses supercritical fluids as alternative media for organic solvents and toxic substances. A fluid is in its supercritical state, when its pressure and temperature exceed their respective critical value (Tc, critical temperature, and Pc, critical pressure) [89]. A supercritical fluid has liquid-like densities with gas-like transport characteristics and moderate solvent power, which can be modulated by changing the pressure and the temperature [90]. Among the several gases used as critical fluids, carbon dioxide (CO2) has paid great attention due to its low critical point (31.3°C, 7.4 MPa), nontoxicity, nonflammability, and low price. Additionally, it is suitable for heat-sensitive materials, and it has generally recognized as safe (GRAS) status [90, 91]. Different supercritical processes have been developed depending on the role of CO2 that may act as a solvent, antisolvent, or a molecular mobility enhancer [85]. Supercritical antisolvent technique (SAS) and rapid expansion of supercritical solution technique (RESS) are among the most investigated processes that involve precipitation processes in supercritical solutions [92]. In the SAS process the drug and the polymer are dissolved in a liquid solvent, and a supercritical antisolvent is added to the solution in a closed chamber at

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ambient pressure. Decreasing the solubility of the solute with increasing the volume of the antisolvent in the mixture results in the precipitation of the drug particles within the polymer matrix [89, 93], while in the RESS process the solute is dissolved in a supercritical CO2 in a high-pressure chamber, and then the solution passes through a small nozzle into a region of lower pressure leading to the precipitation of the drug and the polymer [94]. The influence of operating conditions, like nozzle geometry, pressure, and temperature of supercritical fluid, preexpansion temperature, and pressure and flow rate of drug-polymer solution on the particle size and morphology, has been already investigated [95, 96]. Low polymer amount, small length/diameter ratio for the nozzle, low preexpansion temperature, and high preexpansion pressure promote the formation of particles instead of fibers [92]. Supercritical fluid technology is widely used to encapsulate natural and synthetic compounds, and Table 1 shows some examples of their applications.

2.7

Ionic gelation

Among the variety of hydrophilic polymers, chitosan is widely used to develop nanoparticles due to its crucial characteristics such as mucoadhesivity, nontoxicity, and biocompatibility. Ionic gelation or coacervation has been developed by Calvo and coworkers to prepare chitosan based-nanoparticles [97]. It is based on the transition from liquid state to gel state upon complexation between the negatively charged tripolyphosphate with the positively charged amino group of chitosan at determined pH values to form nanosized coacervates [98–100]. This ionic interaction is a metastable thermodynamic system highly sensitive to variations in ionic strength. Thus various operating conditions should be optimized like the rate of addition of tripolyphosphate, the time of a complete reaction, and the mixing rate [101]. Nanoparticles based on other types of hydrophilic polymers like gelatin and sodium alginate were already been developed by this technique. Table 1 shows some recent uses of ionic gelation method.

3 Surface modification of nanocarriers Nanocarriers can be used for the delivery of therapeutic agents. To use nanoparticles for therapeutic application, it is necessary to identify the interaction and uptake of nanoparticles by the membrane cells. To facilitate the interaction of the nanoparticles inside the cells, it is necessary to make changes at the surface of the nanoparticles themselves [116]. These surface changes consist of the adsorption of biomolecules, such as protein, in a biological environment on the nanocarrier surface. The cellular response depends on the adsorbed biomolecule layer [117]. Actually, great attention to the functionalized nanoparticle systems that could be used for therapeutic and/or diagnostic purposes is given. Among the numerous classes of materials used for nanocarriers fabrication, polymers have attracted great interest due to their easy functionalization. For all these reasons, we can conclude that engineered polymer-based nanocarriers could represent an efficient system for the diagnosis and treatment of many diseases [118]. The following is a brief description of the main surface modification of nanocarriers. Fig. 1 illustrates different types of nanoparticle surface modification.

FIG. 1 Surface modification of polymeric nanoparticles.

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Pegylation

PEGylation is defined as the covalent attachment of polyethylene glycol (PEG) chains to bioactive substances [119]; it is the coating of a particle surface by the covalently grafting, entrapping, or adsorbing of hydrophilic and flexible PEG chains. Actually, it is the most commonly used method to confer stealth property to nanocarriers, that is, the ability to avoid uptake by the reticuloendothelial system (RES), thus resulting in an increase of biocompatibility and blood circulation half-life [120, 121]. There are linear PEG chains with different molecular weight (1500–5000, 20,000 Da). PEG-based diblock copolymers are used to make polymeric micelles and nanoparticles [121]. There are different strategies to immobilize PEG on polymer-based nanocontainers: covalent and noncovalent approaches are used. The most common noncovalent approach used is coating the hydrophobic nanoparticles surface with lipid-PEG conjugates. For gold nanoparticles, thiol binding is the classic approach [122]. In a research work of Sheth et al., polylactic acid (PLA) and polyethylene glycol (PEG) were melt-blended and extruded into films [123]. Stolnik et al. demonstrated that poly(lactide)-poly(ethylene glycol) (PLA/PEG) copolymers can be used as coating for poly (lactic-co-glycolic acid) (PLGA) nanospheres prepared by precipitation-solvent evaporation method. The obtained nanospheres have longer blood circulation time and a reduction of hepatic uptake compared with naked PLGA nanospheres [124]. Cosco et al. encapsulated 9-cis-retinoic acid (9-cis-RA) in PEG-coated PLGA nanoparticles to improve both its stability and effectiveness in anticancer therapy. Nanoparticles were prepared by nanoprecipitation technique; to obtain PEGylated nanoparticles, PEG was added to the organic phase [125]. In another research work, Cosco et al. formulated PEGylated PLA nanocapsules containing gemcitabine hydrochloride for anticancer therapy. PLA nanocapsules were prepared using modified double emulsion method, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt) (DSPE-mPEG2000) was dispersed in the polymeric organic solution to promote the integration of the phospholipid anchors in the polymeric shell of nanoparticles. The obtained PEGylated nanocapsules demonstrated a stronger anticancer activity compared with the free drug on different cancer cell lines [126].

3.2

Antibodies

Antibodies are commonly used as recognition elements for diagnostic and therapeutic. Each antibody has two basic parts: the fragment antigen-binding (Fab) region that recognizes the antigen and fragment constant (Fc) that can be used for conjugation without disrupting the recognition process. Conjugation of antibodies or Fab fragments to nanoparticles is an effective method to functionalize their surface [126]. Diels-Alder reactions were also used effectively to combine antibodies to polymeric nanoparticles [127].

3.3

Aptamer

A new emerging strategy for biorecognition is represented by short, single-stranded oligonucleotides (ssDNA or ssRNA), known as aptamers. They are sometimes called chemical antibodies even if their structure and properties are very different from that of antibodies [128]. Farokhzad et al. synthesized poly(lactic acid)-block-polyethylene glycol (PEG) copolymer with a terminal carboxylic acid functional group (PLA-PEG-COOH) for covalent conjugation to amine-modified aptamers. The in vitro study showed that such nanoparticles can be efficient against prostate cancer cells as vehicles for chemotherapeutic drugs [129]. Moreover, Dhar and his coworkers synthesized aptamer-functionalized pt(IV) prodrug-PLGA-PEG nanoparticles. The 50 amino groups of the aptamer were conjugated to the carboxylate groups of the nanoparticle surface using an amide coupling reagent [130].

3.4

Peptides

Peptides are small molecules composed of amino acids. They can be used to functionalize nanoparticles due to the possibility of a rational choice of the amino acid sequence [131]. Zeng et al. used inverse microemulsion polymerization coupled with a modified hydrophilic peptide imprint molecule to synthesize nanoparticles with surface binding sites for hydrophilic peptides [132].

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Enzymes

Different techniques to immobilize the enzymes on the nanocarrier surface are used: adsorption, covalent binding, encapsulation, entrapment, and cross-linking [133]. Eldin et al. used glutaraldehyde as a coupling agent for the immobilization of b galactosidase on polymeric nanospheres [134]. Urrutia et al. used chitosan partially functionalized with aldehyde groups for the immobilization of b-galactosidase by two-step methods [135]. For the synthesis of enzymatic biosensors, covalent coupling of enzymes to polymeric supports is used [136].

3.6

Small molecules

Small molecules, such as FA (vitamin B9), biotin (vitamin B7), and glycyrrhizin, have also been used for nanocarrier surface modification [136]. Sucrose and a cholic acid have been covalently linked to PLGA to obtain polymeric modified nanoparticles. The results of this work showed that the obtained nanoparticles can be used in cancer therapy due to the targeting function of sucrose [137]. Gu et al. developed a micellar system in which folic acid was attached to the doxorubicin-conjugated poly(ethylene glycol)-poly(e-caprolactone) by a hydrazone linker (FA-PEG-PCL-hyd-DOX) or by a carbamate linker (FA-PEG-PCL-cbm-DOX). They found that the obtained system is able to escape from endo-/ lysosomes and to prolong blood circulation time of the drug that accumulates at the level of the tumors rather than normal tissue [138].

4 Drug delivery and targeting Drug delivery can be defined as a method for introducing drugs into the body. Drug delivery systems (DDS) overcome all the problems related to conventional drug administration: controlled DDS transports the drug in the site of action allowing to decrease the dose of drug necessary to have the therapeutic benefits, thus reducing side effects and improving the pharmacological and therapeutic properties. Nanocarriers with different compositions and biological properties, thanks to their small size (about 100 nm), represent an excellent drug delivery system. They are extensively studied for biomedical application because they are easily taken up by cells compared with larger molecules [139]. Polymeric nanoparticles are one of the most used DDS due to the possibility to obtain them by biocompatible and biodegradable polymers, that is, poly(L-lactide) (PLA) [140] and polyglycolide (PGA) [141]; they are hydrolyzed in the body into biodegradable metabolite monomers, such as lactic acid and glycolic acid [139]. Furthermore, polymeric nanoparticles increase the water solubility of hydrophobic drugs, prolong blood circulation of the drug, and reduce or eliminate fast renal excretion [142]. Paclitaxel is a drug with anticancer properties; to solve the problem related to its administration (toxicity and low solubility in water), Kim et al. developed Genexol-PM, a paclitaxel-containing biodegradable polymeric micellar system. The polymer used was monomethoxy poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA). This new micellar system showed a great advantage compared with chemotherapy with Taxol against ovarian cancer cell line (OVCAR3) and human breast cancer cell line (MCF7) [143]. Shah et al. prepared new copolymeric nanocontainers based on chemical coupling of poly(3-hydroxybutyrate-co-3hydroxyvalerate) P(3HB-co-3HV) or poly(3-hydroxybutyrate-co-4-hydroxybutyrate) P(3HB-co-4HB) to monomethoxy poly(ethylene glycol) (mPEG) through transesterification reaction. They demonstrated that these biodegradable and biocompatible nanocontainers can be used as safe DDS for hydrophobic drugs [144]. Khuroo et al. synthesized tamoxifen-/topotecan-loaded poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles for the treatment of breast cancer. This system allowed to obtain synergism between the two drugs in the treatment of the breast cancer and a reduction of the side effects [145]. Appropriate changes to carriers allow to obtain cell-specific targeting. Drug targeting is the delivery of drug exclusively to the specific cells or cellular components: this is due to a particular mechanism of recognition between drug carriers and specific receptors at the cell surface [146]. We must distinguish two different types of targeting: passive and active drug targeting. Passive targeting is the accumulation of the drug or drug carrier system in a specific site due to physicochemical or pharmacological factors, while active targeting is due to a specific interaction between the delivery system and specific cell component or tissue [147]. Passive targeting is particularly important in anticancer therapy; thanks to the so-called enhanced permeability and retention (EPR) effect in particular pathological conditions, such as inflammation or tumor, the blood vessels become more permeable than in the normal state: in these cases, large molecules and particles ranging from 10 to 500 nm in size, such as polymeric carriers loaded with drug, can release and accumulate the therapeutic agent inside the tumor interstitial space [148].

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Active targeting of nanocarriers is based on the interaction between a receptor and its specific ligand [149]; it can be obtained by functionalizing the polymeric nanoparticles with specific ligands. Zhang et al. prepared doxorubicin-loaded glycyrrhetinic acid-modified alginate nanoparticles (DOX/GA-ALG NPs) for the treatment of liver cancer due to both the passive targeting (EPR) and the active targeting abilities of glycyrrhetinic acid. They used glycyrrhetinic acid to modify the nanoparticles surface and they obtained active targeting because of the abundant of GA receptors on hepatocytes. DOX/GA-ALG NPs caused tumor cell mortality and reduce systemic side effects compared with free DOX [150]. Gu et al. used three polymer blocks PLGA, PEG, and the A10 aptamer to prepare nanoparticles for specific prostate cancer cell targeting. In fact, A10 aptamer binds a specific antigen on the surface of prostate cancer cells [151]. Paclitaxel, one of the most used drugs for the treatment of endometrial cancer, was encapsulated in folate-decorated PLGA-PEG nanoparticles; folate receptor (FR) is overexpressed in endometrial cancer. The obtained system showed a stronger anticancer effect compared with the free drug [152]. Miao et al. used modified b-cyclodextrin to generate copolymer nanoparticles loaded with paclitaxel; integrin was conjugated to the surface for targeting delivery of paclitaxel to integrin-rich tumor cells [153]. SN-38, a highly potent topoisomerase I inhibitor, was encapsulated in PLGA-PEG hyaluronic acid (HA)-decorated nanoparticles for targeted therapy of ovarian cancer. Hyaluronic acid has high affinity and specificity for CD44 receptors, overexpressed in many cancer types [154].

5 Biodistribution of polymer nanoparticles Polymeric nanoparticles and nanocapsules are very effective in treatment of many diseases these days and characterized by ability to cross biological barriers and the release of the drug in the specified tissue or organ. Upon intravenous administration the nanoparticles and nanocapsules were distributed to the peripheral organs and tissues of human body. The main obstacle in reaching these organs is the rapid clearance of nanoparticles by mononuclear phagocytosis system (MPS) in the bloodstream, liver, and spleen. The plasma protein, opsonins, reacts and binds to the surface of the nanoparticles [155], resulting in activation of the MPS, followed by engulfing of nanoparticles by phagocytic cells in the bloodstream and transport it to the liver or spleen for degradation and excretion. Also, Kupffer cells in the liver capture many types of nanoparticles as well as red pulp macrophages in the spleen [122]. In addition, the nonspecific accumulation of nanoparticles in the liver results in hepatocytes, liver sinusoidal endothelial cells, B cells, and Kupffer cell activation [156, 157]. Therfore, the nanoparticles will be cleared within few minutes after intravenous administration. Expanding the nanoparticle blood circulation time (half-life) and increasing the specific organ accumulation are important factors to achieve high therapeutical success, but there are many factors that influence nanoparticle biodistribution and blood circulation half-life such as nanoparticle size, surface charge and chemistry, and targeting ligand functionalization. Many methods were designed to overcome polymeric nanoparticle and nanocapsule rapid clearance; from these methods, hiding or masking the nanoparticles from MPS by surface modification increases the circulation time in the bloodstream and enhances target-specific binding when antigen-ligand is conjugated to the cell surface. For example, coating nanoparticles with PEG and/or polysaccharides were used to overcome nanoparticle clearance. PEG is a hydrophilic polymer characterized with low toxicity and no immunogenicity that binds covalently or noncovalently to the surface of nanoparticles [158]. Polysaccharides, such as heparin, dextran, and chitosan, are also known by their low immunogenicity and excellent biodegradability [159]. PEG coating increases the nanoparticle blood circulation half-life from minutes to hours and improves therapeutic efficacy of drugs delivery, by reducing the plasma protein adsorption, opsonization, and nonspecific uptake [120, 158–160]. In addition, combination coating of PEG and polysaccharide avoids nanoparticle clearance and unspecific accumulation; for example, coating lipid-polymer hybrid nanoparticles with heparin and PEG increased the blood circulation half-life from 0.3 to 72.6 h and decreased nanoparticle accumulation in the liver [161]. In addition, coating the nanoparticles with hydrophilic molecules such as PEG provide neutral surface charge, which eliminate particle aggregation and avoid MPS [148]. Tumor cells have a negative surface charge compared with normal cells, and that would enhance the internalization of positively charged polymeric nanoparticles [162], but unfortunately the positively charged nanoparticles clear quickly in blood circulation and accumulate in the liver and spleen [120]. In addition, high negatively charged nanoparticles were opsonized and cleared by the Kupffer cells from the blood circulation [163], whereas nanoparticles with neutral or low negative surface charge will circulate longer in the blood [164]. The size of nanoparticles also is a very important factor in blood circulation clearance and organ targeting. The preferred particle diameter will vary definitely with the application; in fact the desired diameter of intravascular long circulating nanoparticles has been reported to be between 10 and 100 nm [165]. The nanoparticles that are less than 10 nm in size are cleared through the renal system [160], while particles larger than 100 nm accumulate unspecifically in the liver [166] and >200 nm accumulate in the spleen [167].

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Intravenous administration of nanoparticles tends to evenly disperse throughout the body. The tumor tissue is characterized by high vascular permeability and impaired lymphatic drainage, allowing the accumulation of large nanoparticles through EPR effect [168]. In passive targeting, regardless of EPR effect, 95% of nanoparticles don’t reach the tumor area and accumulate in different organs particularly the liver, spleen, and lungs [169]. On the other hand, active targeting is used to describe specific interactions between a drug and a targeted cell, especially through specific ligand–receptor interactions, which can happen only when the two components are in close proximity (< 0.5 nm) [170–172]. Thus, in active targeting, nanoparticles can target a specific tissue or organ. However, these carriers were not able to guide themselves to the target. In fact, they reach the target cell consequently to the extravasation followed by intratumoral retention and distribution. Indeed, the expression “active targeting” means a specific “ligand–receptor interaction” and occurs only after blood circulation and extravasation. Thus increasing blood circulation and improving EPR effect would enhance the delivery of these nanoparticles to the tumor [169]. Successful biodistribution of polymeric nanoparticles to target tissue or organ requires specific consideration of the nanoparticle characteristics, such as size, PEGylation, surface charge, and functionalization for active targeting. PEGylated nanoparticles with sizes between 10 and 100 nm and neutral or low negative charges avoid MPS, liver, spleen, and kidney clearance; increase blood circulation for hours; and enhance the nanoparticle entry into the tumor by a passive targeting mechanism. In addition, functionalization of nanoparticles with active targeting increased the efficacy of the nanoparticles and accumulation in specific tissue under EPR effect.

6 Conclusion Nanotechnology opens the gate for many scenarios concerning various fatal diseases, such as early detection, diagnosis, and personalized treatments. Due to their size and shape, they were an interesting field of research during the last decades. Their small size allows them to cross many natural barriers, which revolutionize the treatment of many diseases. The use of nanoparticles enhances the therapeutic profile of encapsulated drug in vivo and in vitro and provides a better targeting strategy by interacting with various biomolecules on the surface and inside the cells. However, to obtain the optimal nanoparticles for each situation, the choice of the suitable preparation method is crucial.

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