Multistimuli-responsive magnetic assemblies

Multistimuli-responsive magnetic assemblies

6

Abdulhadi Baykal*, Ayhan Bozkurt*, Ravindran Jeremy*, Sarah Mousa Maadi Asiri*, Michele K. Lima-Tenório†, Chariya Kaewsaneha‡,§, Abdelhamid Elaissari‡ *Institute for Research and Medical Consultations (IRMC), University of Dammam, Dammam, Saudi Arabia, †Department of Chemistry, State University of Ponta Grossa, Ponta Grossa, Paraná, Brazil, ‡Univ Lyon, University Claude Bernard Lyon-1, CNRS, LAGEPUMR 5007, Lyon, France, §School of Bio-Chemical Engineering and Technology, Sirindhorn International Institute of Technology (SIIT), Thammasat University, Pathum Thani, Thailand

6.1 Introduction The development of nanotechnology especially in the field of biomedical nanotechnology brings a revolution in medical discipline for solving many health related problems. Among them are polymer-based nanoparticles, which are very interesting for use as nanocarriers for drug delivery due to their ability to delivery drugs in a specific site reducing the side effects, therapeutics. A broad range of polymeric nanocarriers with diverse sizes, architectures, and surface properties have been designed due to recent developments in synthetic methods. These include micelles, liposomes, dendrimers, nanogel, and polymer nanoparticles. Many polymers, including synthetic and biopolymers, for example, poly (vinyl alcohol), poly(acrylic acid), poly(dimethylsiloxane), poly(N-isopropylacrylamide), polylacticacid, poly(acrylic acid-g-vinylidene fluoride), poly-d,l-lactide-co-glycolide, chitosan, dextran, etc., have been proposed as drug delivery nanocarriers [1–4]. Among them, polymers respond to external stimuli offer a very exciting field of research due to the fact that their properties (viscoelasticity, transparency, conductivity, etc.) can be controlled by modifying the structure and organization of the polymer chains. The stimuli-responsive polymers are unique because these mimic in part the natural systems which respond to various environments within the living system. This characteristic makes these smart polymers important agents for drug delivery systems, among other applications. The recent progress in the synthetic stimuli-responsive polymeric nanocarriers has been discussed with focus on pH-responsive, photoresponsive, and thermo-responsive polymers [5–10]. In the preparation of stimuli-responsive polymeric nanocarriers for therapeutics applications, an important step is the selection of an appropriate stimuli-responsive polymer material according to the final applications including site and mode of administration. Next is the selection of an encapsulation method for the encapsulation of therapeutic agents. Several effective methods such as nanoprecipitation, multiple emulsion method, emulsion evaporation method, layerby-layer method, and polymerization-based method has been frequently applied for encapsulation of numerous active drugs ingredients [11–14]. Various properties, such Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications. https://doi.org/10.1016/B978-0-08-101995-5.00006-4 Copyright © 2019 Elsevier Ltd. All rights reserved.

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

as formulation, particle size, permeability, and sustained release may be turned to suit specific needs. It remains a challenge to address these needs comprehensively, so a versatile strategy is of great interest. For instance, polymer respond to pH alone are unlikely to find widespread medical use owing to the difficulties in making changes in local pH in vivo. The development of systems that can respond to several external stimuli in an intelligent way is challenge for scientists. The recent progress in the synthesis of smart nanocarriers for drug delivery applications significantly realize to the dual- or multiresponsive properties [15–19]. For example, assembling of superparamagnetic iron oxide nanoparticles (SPIONs) and pH-responsive polymer, there is possibility to obtain multisensitive nanocarriers that can respond to external magnetic field and the change of pH at the same time. Under this condition, drug-targeting carrier-based-­ SPIONs can be conducted to the site of the target cell or tissue directly by applying an external magnetic field, leading to decreased circulation time, decreased the required dosage of drug, and thereby reducing side effects. SPIONs have been applied into many different fields including the biomedical field. The superparamagnetic nanoparticles have gained wide acceptance in nanomedicine for theranostic (therapy and diagnosis) applications [20,21]. They can be used to deliver and concentrated the therapeutic agents in a specific area due to their unique properties (superparamagnetic). Their intrinsic magnetic properties enable them to be used as contrast agent in magnetic resonance imaging (MRI) and generate heat for cancer treatment (hyperthermal therapy). Therefore, the design nanocarriers having multistimuli-responsive properties for drug delivery, the combination of ­stimuli-responsive polymers with superparamagnetic nanomaterials is one of an alternative strategy to create such nanocarriers. This chapter is devoted to the recent developments of multistimuli-responsive polymeric nanocarriers having magnetic-based property from proof-of-concept research stage, synthesis to practical used in drug delivery applications. Furthermore, their interested properties and their potential applications in the biomedical domain are also discussed. The commonly explored routes, pioneering works, and recent published articles on these interesting particles are discussed in details.

6.2 Multistimuli-responsive polymeric nanoparticles 6.2.1 Stimuli-responsive polymers The capability of smart polymeric macromolecules to respond to external stimuli, such as pH, temperature, electricity, light intensity, moisture, and redox, has gained interest targeting for drug delivery. The acquisition effect of drug encapsulation and other specific responsive functional moieties into polymeric materials and the respective properties changes in terms of physical and chemical and dimension prospective are attractive features for specific therapeutic approaches. In current scenario, combination of responsive polymers with multi stimulus has generated lot of interest and scope.

Multistimuli-responsive magnetic assemblies157

Smart polymer derived from poly(2-vinyl-4,4-dimethylazlatone) (PVDMA) was synthesized through one-step modification after polymerization [22]. The well-structured polymer was reported to be multi stimulus (pH, thermo, and electrolyte responsive). The homopolymers were prepared by reacting diamine cross linkers with primary or secondary amines (N,N-diethylethylenediamine, N,N-dimethylethylenediamine, 3-morpholinopropylamine, morpholine, and tetrahydrofurfurylamine in aqueous solution) (Fig. 6.1). At ambient temperature, swelling behavior was observed based on the pH stimuli, while swelling ratio tuned with three functional amines (N,N-diethylethylenediamine, N,N-dimethylethylenediamine, and 3-morpholinopropylamine) shows the thermo-­ responsive property. The salt sodium sulfate responsive property is exhibited with 3-morpholinopropylamine functionalized hydrogels. Multistimuli responsive smart biomacromolecules for resilin type of designed protein polymers (An16-resilin) were reported. The biomimetic proteins were like the resilin gene present in Anopheles gambiae mosquito. The disoriented protein was proven to exhibit biphase heat-based transition property with stimuli responses to light, pH, humidity, and ion [23].

6.2.2 Multistimuli-responsive polymeric nanoparticles for drug delivery The effect of designing pH/redox/photo sensitive polymeric template was reported for dual application of imaging and targeted drug delivery [24]. The polymeric micelle (PC-SPMA) responsive to acidic and higher redox environments due to the

Fig. 6.1  Conditions employed for the preparation of the modified PVDMA hydrogels and organogels by sequential reaction with various cross-linkers followed by reaction with different small molecule primary and secondary amines at ambient temperature [22].

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

pH-responsive boronate ester and DTT-responsive disulfide bonds for triggered drug release, respectively. The PC-SPMA was synthesized using cross-linked polymerization between phenylboronic acid-conjugated pluronic (Plu-SS-BA) and lactose-modified chitosan (chitlac, Ch). The conjugation of spiropyran/boronic acid conjugated poly (dimethylamino ethyl methacrylate-co-methacrylic acid) (S-PMA) into cross-linked polymerization leads to the effective encapsulation and carrier of hydrophobic Taxol drug into intracellular environment. Drug-loaded micelles showed an ability to release the drug in response to mildly acidic and higher-DTT conditions (Fig. 6.2), where the boronate ester between Plu-SS-BA and Chitlac is cleaved leading to the controlled release of drug. The facile biodegradation was reported to occur through breaking down of disulfide linkage, which also triggers the drug. The analysis of designed micelles before and after drug Taxol loading was studied using dynamic laser light scattering. The drug loading and delivery pattern had been evaluated using dynamic light scattering technique. In the presence of mild acidic pH 5.0 and 10 mM DDT, the particle size of micelles decreased which were attributed to breaking of boronic ester bonds, while at higher DTT, the redox stimuli disulfide bonds cleaved, respectively. Fig.  6.3 showed in  vitro study drug-release patterns of polymer micelles at pH 7.4, pH 5.0, 10 mM DTT, and pH 5.0/10 mM DTT conditions. The release rates were at about 20%, 70%, and 80% for pH 7.4, 10 mM DTT and pH 5.0 conditions, respectively, due to the higher number of disulfide bonds that were cleaved in the presence of a high concentration of DTT with pH 5.0. As a result maximum amount of drug was released from pH 5.0 and 10 mM DTT combined condition. In the same fashion, the designing of multifunctional nanocomposite of ­meso-2,3-dimercaptosuccinic acid (DMSA) coated iron oxide and anticancer drug DOX-encapsulated (Fe3O4@DMSA/DOX) were reported for pH and photothermal [near-infrared (NIR) light] stimuli application along with DOX delivery for cancer therapy [25]. Results from in vitro study showed that combinational therapy was effective for targeting sub cellular level drug penetration and cause cell death through mitochondrial disruption into human breast cancer MDA-MB-231 cells and exert temperature elevation effect with NIR light environment. Recently, the multistimuli-responsive biohybrid nanoparticles were reported for pH and temperature stimuli along with the ability of intracellular drug delivery [26]. The polymer-protein biodynamer was prepared by conjugating the ­tailor-made aliphatic aldehyde-functionalized poly(di(ethylene glycol)ethyl ether acrylate-co-poly(ethylene glycol) methyl ether acrylate) [P(DEGA-co-PEGA)] copolymer to hydrazine-modified bovine serum albumin (BSA-HyNic) using reversible pyridylhydrazone formation (Fig.  6.4A). The aldehyde-functionalized thermoresponsive copolymer P(DEGA-co-PEGA) (CP-CHO) with average molecular weight of 14.4 kDA was synthesized by reversible addition-­fragmentation chain transfer (RAFT) copolymerization of di(ethylene glycol)ethyl ether acrylate (DEGA) and poly(ethylene glycol) methyl ether acrylate (PEGA) in the presence of the aldehyde-functionalized RAFT agent (DMP-CHO). The BSAHyNiC-modified protein was carried out through linking in phosphate-buffered

HO

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Fig. 6.2  Schematic presentation of Taxol loading on PC-SPMA micelles and Taxol release under different conditions [24].

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Multistimuli-responsive magnetic assemblies159

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications 140 DTT/pH 5.0 pH 5.0 10 mM DTT pH 7.4

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Fig. 6.3  In vitro drug-release patterns of PC-SPMA/Taxol at pH 7.4, pH 5.0, in the presence of 10 mM DTT, and pH 5.0/10 mM DTT [24].

saline (PBS) solution pH 8.0 with following hydrazine cleavage in MES buffer at slightly acidic at pH 4. Followingly, thermoresponsive biodynamer (CP-phzBSA) occurs through bioconjugation step occurs between aldehyde-functionalized P(DEGA-co-PEGA) copolymer (CP-CHO) and BSA-HyNiC in PBS solution at slightly neutral pH condition of 7.4. The biodynamer self-assembled into spherical micelles at a temperature above its lower critical solution temperature (LCST). Subsequently, BSA molecules within the hydrophilic coronae of the micelles were readily cross-linked via reaction with cystamine at 45°C, and multistimuli-­ responsive nanoparticles were generated (Fig.  6.4B). The biohybrid nanoparticles reversibly swelled and shrank as the cores of the nanoparticles were solvated below the LCST and desolvated above the LCST. The accessible reversibility of the pyridylhydrazone bonds imparts pH-responsive and dynamic characteristics to the nanoparticles. The size of biohybrid nanoparticles gradually decreased in an intracellular-­ mimicking acidic milieu (pH 5.0) because of the hydrolysis of pyridylhydrazone bonds. In the presence of 10 mM glutathione responsiveness, the reductive cleavage of the disulfide bridges triggered the dissociation of nanoparticles. In the same way, in the presence of trypsin or a-chymotrypsin, protease-­mediated hydrolysis of BSA polypeptide chains triggered a rapid dissociation of the biohybrid nanoparticles. Results from in vitro cytotoxicity and cellular uptake showed that these biohybrid nanoparticles were highly biocompatible and effectively internalized by HepG2 cells. Furthermore, dual drugs [doxorubicin (Dox) and curcumin (Cur)] release patterns from pH-responsive nanoparticles of poly β-amino ester-based copolymer were studied [27]. The dual drugs encapsulation was found to be homogeneously

Multistimuli-responsive magnetic assemblies161

Fig. 6.4  Outline for the synthesis of aldehyde-functionalized P(DEGA-co-PEGA) copolymer (CP-CHO), and the bioconjugation of the copolymer to hydrazine-modified BSA (BSA-HyNic) through pyridylhydrazone linkage (A) and the formation of multistimuli responsive biohybrid nanoparticles (B) [26].

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications 20 Intensity (percent)

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Fig. 6.5  Particle size dispersion using DLS and TEM (scale bar of 200 nm) (A), variation in particle size with pH stimuli (B) and in vitro drug release of Dox and Cur (C and D). In vivo antitumor effect in SMMC 7721 tumor-bearing mice (E–H), tumor progression as a function of time (E), body weight as a function of time (F), tumor weight at the end of the experiment (G), and picture of excised tumors at the end of the experiment (H). Data were presented as mean ± SD (n = 5). Statistical significance between groups: VS saline control group *P < .05, free D + C VS D + C/NPs #P < .05 [27].

Multistimuli-responsive magnetic assemblies163

dispersed with narrow particle size about 100 nm (Fig. 6.5A). Under the pH condition of physiological (7.4) and tumor condition (5.8), an increase in particle size was observed along controlled release with pH stimuli (Fig. 6.5B). In vitro study, the percentage of Dox and Cur release was estimated to be 59.37% and 66.63%, respectively, over 192 h release study (Fig.  6.5C and D). The presence of drugs with pro apoptotic (Dox) and antiangiogenic (Cur) properties were reported to be efficient in inhibiting malignant neoplasm of liver cancer. So, inhibiting of tumor cells (SMMC 7712) in vivo study of free drugs and nanoparticle encapsulated Dox and Cur was studied over tumor with mean tumor volume of 8737 mm3 grown in saline for 14 days (Fig. 6.5E–H). After treatment of free drug combination, the tumor size reduction (5686 mm3) was found to be ineffective with inhibition rate of 32.6%, while nanoparticle encapsulated drugs showed significantly higher inhibition rate of 73.37% (Fig.  6.5E–H). Furthermore, the body weight loss was also found to be minimal compared to control group, which indicates the less cytotoxicity effect induced by synergetic presence of Dox and Cur. The stimuli response to pH, drug delivery, and fluorescent are studied using ­chitosan-PEG linked N-octyl-N′-(2-carboxyl-cyclohexamethenyl) polymer grafted with folic acid (FA; 5.1%) and thiazole orange (TO; 0.216%), respectively [28]. The drug release study was performed using 5-fluorouracil with drug encapsulation efficiency of 42.76% for 10 mg/mL. The exceptional pH sensitive drug release was shown at two pH condition (4.0 and 7.4). The drug encapsulation was stable at pH 7.4, while drug release up to 95% was observed during the 4 h study. Table 6.1 shows summary of multiresponsive nanoparticles involving various encapsulations and administration routes.

6.3 Magnetic nanocarriers 6.3.1 Magnetic nanoparticles in drug delivery The advances on biomedical nanotechnology have offered a variety of opportunities to fight against many diseases. Drug and gene delivery, protein and peptide delivery, and recent advancements of theranostics are the important subfields along with other applications. Among them, drug delivery systems have been extensively explored and are very promising, especially due to their ability to delivery drugs in a specific site reducing the side effects. In the last decade, much efforts have been devoted on developing new strategies for cancer drug delivery, to improve the efficacy of chemotherapeutic treatment [29]. The main challenge is the design of therapy approaches able to address the tumor, and delivery the drug to the right place at the right time. Magnetic nanoparticles (MNPs) represent a promising platform for targeted delivery of anticancer drugs (doxorubicin, docetaxel, idarubicin, and paclitaxel). They can be used to deliver and concentrate the therapeutic agents in a specific area, by applying an external magnetic field (Fig. 6.6).

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Table 6.1  Summary of multiresponsive nanoparticles involving various encapsulations and administration routes Polymers

Type of carriers

Drugs

Finding

References

The micelles exhibited high capacity to entrap Taxol and control the release of the drug under different physiological conditions (pH 5.0 and 10 mM DTT). Maximum amount of drug was released from pH 5.0 and 10 mM DTT combined condition The meso-2,3-dimercaptosuccinic acid coated Fe3O4 core-shell nanoparticles effectively carried doxorubicin drug penetrate to targeting sub cellular level. Cancer cells death caused by drug and exert temperature elevation effect with NIR light

[24]

Cross-linked spiropyran and phenylboronic acid-conjugated poly(dimethylamino ethyl methacrylate-co-methyl acrylic acid)

Micelles

pH, redox, fluorescent

Taxol

Meso-2,3dimercaptosuccinic acid

Core-shell

pH, photothermal

Doxorubicin

Aldehyde-functionalized poly(di(ethylene glycol) ethyl ether acrylate-copoly(ethylene glycol) methyl ether acrylate) conjugated hydrazine-modified bovine serum albumin

Corona cross-link nanoparticles

pH, temperature, enzyme

Bovine serum albumin

The dissociation of biohybrid nanoparticles (bonds cleavage) responded to pH 5.0, 10 mM glutathione responsiveness, and in the presence of trypsin or a-chymotrypsin, protease mediated. Results from in vitro cytotoxicity and cellular uptake showed that these nanoparticles were highly biocompatible and effectively internalized by HepG2 cells

[25]

[26]

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Stimuli

Nanoparticles

pH

Doxorubicin and curcumin

Chitosan-PEG linked N-octyl-N′-(2-carboxylcyclohexamethenyl) polymer grafted with folic acid and thiazole orange

Nanoparticles

pH, fluorescent

5-Fluorouracil

Both drugs released (~60%) with pH stimuli. After treatment of nanoparticles, the tumor size reduction was found to be effective with inhibition rate of 73.37% Drugs released up to 95% when changing pH from 7.4 to 4.0

[27]

[28]

Multistimuli-responsive magnetic assemblies165

d-α-Tocopheryl polyethylene glycol 1000-block-poly (βamino ester) copolymers

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Magnetic targeting

Administration of MNPs

MNPs circulating in the bloodstream

Concentration of MNPs under magnetic field

Fig. 6.6  Schematic representation of magnetic targeting.

Moreover, the external magnet can be used as trigger to control the drug release, oscillating or heating the nanocarrier. In case of polymer-based magnetic nanocarriers, the drugs can also be released either by degradation or by a condition-dependent manner (e.g., pH). If compared with healthy tissues, the extracellular pH of tumor tissues is slightly acid. The existence of acid-sensitive polymer combined with a magnetic nanocarrier assists the release of drug either in extracellular fluids or into the cancer cells reducing side effects caused by chemotherapy and also increasing the drug release efficiency [30]. Thus, a controlled drug delivery approach pH-responsive based on MNPs should increase the efficiency of the employed agents and protect healthy cells against side effects. The most commonly employed magnetic particles for drug delivery systems are the SPIONs [31]. However, when the SPIONs are not coated or stabilized, they are prone to aggregation and thereof may be trapped by the immune system. In this context, various coatings, such as dextran, starch, poly(ethylene glycol), poly(ethyleneimine), poly(vinyl alcohol), and poly(acrylic acid), can impart desired characteristics and also improve biocompatibility of the MNPs [32–34]. There are two ways to design MNPs for drug delivery: (i) the chemotherapeutic agent may be encapsulated within of the nanocarrier or (ii) the drug can be attached onto the surface of the MNPs, both providing protection to the drug until reach the target [35]. In the second approach, the MNPs can be modified with organic polymers or inorganic oxides to make them biocompatible with functional groups which can interact with the drug by chemical bonds or electrostatic forces. Polymer-based MNPs can additionally be functionalized with cancer specific antibodies or FA. This latter is a promising targeting ligand capable of attaching to cancer

Multistimuli-responsive magnetic assemblies167

cells since folate receptors are often overexpressed on the surface of many tumor types [36]. For example, hybrid nanoparticles with poly (lactide-co-glycolide) (PLGA) nanoparticle “core,” surface modified with folate-chitosan conjugate “shell” provided receptor-targeted drug (docetaxel) and SPIONs delivery for anticancer therapy and MRI, respectively. Furthermore, triggered drug release from nanoparticles at acidic pH was observed, since chitosan coating is pH sensitive [37,38]; those nanoparticles have also been investigated for the tumor-targeting ability of FA conjugated poly(ethyleneimine)-coated superparamagnetic iron oxide (FA-PEI-Fe3O4). The obtained results showed that the proposed magnetic carriers have great potential as an effective tumor-targeting agent and could be evaluated as a promising MRI contrast agent that specifically targets FA receptors overexpressing tumor cells. Table 6.2 lists some examples of MNPs-based drug delivery systems.

6.3.2 MNPs in theranostic application Nanotechnology has called the attention to the possible application of MNPs as multifunctional materials. For instance, MNPs have been investigated for diagnosis and therapy, and understanding of their properties and behavior has offered an opportunity to draw them closer. The main target is to render the MNPs a dual-purpose, by combining different active agents. The term “theranostics” was coined to define drugs and methods which are used for simultaneous diagnosis and therapy. Theranostics can be also defined as an integrated system by which is possible to diagnose, deliver targeted therapy, and monitor the response to therapy. As a result, theranostic nanomedicine has emerged as an important area of nanotechnology, with important contributions for the development of the next generation of drugs. One of the biggest challenges facing the medical research in our time is to treat patients with diseases that are the main cause of morbidity and mortality, because some of these require rapid diagnosis and long treatment duration. Moreover, the approaches usually used for treatment of these have considerable harmful side effects. Cancer is one of these diseases difficult to treat and, in many cases, the timely diagnosis and prognosis are difficult. By chance the earlier research on theranostics is mostly inclined toward oncology, once theranostic systems could save critical time for treatment of cancer, where the lapse between diagnosis and therapy is very important, as well as reduce related side effects of conventional methods of treatment by the controlled release of therapeutic agents at the specific site. A representative scheme of a nanoparticle to be applied for cancer theranostics is given in Fig. 6.7. As mentioned, the aim of theranostics is to prepare a nanoparticulate system with both imaging, targeting, and therapeutic agents, which can serve for simultaneous diagnosis (imaging) and therapy (drug release). The knowledge necessary for a successful obtaining of theranostic materials is wide and requires a solid understanding of detection and therapy mechanisms [46]. The physical properties of a theranostic approach must be stable under physiological conditions to carry the therapeutic molecules and to penetrate through any biological barriers to the target, while having no significant toxic side effects [47]. In this sense, it is important to consider the factors, from preparation (such as compatibility of the chemicals used, preparation conditions,

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Examples of MNPs-based drug delivery systems

MNPs

Coating agents

Active ingredients

References

Iron oxide Iron oxide Iron oxide Iron oxide

Poly(lactide-co-glycolide) Dextran Chitosan and maltose Poly(N-isopropylacrylamide) and carboxymethylchitosan Starch and N′,N′-dimethylacrylamide Poly(lactide-co-glycolide) and chitosan Poly(N-isopropylacrylamide) and chitosan

Cisplatin Doxorubicin and green-fluorescent FITC 5-Fluorouracil Indomethacin

[39] [40] [41] [42]

Prednisolone Doxorubicin Curcumin

[43] [44] [45]

Co-doped zinc ferrite Mn- and Zn-substituted ferrite Gadolinium-doped nickel ferrite

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Table 6.2 

Multistimuli-responsive magnetic assemblies169

Targeting agent Imaging agent

Tumor cell surface

Radiation

Therapeutic agent

Imaging

Receptor

Endocytosis

Tumor cell surface

Drug release

Fig. 6.7  Representative scheme suggesting the interaction between cancer cells and nanoparticles, presenting different active agents which allow the cancer diagnosis and therapy.

formulations) until the elimination of metabolites of active molecules and other materials (toxicity of the materials and their metabolic products, pharmacokinetics, and pharmacodynamic parameter evaluation) can influence these properties. Minute-sized particles containing both therapeutic and diagnostic agents have been prepared and used for theranostic applications. Magnetic particles have attracted much interest in this field due to their unique physical properties (superparamagnetic nanoparticles). Their intrinsic magnetic properties enable them to be used as contrast agent in MRI (diagnosis), and therapeutic agent as well (e.g., drug delivery and hyperthermia). When modified with proper polymers, the magnetic particles can carry drugs and controlling its release. In addition, the polymer used on magnetic nanoplatform designing can provide the nanoparticles dispersion stability and ability to conjugate targeting ligands, and their interaction with cell membranes [48–50]. In the last years, a lot of attention focused on magnetic-based colloidal nanoparticles preparation for theranostic application. Regarding diagnosis, MRI is the mostly employed diagnostic technique using magnetic materials as contrast agents. Among them, gadolinium, gold, silver, and iron oxide are being well investigated to find a suitable one with less toxicological effects. However, iron oxide particles are of great interest, because of superparamagnetic activity [51–53]. There is a continuous progress in the development of magnetic-based colloidal approaches with potential to be applied as theranostic agent in cancer disease [48,53–55]. As such, improvements can be expected in cancer diagnosis and therapy soon.

6.4 Multistimuli-responsive magnetic assemblies SPIONs are of great interest to scientist, researchers, and nanotechnologist, due to their worthy magnetic properties. Synthesis and characterization of SPIONs has been studied with considerable extent great interest owing to the novel mesoscopic properties shown by MNPs of quantum dimensions located in the transition region between atoms and bulk solids [56]. SPIONs have considerable novel application including magnetic fluids recording, biotechnology/biomedicine, catalysis, electrochemical, photocatalysis, bioelectrochemical sensing, microwave absorption, MRI, medical

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d­ iagnosis, data storage, environmental remediation and, as an electrode, for supergaiters and lithium ion batteries [57,58]. SPIONs have strange and distinguished properties which greatly changed, as the size of the particles changed due to their large surface to volume ratio and this leads to high surface energy of the nanoparticles and an ability to aggregate due two well-known forces called as Van-der Waals forces and magnetic dipole-dipole interactions [56,59]. Recently, SPIONs have shown exciting opportunities to develop drug delivery systems and at the same time controlled drug release, achieve drug targeting and biomedical imaging. The loaded drugs in SPIONs can be transported to the targeted area inside the body by applying an external magnetic field, released at a specific controlled rate in response to environmental stimuli. Thus, using MRI techniques it response can be tracked [60]. SPIONs also shows a remarkable advances interest in multistimuli-responsive for potential applications in medical and industrial field, such as biomedical devices [61,62], drug carriers [63,64], MRI [63,65,66], gene delivery [63,67,68], biosensing [69,70] etc. Stimuli-responsive of iron oxide nanoparticles significantly changes their structural properties, magnetic, optical, electrical, catalytic, and mechanical properties on the attachment of a wide variety of molecules, such as polymers, inorganic systems, and macromolecules. For different biomedical applications, it is necessary to develop new and better synthetic strategies to stabilize these SPIONs with these molecules [71]. Since few years, surface engineering of the SPIONs have been studied by many researchers and the attachment of bioactive molecules into SPIONs has considered widely for several important applications [72,73]. There are two major ways to fabricate or engineer the surface of SPIONs for drugs delivery system and those are either encapsulating the SPIONs within macromolecules or inorganic or a polymeric coating [74] or embedding the SPIONs in polymer matrices and then a conjugated drug on the surface of particles [62,75–77]. Embedding the SPIONs in polymeric matrices reduces the aggregation of nanoparticles in aqueous suspensions, however; it fails to create the required density of surface functional groups for further conjugation a therapeutic payload or other molecules. Therefore, the second approach which is encapsulating the SPIONs by dendrimeric macromolecules proved itself as one of the promising design technique to create multistimuli-responsive materials by limiting the aggregation process and by providing uncompromised and multiple surface functionalities. There are many promising molecules are listed in the literature to ­endowments-responsive such as FA, caffeic acid, carboxylic acid, silica, etc., selected for being grafted on the SPIONs. As for example, Omar et al. prepared the silica@iron oxide (SiO2-Fe2O3) nanovectors using with ultralarge micropores system (Fig. 6.8). They used this encapsulating nanovector for the high loading of large proteins and their delivery in cancer cells [78]. Moreover, Akal et al. fabricated the FA-conjugated SPIONs as a nanodrug for targeting tumor cells [79]. The prepared nanodrugs SPION@APTES@FA-PEG used in hyperthermia application on U87 brain tumor treatment as an alternative biomedicine. The stimuli-responsive of this prepared was observed and considered to be used as a nanodrug with less reaction to healthy cells and economically low cost to tumor therapy and prognosis (Fig. 6.9).

Multistimuli-responsive magnetic assemblies171

Fig. 6.8  Silica-iron oxide (SiO2-Fe2O3) loaded of large proteins (mTFP-Ferritin), (A) the proposed protein-nanoparticles (NPs) interactions with nanovector and (B) protein delivery via SiO2-Fe2O3 NPs to cancer cells, respond by pH-triggered [78].

However, encapsulating these SPIONs by dendrimeric macromolecules have greater advantages than the polymeric macromolecules. Thus, dendrimeric macromolecules provides adjustable multiple functional groups on their surface and an internal cavity that can be utilized to place the guest molecules [80]. Dendrimers macromolecules are three-dimensional structure and having radial symmetry which results in a spherical morphology [81]. Due to its hyperbranched structure, chemical properties of the internal cavities and external free functional groups are depended on it and responsible for their enhanced reactivity. A wide variety of tailorable surface groups, possible chemical compositions, structural properties, internal chemical environments, and architecture of these dendrimers encapsulated SPION drugs can be made, which depend on the selectivity of the core and branching molecules. A desirable physical and chemical property of multifunctionalized dendrimers can also be synthesized just by changing the terminal functional group [82,83]. Several dendrimers such as polyethyleneimine, polyamidoamine, and polypropyleneimine were used for biomedical application, such as gene delivery [84,85], biosensing [70], MRI [86,87], bioseparation [88], drug delivery [75,84,89], etc. As for example, Qie et al. [88] prepared the polyamidoamine (PAMAM)-based magnetite nanoparticles by “single-spot” novel method (Fig. 6.10). This NPs was applied for biomedical application for the purification and adsorption of DNA from various foods’ cell. The result indicated that the prepared PAMAMmagnetite nanoparticles provide a facial approach for the genomic analysis.

TEOS NH4OH

OH

Fe3O4

APTES

H2N

FA-PEG-COOH

-F A EG -P NH

NH NH2

Fe3O4

H2 N

NH2

2

NH2

2

NH2

Quercetin (Q)

DNA

Inhibition of cell cycle

Endosome

Receptormediated endocytosis

-F A NH2

NH 2

Fig. 6.9  Synthesis of SPION@APTES@FA-PEG@CQ nanodrug and its effect mechanism on U87 brain tumor cells [79].

NH-Q

-Q

Drug releasing

EG

Fe3O4 NH

Degradation of quercetin

-P NH

NH2

H-

Application on cancer cell lines

N

Nucleus

NH-Q

Apoptosis

G PE

A -F

P53 activation

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

2

NH

NH

NH

2

HO

NH2

G2

NH

Fe3O4 NH

H

H

O

O

Mitochondria

E -P

NH2

2

NH

O

H

OH

OH

FA

172

Fe3O4

HO

Multistimuli-responsive magnetic assemblies173

Fig. 6.10  TEM (A) and SEM (B) images of PAMAM-magnetite nanoparticles, (scale bar = 100 nm) [88].

In this chapter, we have discussed the multistimuli-response of magnetic assemblies and its application in biomedical fields. There are many important methods are found in the literature to enhanced the multistimuli-response of these assemblies but most important is the embedding the SPIONs in polymeric matrices and encapsulating the SPIONs within macromolecules or inorganic or a polymeric coating. The encapsulating SPIONs by dendrimeric macromolecules give extraordinary results. Thereby, increase the reactivity and limited the aggregation of SPIONs. These assemblies embed SPIONs as the inner shell and are also able to encapsulate massive quantities of drugs within the core domain.

6.5 Multistimuli-responsive magnetoliposomes MNPs, such as maghemite (γ-Fe2O3) and magnetite (Fe3O4), have permanent magnetization at a certain size, which is typically above 20 nm [90]. MNPs own only one magnetic domain, and accordingly exhibit superparamagnetic behavior above the temperature which is named as blocking temperature [91]. During last few decades MNPs have been applied into many different fields including the biomedical field [92–94]. In nanomedicine, SPIONs have gained wide acceptance in diagnosis and are used for contrast enhancement in MRI [95]. MNPs can be used in magnetic targeting and thermal therapy, which allow monitoring the biodistribution in vivo noninvasively [96,97]. Nanovesicles that bear phospholipids in ordered concentric bilayers named as liposomes. Aqueous compartments may be enclosed in liposomes where that are like a spherical shell similar to biological membranes. The hydrophilic portion of the phospholipid in the head attracts water, but the lipophilic tail repels. In this context, it has amphipathic nature. Therefore, drug can be intercalated into the lipid bilayer or encapsulated both in the aqueous core based upon its physicochemical properties. Their biodegradable and entrapping ability as well as nontoxic nature makes liposomes suitable for many different applications [98]. The sizes can range from 20 nm to 10 μm.

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Multifunctional magnetoliposomes are a kind of colloidal system which is produced by mixing of MNPs with liposomal drug carrier. They are one of the most interesting stimuli-responsive MNPs due to the multivalent properties of both the triggers and the carriers with different functions [99]. Magnetoliposomes provide combined drug delivery and hyperthermia treatment at a specific target site under coinstantaneous tracking via MRI (Fig. 6.11). Multiresponsive liposomes are essentially important carriers intelligently designed to experience differences in their structure and depending on the physical possessions they can be modified in the environment [100]. Changes via stimuli may occur externally (magnetic field, light, ultrasounds) or internally (i.e., temperature, change in pH or the existence of specific enzymes). This property is very commonly used for triggering the drug at the target, declining side effects throughout sequential modulation [100,101]. The liposomes must remain stable until they reach the target site and the drug is eluted at a high enough dosage. The use of these drug delivery nanosystems results primarily in lower systemic toxicity, which is a big issue in cancer therapy, through selective delivery of active drug in disease sites. Either passive (external) or active (internal) targeting can be utilized for selective delivery system [99,100]. Physical properties of the liposomes together with the micro anatomy of the target tissue are used for passive targeting to obtain selective localization. A special kind of ligand is required to bind the liposome surface to the pathological cells in active targeting. There are already drugs that demonstrate selective tumor localization in animal models and humans, such as DOXIL which is a good example of passive targeting [101,102]. Liposome drug delivery nanosystems suffered from the very fast blood clearance by the reticuloendothelial system (RES). Therefore, the possibility of coating the liposome with the synthetic polymer polyethyleneglycol

Magnetoliposome injection Magnetic field

Tumor

Drug-loaded magnetoliposome

Drug release

Fig. 6.11  Schematic presentation of a magnetoliposome hybrid drug delivery system [99].

Multistimuli-responsive magnetic assemblies175

(PEG) increased significantly the liposome’s half-life in the blood [103], establishing these vesicles as successful drug delivery vehicles. As a long blood circulation time is generally desirable for any vesicle intended for medical usage, adding a small percentage of Polyethylene glycol (PEG)-derivatized lipids in the membrane is an option to obtain this property. PEG chains reduce the overall uptake efficiency by macrophages, and liposomes with this attribute are termed “stealth”. These long-circulating liposomes accumulate significantly in tumors due to their leaky vasculature and the lack of an effective lymphatic drainage system, called the enhanced permeability and retention effect (EPR effect) [104]. The use of site-­ specific triggers is an alternative way to increase the drug bioavailability at the target site that can release drugs specifically to the diseased tissue. Enhanced specific drug release can be achieved by combination of this active triggering with the active targeting. Strategies include liposomes coupled to specific antibodies for active liposome targeting [104,105]. In addition, liposomes coated with ligands targeting proteins of cancer cell membranes or endothelial cells lining the newly generated blood vessels in the tumor are the alternatives. Some examples of site-specific biological triggers include pH, temperature, and redox microenvironment [106,107]. Physical targeting of drugs and local hyperthermia is also achievable using external stimuli, such as a magnetic field. Recently, the researchers have focused on further improvement by either biophysical targeting or local triggered drug release from responsive liposomal formulations to increase the drug concentration at the target site [108,109]. Hence, the interest toward the targeted and thermosensitive liposomes (TSLs) have been increased due to the capacity of releasing encapsulated molecules when the temperature reach near Tm caused by the decomposition of TSLs [110].

6.5.1 Multiresponsive magnetoliposomes for drug delivery In liposomal drug delivery, targeting with folate-mediated receptor was mentioned to be promising for various cancer cells. Recently several targeting approaches have been announced, but the folate receptor-mediated active targeted delivery is still limited by the insufficient drug release at tumor site which can be improved by local temperature triggered drug release from the TSLs [111]. Methotrexate (MTX) has acted as anticancer drug, also due to the similar structure with folate, it shows promising targeting effect toward folate receptor over expressed cancer cells, such as human cervical carcinoma (HeLa) cells [112,113]. Yuxin Guo et al. reported a multiple functional methotrexate-based thermosensitive magnetoliposomes (MTX-MagTSLs) which trigger the drug delivery via light/­ magnetic hyperthermia [114] and designed the MTX modified TSLs encapsulating MNPs/Cy5.5 in lipid bilayer and Dox in hydrophilic lumen, combining biological/ physical targeting and fluorescence/MR imaging for the cancer therapy. Magnetic and folate receptor targeting effect support and accelerate MTX-MagTSLs targeting to tumor tissue from intravenous injection in nude mouse, then proceed cell uptake and accelerate drug release at tumor site under the simultaneous application of AMF and laser followed by working finally in nuclear to cause tumor cell killing accurately.

176

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

In this study, MTX-MagTSLs were prepared by the thin-film dispersion method using MNPs and TSLs. In this process, total lipids composed of DPPC: Chol:SA:DSPEMPEG2000:DSPE-PEG2000-MTX (mol ratio 67:17:13:1:2). Hydrophobic MNPs/Cy5.5 was encapsulated in lipid bilayer. Dox was loaded according to previously reported method with an ammonium sulfate gradient loading [114]. A schematic targeting of MTX-MagTSLs to tumor site and releasing Dox locally is presented in Fig. 6.12.

Normal cell

Blood vessel

Tumor cell Combined magnetic and folate receptor targeting

Alternating magnetic field

MRI Fluorescent imaging

Monitoring

r

se

La

Nucleus Fig. 6.12  Schematic illustration of multifunctional MTX-MagTSLs which are targeted to tumor site under constant magnetic field (CMF) and folate receptor targeting, followed by triggering Dox release under light/magnetic hyperthermia simulation synchronously to achieve the effect of drug treatment [114].

Multistimuli-responsive magnetic assemblies177

6.5.2 Multiresponsive magnetoliposomes in vivo applications For anticancer effect, HeLa tumor-bearing nude mice were separated into seven different groups as follows [114]: PBS, free Dox, MagTSLs, MTX-MagTSLs, MTXMagTSLs/CMF, MTX-MagTSLs/CMF/AMF, and MTX-MagTSLs/CMF/AMF/ Laser. Each group comprised six mice. Intravenously injection was done at 2 mg/kg for every 2 days with different formulation (Dox). They compared MTX-MagTSLs/ DUAL and MTX-MagTSLs/CMF/DUAL for targeting ability. The tumor sizes were measured using a caliper for every 2  days and calculated as volume = (tumor length) × (tumor width)2/2, until the animals were given a euthanasia on day 15. Each group's survival situation was recorded as well. For histological test, the heart, liver, spleen, lung, kidney, and tumor harvested from all groups were fixed in 10% buffered formalin, then placed in paraffin, sectioned, stained with hematoxylin/eosin (H&E), and examined by digital microscopy. For fluorescence and MR imaging, they checked the targeting capability of TSLs, MagTSLs, MTX-TSLs, MTX-MagTSLs, and MTX-MagTSLs/CMF which were injected intravenously into the HeLa tumor-bearing nude mice. In vivo biodistribution was investigated by a noninvasive NIR optical imaging technique. Due to the absence of folate receptor-mediated targeting, TSLs and MagTSLs group presented weak fluorescence signal in tumor region as compared to the MTX-TSLs and MTX-MagTSLs (Fig. 6.13A). It seems that MTX-MagTSLs at tumor site in the MTX-MagTSLs/CMF group was higher than groups with single targeting (MTX-MagTSLs and MTX-TSLs) or without targeting (MagTSLs and TSLs). This result is captured form the stronger fluorescence signal of the MTX-MagTSLs/CMF in tumor region over 8 h. Hence, the fluorescence signal from strong to weak tumor harvested from mice of all groups at 12 h postinjection was as follows, MTX-MagTSLs/CMF > mTX-MagTSLs ≈ mTXTSLs > magTSLs ≈ TSLs (Fig.  6.13B). Also, they demonstrated dual role targeting ability of MTX-MagTSLs under CMF and higher accumulation of MTX-MagTSLs/ CMF at the tumor site. They examined the suitability of MTX-MagTSLs for in vivo MRI, HeLa tumor-bearing nude mice were further established for in vivo MRI evaluation using a 7-T MRI scanner. MR images were acquired for 4, 8, and 12 h after the intravenous injection of MTX-MagTSLs with a magnet at the tumor position (Fig. 6.13C). A sustained attenuation of the T2 contrast signal at the tumor position was detected from 0 to 8 h after MTX-MagTSLs injection, indicating the effective accumulation of MTX-MagTSLs at the tumor site via both magnetic targeting and folate receptor-mediated targeting effect. The maximum decreased MRI signal intensities at tumor site was achieved at 8-h postinjection, varying 10.72% compared with the initiative value, followed by a gradual recovery of MRI signal after 8-h postinjection, hinting the MTX-MagTSLs could act as suitable negative (T2) contrast agents in MRI applications. As control, MR images of MTX-MagTSLs without a magnet at 0, 4, 8, and 12 h postinjection revealed a sustained attenuation of the T2 contrast signal at the tumor position (Fig. 6.13D), and there was a relatively lower MRI signal intensities attenuation (5.69%) compared with the MTX-MagTSLs/CMF group at tumor site, suggesting the less effective accumulation of MTX-MagTSLs in the tumor region without the magnetic targeting effect.

178

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Fig. 6.13  In vivo imaging of MTX-MagTSLs. (A) In vivo fluorescence images of the HeLa tumor-bearing nude mice after intravenous injection of PBS, MTX-MagTSLs, MTX-MagTSLs/CMF, MagTSLs, TSLs, and MTX-TSLs, respectively. (B) ex vivo fluorescence images of the tumor excised from HeLa tumor-bearing nude mice treated with PBS, MTX-MagTSLs/CMF, MagTSLs, MTX-MagTSL, TSLs, and MTX-TSLs at 12-h postinjection respectively. (C) In vivo pseudo-color processing T2-weighted MR images of MTX-MagTSLs with a magnet. (D) In vivo pseudo-color processing T2-weighted MR images of MTX-MagTSLs without a magnet [114].

In summary, both light/magnetic hyperthermia triggered drug release and magnetic/MTX active targeting synergistically increased cytotoxicity to tumor cells and tissues while leading to a reduction of side effects compared with free Dox. Therefore, these multifunctional liposomes can be used as the potential carriers for precise ­cancer-related diagnosis and treatments.

Multistimuli-responsive magnetic assemblies179

6.6 Glucose-responsive MNPs There has been increasing interest in the activation of magnetic nanomaterials for biomedical applications. Investigating the magnetic properties of nanoparticles (NPs) and the influence of their composition on biological processes is a critical step in the engineering and development of new-generation composite materials. They can be dramatically useful in medical applications, including magnetic separation, MRI, cancer diagnosis, hyperthermia, tissues engineering, and drug delivery [115]. In this context, the term “nanobiomagnetism” can be defined as the intersection of nanomagnetism and medicine that focuses on biological systems and/or process [3]. Cancer is one of the causes of death worldwide [116]. Several systems are used in anticancer treatment field including surgery, radiotherapy, and chemotherapy, or a combination of these as determined by tumor stage, kind, and available resources. Recent researches have focused on designing biocompatible nanocarrier with decreasing side effects. MNPs are one among spectrum of cancer drug delivery systems being investigated for treating solid tumors. Because their multifunctional properties like (a) noninvasiveness, due to the potential of “magnetic targeting” [117], (b) capability to act as a biocompatible drug carrier [118], and (c) intrinsic magnetic properties that enable tracking through MRI. Cancer cells are generally more vulnerable to temperature change than normal cells. Thus, hyperthermia is employed as a therapeutic for inhibiting cancer cell growth [119], electromagnetic radiation is commonly used as a heat source [120]. Therapeutic hyperthermia had achieved some success but is not yet considered standard of care therapies. The lack of differential normal tissue, inability to target hyperthermia directly to tumors, cancer cytotoxicity, and an insufficient understanding of the mechanism of hyperthermia cytotoxicity make hyperthermia unable to be applied in mainstream cancer therapy. Recently, hyperthermia has been directed specifically to cancer cells by MNPs through an alternating magnetic field (AMF) for targeted therapeutic heating of tumors instead of surgery, radiotherapy, and chemotherapy [121]. Additionally, it is useful to achieve the temperature needed with as low as possible weight of MNPs. Glucose-conjugated ferromagnetic nanoparticles (Glu-MNPs) are used for targeting and focusing accurately to raise the effect of high-frequency electromagnetic fields induced hyperthermia in solid tumors. Tumors showed high metabolic activity for glucose comparing with other somatic cells. Increasing of accumulation of GluMNPs on tumor and accuracy of radio frequency electromagnetic field (RF-EMF) energy absorption in solid tumors, precede RF-EMF induced hyperthermia [121]. In the cell membrane of human cancer cells, glycolytic enzyme and glucose transporter GLUT-1 be overexpressed and require more glucose than normal tissue [122]. The phenomenon had discovered by the German scientist Otto Warburg, and therefore it is called Warburg effect [123]. Compared with traditional probes, the functional MNPs are more cost-effective and Fe3O4 MNPs are known to own photothermal properties. Moreover, the cell toxicity of the glucose-Fe3O4 MNPs was low. Within 1 min, around 30% hepatocellular cancer cells HepG2 treated with the Glu-Fe3O4 MNPs and illuminated by NIR for 1 min survived, while only ~10% normal cells were damaged [124].

180

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Glucose is one of the easiest and fastest catabolize metabolite; breast tumors have a prominent level of metabolic activity. Therefore, glucose-conjugate Fe3O4 MNP is selectively deposited in tumor tissue. The magnetization of the NPs is a single-giant magnetic moment, the total of all the individual magnetic moments and is proportional to the concentration of Glu-Fe3O4 MNP [121]. However, the limitations of using NPs in cancer treatment have been detailed as followed: (i) the need to apply high local magnetic field and suitable thermal gradients for the treatment, (ii) thermal resistance at the cellular level can be created in the range 43–70°C because of the initiation of heat shock proteins synthesis, (iii) the temperature above 45°C can change blood vessels permeability and may shut down tissue perfusion (Fig. 6.14) and may need 30–60 min, placing strict and challenging technical requirements, (iv) inhomogeneous distribution of MNPs leads to make complete tumor eradication impossible, (v) targeted radio frequency therapy with MNPs is often not appropriate for disseminated and abdominal tumors, (vi) slow biodegradation of NPs in the body and side effects of their accumulation in the spleen, muscles, liver, and other organs, and (vii) due to high equipment and treatment costs, the electromagnetic hyperthermia is usually very expensive [121].

6.6.1 Glucose and magnetic responsive for hyperglycemia theranostic Nitric oxide (NO) is one of the most important biological signaling modulators in different physiological processes. To control in the glucose hemostasis and spatiotemporally regulation NO release and delivery, and based on specific enzymatic reactions between glucose and glucose oxidase (GOx), it had been developed the glucose and magnetic-responsive NO bubble generation theranostic delivery system. As shown in

Fig. 6.14  Thermal-induced damage of blood vessels [121].

Multistimuli-responsive magnetic assemblies181

Fig. 6.15  Schematic diagram of microvesicles encapsulated MNPs and glucose oxidase for dual-stimuli responsive programmable delivery model [125].

Fig.  6.15, GOx-MMVs structure includes of l-arginine (NO pro-drug) in the inner core, in the shell MNPs, and on the surface GOx assembled. Firstly, to reduce the hyperglycemia levels, the GOx-MMVs carrier is applied as a smart glucose stimuli system. Then by helping of AMF, spatiotemporally controlling the NO gas generation and delivery can be realized by invoking the reaction of H2O2 and l-arginine [125,126]. The NO molecule can work as both efficient ultrasound scatters to develop ultrasound imaging and diabetic nephropathy therapeutic agents. As a result, in vivo, the sequential in situ conversion has been possible in db/db type 2 diabetic mice for dose regulation of hyperglycemic levels and NO therapy for renal hypoxia [125]. Glucose level in the human body needs to a quick monitoring. Enzymatic glucose sensors require highly sensitive. The environmental factors, such as toxic chemicals, humidity, temperature, and pH values, are some of the factors that effect on the sensors. Moreover, due to cross-linking and electro-polymerization, glucose oxidase immobilization which is contained adsorption is an expensive and complicated process [127]. Thus, nonenzymatic glucose sensors became more attractive in the biosensor industry, because they have many advantages like, long-term stability, high selectivity, resistance to thermal implications with low cost and simple synthesis techniques [128]. Core-shell nanocomposite based on chemical oxidative polymerization of pyrrole on ZnFe2O4 NPs surface for an amperometric enzyme less glucose sensor has electro catalytic activity for the oxidation of glucose in alkaline solution. The sensor offered good activity for the determination of glucose with the linear concentration range of 0.1–8 mM [129].

6.6.2  β-CD-capped multiresponsive MNPs and drug loading 6.6.2.1 Basic properties of β-CD Cyclodextrins (CDs) are a family of cyclic oligomers obtained by enzymatic digestion of starch [130]. CDs nomenclature depends on the number of glucose units in the structure (Fig. 6.16). The α-CD, β-CD, and γ-CD include on 6, 7, and 8 glucopyranose units, respectively. They have similar structures and are homogeneous, crystalline, nonhygroscopic in nature and hydrophobic inner cavity and hydrophilic exterior [131].

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Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

Fig. 6.16  Structures of CDs [130]. (A) Chemical structure and (B) 3D structure.

Although the number of hydroxyl groups in β-CD is greater than α-CD, β-CD has a lower solubility. This is due to the internal hydrogen bond network that created between the secondary hydroxyl groups. Furthermore, β-CD is the most accessible, useful, and the lowest priced. The major properties of CDs are summarized in Table 6.3. The irritating of β-CD is less than α-CD after i.m. injection, connects cholesterol, the upper intestinal tract absorbs a little amount of β-CD (1%–2%) after oral administration, no metabolism in the upper intestinal tract, metabolized by bacteria in cecum and colon. Moreover, the water solubility of several poorly water-soluble substances increases with addition of β-CD. In some situations, this lead to in improved bioavailability, raising the pharmacological influence allowing a decrease in the dose of the drug administered. Currently, in pharmaceutical formulations field, β-CD is the most common CD, and therefore, perhaps the best studied CD in humans. The high doses may be harmful and is not recommended. β-CD is applied to incorporate drugs into aqueous vehicles [133]. Table 6.3 

Cyclodextrins properties [132]

Properties

α-Cyclodextrin β-Cyclodextrin γ-Cyclodextrin

Number of glucopyranose units Molecular weight (g/mol) Solubility in water at 25°C (%, w/v) Outer diameter (Å) Cavity diameter (Å) Height of torus (Å) Cavity volume (Å)

6 972 14.5 14.6 4.7−5.3 7.9 174

7 1135 1.85 15.4 6.0−6.5 7.9 262

8 1297 23.2 17.5 7.5−8.3 7.9 427

Multistimuli-responsive magnetic assemblies183

6.6.2.2  β-CD multiresponsive of MNPs The unique properties of MNPs with features of β-CD molecular offer special and promising applications in separation, detection, and drug targeting. The first report about the synthesis of Fe3O4 MNPs functionalized with β-CD as nanocarriers for hydrophobic drug delivery has been presented by Banerjee and Chen. The studies for loading capacity and release profile of Fe3O4/CDs nanoconjugates for ketoprofen and retinoic acid showed that β-CD and hydroxypropyl-β-cyclodextrins (HP-β-CDs) modified MNPs could be used for controlling of hydrophobic drugs [134,135]. MNPs became prominent inorganic compounds of such multifunctional nanocomposites, because colloidal MNPs, typically iron oxide (Fe3O4), show superparamagnetic behavior which respond to the external magnetic field, and able to be guided magnetically inside a biological system, like tumor or artery by an external magnetic field [136] and followed by MRI. The fact that after removal of the external magnetic field the magnetization disappears, and thus avoids aggregation, is a good benefit for in  vivo applications. After coating of MNPs by an inorganic material like silica or gold, nonpolymeric organic like surfactant or polymer (e.g., PEG, chitosan) many properties improve significantly, such as biocompatibility, stability, as well as increase applicability by integrating more functionalities through chemical and/or physical techniques [137]. Silica is a good biocompatible material and less prone to degradation in a biological environment, thus, Fe3O4@SiO2 core-shell nanocomposites form the basis of most multifunctional nanocomposites [138]. Due to mesopores of silica, it can only hold water-soluble drug molecules. The most kinds of magnetic-mesoporous silica nanocomposites carry hydrophilic drugs. In a drug carrier field, β-CD is not only transport of hydrophobic drugs, facilitates solubilization, and stabilization but also minimizes the unwanted side effects for the drugs [139]. The applications of MNPs-CD nanocomposites as-synthesized magnetic nanocarriers in biomedical research may be limited, because the agglomeration of the particles. The high uniform magnetic nanocomposite which contains Fe3O4@SiO2 core-shell structure, with a host for fluorescent dye (FITC), cancer-targeting ligand (FA), and a hydrophobic drug storage-delivering vehicle (β-CD) can create an interesting system. Evaluation of the feasibility of this nanocomposite is with investigating of the capability in discriminating between healthy cells and cancerous, fluorescent imaging, cellular uptake, and formation of hydrophobic drug [140]. To enhance performance of MNPs as a drug carrier and bio separation, surface modification of pristine MNPs is a frequently used technique. Layer-by-layer method can present a feasible way for preparation superparamagnetic of nanocomposites with a relatively high saturation magnetization value of 69 emu/g. (3-Aminopropyl) triethoxysilane-coated Fe3O4 magnetic nanoparticles (APTES-MNPs) was combined with β-CD [141]. Several distinctive features had been integrated in a single nanosystem: (a) the silane coating outside Fe3O4 cores derived from the hydrolysis of APTES acted as a coupling agent and provided amino group (–NH2) for connecting the CD molecule; (b) for biomolecules and drugs, the outermost CD moieties can work as specific containers and inclusion sites; (c) the innermost magnetic cores are able to respond and

184

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

sense to an externally applied magnetic field and their action in vivo or in vitro can be artificially manipulated and navigated. This nanosystem includes a wide variety of biomedical applications as a very promising drug carrier and bioseparator [141]. The bucket-shaped oligosaccharide, β-CD, can resolve in water due to a hydrophilic external edge, and accommodates guest molecules of suitable size through a hydrophobic cavity. β-CD forms inclusion complexes shape with the preferred drugs, therefore, it is used as a fit and find detector to understand the openness of the MNP surface-loaded drugs. Nontoxic polymers and MNPs have been used to improve strategies of applying chemotherapy agents for drugs delivery in cancer cells [142,143].

6.7 Conclusion This chapter focused on the great importance of stimuli-responsive polymer-based nanocarriers for drug delivery system. The design of stimuli-responsive nanocarriers may represent an attractive alternative to targeted drug delivery. In fact, the systems are designed to improve the therapeutic efficacy of conventional drug, because drug efficacy is often altered by nonspecific cell and tissue biodistribution, and because some drugs are rapidly metabolized or excreted from the body. Efficient drug delivery systems allow for precisely controlled pharmacokinetics and preferentially localized delivery to reduce systemic side effects and required dosage. The wide range of stimuli able to trigger the drug release at the right place and time, and the diversity of responsive materials that can be assembled in different architectures, allow great flexibility in the design of stimuli-responsive systems. The main task in the creation of nanocarriers for drug delivery is complete understanding of drug releasing mechanism. This involves the understanding of stimuli-responsiveness of nanocarriers approach to materials for the preparation of nanocarriers. In addition there are others factors involved in this whole process like biodegradability and biocompatibility of the materials. Furthermore, conditions for preparation of nanocarriers through a specific technique and modifications according to the route of administration, materials toxicity, pharmacokinetic, and pharmacodynamics profiles should also be considered to evaluate benefits. Development of stimuli-responsive nanocarriers for cancer drug delivery has attracted a great deal of attention among all other drug delivery systems. pH-­ sensitive drug delivery systems have attracted a great deal of attention among all other ­stimuli-responsive systems because of the acidic microenvironment of the tumor tissue compared to the normal tissue. In addition, intervention with an extracorporeal stimulus, such as magnetic field will lead to high spatiotemporal control over therapeutic delivery and extreme dose control. The synthesis of nanocarriers having ­multistimuli-responsive is one of the keys in the developments of such drug delivery system. SPIONs represent a promising platform for targeted delivery of anticancer drugs. Assembling of iron oxide NPs and pH-sensitivity polymer, obtain dual sensitive nanocarriers that can respond to external magnetic field and the change of pH at the same time. Under this condition cancer drug-targeting

Multistimuli-responsive magnetic assemblies185

c­ arrier-­based-­superparamagnetic iron oxide NPs can be conducted to the site of the target cell or tissue directly by applying an external magnetic field, leading to decreased circulation time, decreased the required dosage of drug, and thereby reducing side effects. Although stimuli-responsive polymeric nanocarriers and magnetic nanomaterials in drug delivery system have been well known for several decades, they still remain a subject of vigorous investigation both in academic and in industry fields. Combination of stimuli-sensitive function and magnetic properties in nanocarriers to enhance efficiency of drug delivery system to advanced nanocarriers for therapeutics will be a very interesting area of research in the future. Since clinical success remains relatively rare, it will be a great challenge to develop and investigate the practical biomedical applications.

References [1] W.B. Liechty, D.R. Kryscio, B.V. Slaughter, N.A. Peppas, Polymers for drug delivery systems, Annu. Rev. Chem. Biomol. Eng. 1 (2010) 149–173. [2] A. Kumari, S.K. Yadav, S.C. Yadav, Biodegradable polymeric nanoparticles based drug delivery systems, Colloids Surf. B: Biointerfaces 75 (2010) 1–18. [3] S.F. Medeiros, A.M. Santos, H. Fessi, A. Elaissari, Stimuli-responsive magnetic particles for biomedical applications, Int. J. Pharm. 403 (2011) 139–161. [4] J.P. Honey, J. Rijo, A. Anju, K.R. Anoop, Smart polymers for the controlled delivery of drugs: a concise overview, Acta Pharm. Sin. B 4 (2) (2014) 120–127. [5] X. Gao, Y. Cao, X. Song, Z. Zhang, X. Zhuang, C. He, X. Chen, Biodegradable, pH-­ responsive carboxymethyl cellulose/poly(acrylic acid) hydrogels for oral insulin delivery, Macromol. Biosci. 14 (2014) 565–575. [6] C.L. Peng, L.Y. Yang, T.Y. Luol, P.S. Lai, S.L. Yang, W.J. Lin, M.J. Shieh, Development of pH sensitive methacrylate based nanoparticles for photodynamic therapy, Nanotechnology 21 (2010) 1–11. [7] S. Barman, J. Das, S. Biswas, T.K. Maitib, N.D. Pradeep Singh, A spiropyran–coumarin platform: an environment sensitive photoresponsive drug delivery system for efficient cancer therapy, J. Mater. Chem. B 5 (2017) 3940–3944. [8] C.  Yao, M.  Wu, C.  Zhang, X.  Lin, Z.  Wei, Y.  Zheng, D.  Zhang, Z.  Zhang, X.  Liu, Photoresponsive lipid-polymer hybrid nanoparticles for controlled doxorubicin release, Nanotechnology 28 (2017) 1–11. [9] J.J. Kang-Mielera, W.F. Mieler, Thermo-responsive hydrogels for ocular drug delivery, Dev. Ophthalmol. 55 (2016) 104–111. [10] K.E. Washington, R.N. Kularatne, J. Du, Y. Ren, M.J. Gillings, C.X. Geng, M.C. Biewer, M.C. Stefan, Thermoresponsive star-like γ-substituted poly(caprolactone)s for micellar drug delivery, J. Mater. Chem. B 5 (2017) 5632–5640. [11] P. Prabu, A.A. Chaudhari, N. Dharmaraj, M.S. Khil, S.Y. Park, H.Y. Kim, Preparation, characterization, in-vitro drug release and cellular uptake of poly(caprolactone) grafted dextran copolymeric nanoparticles loaded with anticancer drug, J. Biomed. Mater. Res. A 90A (2008) 1128–1136. [12] K. Sonaje, J.L. Italia, G. Sharma, V. Bhardwaj, K. Tikoo, M.N. Kumar, Development of biodegradable nanoparticles for oral delivery of ellagic acid and evaluation of their antioxidant efficacy against cyclosporine A-induced nephrotoxicity in rats, Pharm. Res.

186

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

24 (5) (2007) 899–908. [13] J. Zhou, M.V. Pishko, J.L. Lutkenhaus, Thermoresponsive layer-by-layer assemblies for nanoparticle-based drug delivery, Langmuir 30 (2014) 5903–5910. [14] S.  Sanyal, H.-C.  Huang, K.  Rege, L.L.  Dai, Thermo-responsive core-shell composite nanoparticles synthesized via one-step pickering emulsion polymerization for controlled drug delivery, J. Nanomed. Nanotechnol. 2 (2011) 1–7. [15] S.  Rittikulsittichai, A.G.  Kolhatkar, S.  Sarangi, M.A.  Vorontsova, P.G.  Vekilov, A.  Brazdeikis, T.R.  Lee, Multi-responsive hybrid particles: thermo-, pH-, photo-, and magneto-responsive magnetic hydrogel cores with gold nanorod optical triggers, Nanoscale 8 (2016) 11851–11861. [16] C.-M. Su, C.-Y. Huang, Y.-L. Chen, T.-R. Ger, pH-responsive magnetic micelles gelating-poly(NIPAAm-co-DMAAm-co-UA)-g-dextran/Fe3O4 as a hydrophilic drug carrier, RSC Adv. 7 (2017) 28207–28212. [17] J.-M.  Shen, W.-J.  Tang, X.-L.  Zhang, T.  Chen, H.-X.  Zhang, A novel carboxymethyl ­chitosan-based folate/Fe3O4/CdTe nanoparticle for targeted drug delivery and cell imaging, Carbohydr. Polym. 88 (2012) 239–249. [18] M.  Amoli-Diva1, K.  Pourghazi, Magnetic nanoparticles grafted pH-responsive poly­ (methacrylic acid-co-acrylic acid)-grafted polyvinylpyrrolidone as a nano-carrier for oral controlled delivery of atorvastatin, Nanomed. Res. J. 2 (1) (2017) 18–27. [19] S. Kayal, R.V. Ramanujan, Doxorubicin loaded PVA coated iron oxide nanoparticles for targeted drug delivery, Mater. Sci. Eng. C 30 (2010) 484–490. [20] D.  Yoo, J.-H.  Lee, T.-H.  Shin, J.  Cheon, Theranostic magnetic nanoparticles, Acc. Chem. Res. 44 (10) (2011) 863–874. [21] O.L.  Gobbo, K.  Sjaastad, M.W.  Radomski, Y.  Volkov, A.  Prina-Mello, Magnetic nanoparticles in cancer theranostics, Theranostics 5 (11) (2015) 1249–1263. [22] Y.  Pei, O.R.  Sugita, J.Y.  Quek, P.J.  Roth, A.B.  Lowe, pH-, thermo- and electrolyte-­ responsive polymer gels derived from a well-defined, RAFT-synthesized, poly(2-­vinyl4,4-dimethylazlactone) homopolymer via one-pot post-polymerization modification, Eur. Polym. J. 62 (2015) 204–213. [23] R.  Balu, N.K.  Dutta, N.R.  Choudhury, C.M.  Elvin, R.E.  Lyons, R.  Knott, A.J.  Hill, An16-resilin: an advanced multi-stimuli-responsive resilin-mimetic protein polymer, Acta Biomater. 10 (2014) 4768–4777. [24] S.Y. Lee, H. In, S.Y. Park, pH/redox/photo responsive polymeric micelle via boronate ester and disulfide bonds with spiropyran-based photochromic polymer for cell imaging and anticancer drug delivery, Eur. Polym. J. 57 (2014) 1–10. [25] Y. Oh, J.Y. Je, M.S. Moorthy, H. Seo, W.H. Cho, pH and NIR-light-responsive magnetic iron oxide nanoparticles for mitochondria-mediated apoptotic cell death induced by chemophotothermal therapy, Int. J. Pharm. 531 (2017) 1–13. [26] L.  Wang, L.  Liu, B.  Dong, H.  Zhao, M.  Zhang, W.  Chen, Y.  Hong, Multi-stimuliresponsive biohybrid nanoparticles with cross-linked albumin coronae self-assembled by a polymer-protein biodynamer, Acta Biomater. 54 (2017) 259–270. [27] J.  Zhang, J.  Li, Z.  Shi, Y.  Yang, X.  Xie, S.M.  Lee, Y.  Wang, K.W.  Leong, M.  Chen, pH-sensitive polymeric nanoparticles for co-delivery of doxorubicin and curcumin to treat cancer via enhanced pro-apoptotic and antiangiogenic activities, Acta Biomater. 58 (2017) 349–364. [28] F. Xuening, L. Shubei, C. Lingyun, Z. Baolian, Y. Miaozhuo, Multifunctional polymer drug loading system with pH-sensitive, fluorescent and targeting property, Mater. Sci. Eng. C 77 (2017) 1151–1159. [29] T.  Neuberger, B.  Schöpf, H.  Hofmann, M.  Hofmann, B.  von Rechenberg, Superparamagnetic nanoparticles for biomedical applications: possibilities and limita-

Multistimuli-responsive magnetic assemblies187

tions of a new drug delivery system, J. Magn. Magn. Mater. 293 (2005) 483–496. [30] D. Wang, J. Zhou, R. Chen, R. Shi, G. Zhao, G. Xia, R. Li, Z. Liu, J. Tian, H. Wang, Z.  Guo, H.  Wang, Q.  Chen, Controllable synthesis of dual-MOFs nanostructures for pH-responsive artemisinin delivery, magnetic resonance and optical dual-model ­imaging-guided chemo/photothermal combinational cancer therapy, Biomaterials 100 (2016) 27–40. [31] A. Akbarzadeh, M. Samiei, S. Davaran, Magnetic nanoparticles: preparation, physical properties, and applications in biomedicine, Nanoscale Res. Lett. 7 (2012) 1–13. [32] M. Erdem, S. Yalcin, U. Gunduz, Folic acid-conjugated polyethylene glycol-coated magnetic nanoparticles for doxorubicin delivery in cancer chemotherapy: preparation, characterization and cytotoxicity on HeLa cell line, Hum. Exp. Toxicol. 36 (2017) 833–845. [33] A.  Akbarzadeh, H.  Mikaeili, N.  Zarghami, R.  Mohammad, A.  Barkhordari, S.  Davaran, Preparation and in  vitro evaluation of doxorubicin-loaded Fe3O4 magnetic nanoparticles modified with biocompatible copolymers, Int. J. Nanomed. 7 (2012) 511–526. [34] S. Dutta, S. Parida, C. Maiti, R. Banerjee, M. Mandal, D. Dhara, Polymer grafted magnetic nanoparticles for delivery of anticancer drug at lower pH and elevated temperature, J. Colloid Interface Sci. 467 (2016) 70–80. [35] M. Faraji, Y. Yamini, M. Rezaee, Magnetic nanoparticles: synthesis, stabilization, functionalization, characterization, and applications, J. Iran. Chem. Soc. 7 (2010) 1–37. [36] G.L. Zwicke, G.A. Mansoori, C.J. Jeffery, Utilizing the folate receptor for active targeting of cancer nanotherapeutics, Nano Rev. 3 (18496) (2012) 1–11. [37] A.  Shanavas, S.  Sasidharan, D.  Bahadur, R.  Srivastava, Magnetic core-shell hybrid nanoparticles for receptor targeted anti-cancer therapy and magnetic resonance imaging, J. Colloid Interface Sci. 486 (2017) 112–120. [38] L. Li, F.M. Gao, W.W. Jiang, X.L. Wu, Y.Y. Cai, J.T. Tang, X.Y. Gao, F.P. Gao, Folic acid-conjugated superparamagnetic iron oxide nanoparticles for tumor-targeting MR imaging, Drug Deliv. 23 (2016) 1726–1733. [39] M. Ashjari, S. Khoee, A.R. Mahdavian, Controlling the morphology and surface property of magnetic/cisplatin-loaded nanocapsules via W/O/W double emulsion method, Colloids Surf. A Physicochem. Eng. 408 (2012) 87–96. [40] M.P. Arachchige, S.S. Laha, A.R. Naik, K.T. Lewis, R. Naik, B.P. Jena, Functionalized nanoparticles enable tracking the rapid entry and release of doxorubicin in human pancreatic cancer cells, Micron 92 (2017) 25–31. [41] L. Alupei, C.A. Peptu, A.M. Lungan, J. Desbrieres, O. Chiscan, S. Radji, M. Popa, New hybrid magnetic nanoparticles based on chitosan-maltose derivative for antitumor drug delivery, Int. J. Biol. Macromol. 92 (2016) 561–572. [42] N.  Rodkate, M.  Rutnakornpituk, Multi-responsive magnetic microsphere of poly(N-isopropylacrylamide)/carboxymethylchitosan hydrogel for drug controlled release, Carbohydr. Polym. 151 (2016) 251–259. [43] M.K. Lima-Tenório, E.T. Tenório-Neto, F.P. Garcia, C.V. Nakamura, M.R. Guilherme, E.C. Muniz, E.A.G. Pineda, A.F. Rubira, Hydrogel nanocomposite based on starch and co-doped zinc ferrite nanoparticles that shows magnetic field-responsive drug release changes, J. Mol. Liq. 210 (2015) 100–105. [44] W.  Montha, W.  Maneeprakorn, N.  Buatong, I.M.  Tang, W.  Pon-On, Synthesis of doxorubicin-PLGA loaded chitosan stabilized (Mn, Zn)Fe2O4 nanoparticles: biological activity and pH-responsive drug release, Mater. Sci. Eng. C 59 (2016) 235–240. [45] T.  Yadavalli, S.  Ramasamy, G.  Chandrasekaran, I.  Michael, H.A.  Therese, R.  Chennakesavulu, Dual responsive PNIPAM-chitosan targeted magnetic nanopolymers for targeted drug delivery, J. Magn. Magn. Mater. 380 (2015) 315–320.

188

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

[46] N. Ahmed, H. Fessi, A. Elaissari, Theranostic applications of nanoparticles in cancer, Drug Discov. Today 17 (2012) 928–934. [47] A.K. Sahoo, S. Banerjee, S.S. Ghosh, A. Chattopadhyay, Simultaneous RGB emitting au nanoclusters in chitosan nanoparticles for anticancer gene theranostics, ACS Appl. Mater. Interfaces 6 (2014) 712–724. [48] Y. Huang, K. Mao, B. Zhang, Y. Zhao, Superparamagnetic iron oxide nanoparticles conjugated with folic acid for dual target-specific drug delivery and MRI in cancer theranostics, Mater. Sci. Eng. C 70 (2017) 763–771. [49] L.J. Ao, B. Wang, P. Liu, L. Huang, C.X. Yue, D.Y. Gao, C.L. Wu, W. Su, A folate-­ integrated magnetic polymer micelle for MRI and dual targeted drug delivery, Nanoscale 6 (2014) 10710–10716. [50] H.P. Chen, M.H. Chen, F.I. Tung, T.Y. Liu, A novel micelle-forming material used for preparing a theranostic vehicle exhibiting enhanced in vivo therapeutic efficacy, J. Med. Chem. 58 (2015) 3704–3719. [51] M.  Ma, F.  Yan, M.H.  Yao, Z.J.  Wei, D.L.  Zhou, H.L.  Yao, H.R.  Zheng, H.R.  Chen, J.L.  Shi, Template-free synthesis of hollow/porous organosilica-Fe3O4 hybrid nanocapsules toward magnetic resonance imaging-guided high-intensity focused ultrasound therapy, ACS Appl. Mater. Interfaces 8 (2016) 29986–29996. [52] M.K.  Lima-Tenorio, E.A.G.  Pineda, N.M.  Ahmad, G.  Agusti, S.  Manzoor, D.  Kabbaj, H. Fessi, A. Elaissari, Aminodextran polymer-functionalized reactive magnetic emulsions for potential theranostic applications, Colloids Surf. B: Biointerfaces 145 (2016) 373–381. [53] S. Wang, W.T. Yang, H.L. Du, F.F. Guo, H.J. Wang, J. Chang, X.Q. Gong, B.B. Zhang, Multifunctional reduction-responsive SPIO&DOX-loaded PEGylated polymeric lipid vesicles for magnetic resonance imaging-guided drug delivery, Nanotechnology 27 (165101) (2016) 1–11. [54] Z.Y.  Xiao, C.  Peng, X.H.  Jiang, Y.X.  Peng, X.J.  Huang, G.Q.  Guan, W.L.  Zhang, X.M. Liu, Z.Y. Qin, J.Q. Hu, Polypyrrole-encapsulated iron tungstate nanocomposites: a versatile platform for multimodal tumor imaging and photothermal therapy, Nanoscale 8 (2016) 12917–12928. [55] W.H. Chiang, W.C. Huang, C.W. Chang, M.Y. Shen, Z.F. Shih, Y.F. Huang, S.C. Lin, H.C. Chiu, Functionalized polymersomes with outlayered polyelectrolyte gels for potential tumor-targeted delivery of multimodal therapies and MR imaging, J. Control. Release 168 (2013) 280–288. [56] B.H. Sohn, R.E. Cohen, Processible optically transparent block copolymer films containing superparamagnetic iron oxide nanoclusters, Chem. Mater. 9 (1997) 264–269. [57] M. Amir, U. Kurtan, A. Baykal, Rapid color degradation of organic dyes by Fe3O4@ his@ag recyclable magnetic nanocatalyst, J. Ind. Eng. Chem. 27 (2015) 347–353. [58] Y.I.  Kim, D.  Kim, C.S.  Lee, Synthesis and characterization of CoFe2O4 magnetic nanoparticles prepared by temperature-controlled co-precipitation method, Phys. B Condens. Matter 337 (2003) 42–51. [59] D.  Brabazon, Nano characterization techniques for dental implant development, in: K. Subramanium, W. Ahmed (Eds.), Emerging Nanotechnologies in Dentistry, Elsevier, Netherlands, 2011, pp. 307–331. (Chapter 18). [60] Y.  Zhang, W.  Ma, D.  Li, M.  Yu, J.  Guo, C.C.  Wang, Benzoboroxole-functionalized magnetic core/shell microspheres for highly specific enrichment of glycoproteins under physiological conditions, Small 10 (2014) 1379–1386. [61] L. Zhang, W.F. Dong, H.B. Sun, Multifunctional superparamagnetic iron oxide nanoparticles: design, synthesis and biomedical photonic applications, Nanoscale 5 (2013) 7664–7684.

Multistimuli-responsive magnetic assemblies189

[62] E.  Roy, S.  Patra, R.  Madhuri, P.K.  Sharma, Stimuli-responsive poly(N-­ isopropylacrylamide)-co-tyrosine@gadolinium: iron oxide n­anoparticle-based nano-­t heranostic for cancer diagnosis and treatment, Colloids Surf. B: Biointerfaces 142 (2016) 248–258. [63] C.  Wang, S.  Ravi, U.S.  Garapati, M.  Das, M.  Howell, J.  Mallela, S.  Alwarappan, S.S.  Mohapatra, S.  Mohapatra, Multifunctional chitosan magnetic-graphene (CMG) nanoparticles: a theranostic platform for tumor-targeted co-delivery of drugs, genes and MRI contrast agents, J. Mater. Chem. B 1 (2013) 4396–4405. [64] S. Yalcın, M. Erkan, G. Ünsoy, M. Parsian, J. Kleeff, U. Gündüz, Effect of gemcitabine and retinoic acid loaded PAMAM dendrimer-coated magnetic nanoparticles on pancreatic cancer and stellate cell lines, Biomed. Pharmacother. 68 (2014) 737–743. [65] A. Mandal, S. Sekar, M. Kanagavel, N. Chandrasekaran, A. Mukherjee, T.P. Sastry, Collagen based magnetic bionanocomposite as MRI contrast agent and for targeted delivery in cancer therapy, Biochim. Biophys. Acta Gen. Subj. 1830 (2013) 4628–4633. [66] X. Ma, A. Gong, B. Chen, J. Zheng, T. Chen, Z. Shen, A. Wu, Exploring a new SPIONbased MRI contrast agent with excellent water-dispersibility, high specificity to cancer cells and strong MR imaging efficacy, Colloids Surf. B: Biointerfaces 126 (2015) 44–49. [67] A.P. Majewski, A. Schallon, V. Jérôme, R. Freitag, A.H.E. Müller, H. Schmalz, Dualresponsive magnetic core–shell nanoparticles for nonviral gene delivery and cell separation, Biomacromolecules 13 (2012) 857–866. [68] Z. Shan, Y. Jiang, M. Guo, J.C. Bennett, X. Li, H. Tian, K. Oakes, X. Zhang, Y. Zhou, Q.  Huang, H.  Chen, Promoting DNA loading on magnetic nanoparticles using DNA condensation strategy, Colloids Surf. B: Biointerfaces 125 (2015) 247–254. [69] H. Liu, S. Li, L. Liu, L. Tian, N. He, An integrated and sensitive detection platform for bio sensing application based on Fe@au magnetic nanoparticlesas bead array carries, Biosens. Bioelectron. 26 (2010) 1442–1448. [70] S. Chandra, N. Barola, D. Bahadur, Impedimetric biosensor for early detection of cervical cancer, Chem. Commun. 47 (2011) 11258–11260. [71] D.  Ling, T.  Hyeon, Iron oxide nanoparticles: chemical design of biocompatible iron oxide nanoparticles for medical applications, Small 9 (2013) 1449. [72] M.  Mahmoudi, S.  Sant, B.  Wang, S.  Laurent, T.  Sen, Superparamagnetic iron oxide nanoparticles (SPIONs): development, surface modification and applications in chemotherapy, Adv. Drug Deliv. Rev. 63 (2011) 24–46. [73] D. Ling, M.J. Hackett, T. Hyeon, Surface ligands in synthesis modification, assembly and biomedical applications of nanoparticles, Nano Today 9 (2014) 457–477. [74] X. Lu, R. Jiang, M. Yang, Q. Fan, W. Hu, L. Zhang, Z. Yang, W. Deng, Q. Shen, Y. Huang, X. Liu, W. Huang, Monodispersed grafted conjugated polyelectrolyte-­stabilized magnetic nanoparticles as multifunctional platform for cellular imaging and drug delivery, J. Mater. Chem. B 2 (2014) 376–386. [75] K. Rouhollah, M. Pelin, Y. Serap, U. Gozde, G. Ufuk, Doxorubicin loading, release, and stability of polyamidoamine dendrimer-coated magnetic nanoparticles, J. Pharm. Sci. 102 (2013) 1825–1835. [76] X.L. Liu, E.S.G. Choo, A.S. Ahmed, L.Y. Zhao, Y. Yang, R.V. Ramanujan, J.M. Xue, D.D.  Fan, H.M.  Fan, J.  Ding, Magnetic nanoparticle-loaded polymernano spheres as magnetic hyperthermia agents, J. Mater. Chem. B 2 (2014) 120–128. [77] L.  Sun, Q.  Wu, F.  Peng, L.  Liu, C.  Gong, Strategies of polymeric nanoparticles for enhanced internalization in cancer therapy, Colloids Surf. B: Biointerfaces 135 (2015) 56–72.

190

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

[78] H.  Omar, J.G.  Croissant, K.  Alamoudi, S.  Alsaiari, I.  Alradwan, M.A.  Mahrati, D.H. Anjum, P. Martins, R. Lamantin, J. Epimer, B. Moussa, A. Almalik, N.M. Khashab, Biodegradable magnetic silica@iron oxide nanovectors with ultra-large mesopores for high protein loading, magnetothermal release, and delivery, J. Control. Release 259 (2017) 187–194. [79] Z.Ü. Akal, L. Alpsoy, A. Baykal, Superparamagnetic iron oxide conjugated with folic acid and carboxylated quercetin for chemotherapy applications, Ceram. Int. 42 (2016) 9065–9072. [80] A. Baykal, M.S. Toprak, Z. Durmus, M. Senel, H. Sozeri, A. Demir, Synthesis and characterization of dendrimer-encapsulated iron and iron-oxidenanoparticles, J. Supercond. Nov. Magn. 25 (2012) 1541–1549. [81] R. Esfand, D.A. Tomalia, Poly(amidoamine) (PAMAM) dendrimers: From biomimicry to drug delivery and biomedical applications, Drug Discov. Today 6 (2001) 427–436. [82] P. Goyal, K. Yoon, M. Weck, Multi-functionalization of dendrimers through orthogonal transformations, Chem. Eur. J. 13 (2007) 8801–8810. [83] N.  Fischer-Durand, M.  Salmain, B.  Rudolf, L.  Jugé, V.  Guérineau, O.  Laprévote, A.  Vessières, G.  Jaouen, Design of a new multi-functionalized PAMAM dendrimer with hydrazide-terminated spacer arm suitable for metal-carbonyl multi-labeling of ­aldehyde-containing molecules, Macromolecules 40 (2007) 8568–8575. [84] Y. Zhang, C. Zhou, K. Kwak, X. Wang, B. Yung, L.J. Lee, Y. Wang, P. Wang, R. Lee, Efficient siRNA delivery using a polyamidoamine dendrimer with a modified pentaerythritol core, Pharm. Res. 29 (2012) 1627–1636. [85] L.A. Tziveleka, A.M.G. Psarra, D. Tsiourvas, C.M. Paleos, Synthesis and characterization of guanidinylated poly(propylene imine) dendrimers as gene transfection agents, J. Control. Release 117 (2007) 137–146. [86] V.J. Venditto, C.A.S. Regino, M.W. Brechbiel, PAMAM dendrimer based macromolecules as improved contrast agents, Mol. Pharm. 2 (2005) 302–311. [87] S.  Langereis, Q.G.  de Lussanet, M.H.P.  van Gundersen, E.W.  Meijer, R.G.H.B.  Tan, A.W.  Griffins, J.M.A.  van Engelshoven, W.H.  Backes, Evaluation of Gd(III) DTPAterminated poly(propylene imine) dendrimers as contrast agents for MR imaging, NMR Biomed. 19 (2006) 133–141. [88] F. Qie, G. Zhang, J. Hou, X. Sun, S.Z. Luo, T. Tan, Extracting genomic DNA of food stuff by polyamidoamine (PAMAM)-magnetite nanoparticles, Talanta 93 (2012) 166–171. [89] C.M.  Paleos, D.  Tsiourvas, Z.  Sideratou, L.  Tziveleka, Acid- and salt-triggered multifunctional poly(propylene imine) dendrimer as a prospective drug delivery system, Biomacromolecules 5 (2004) 524–529. [90] L. Li, W. Jiang, K. Luo, H. Song, F. Lan, Y. Wu, Z. Gu, Superparamagnetic iron oxide nanoparticles as MRI contrast agents for non-invasive stem cell labeling and tracking, Theranostics 3 (2013) 595–615. [91] A.H. Lu, E.L. Salabas, F. Schüth, Magnetic nanoparticles: synthesis, protection, functionalization, and application, Angew. Chem. Int. Ed. 46 (2007) 1222–1244. [92] T.J. Yoon, W. Lee, Y.S. Oh, J.K. Lee, Magnetic nanoparticles as a catalyst vehicle for simple and easy recycling, New J. Chem. 27 (2003) 227–279. [93] I. Koh, L. Josephson, Magnetic nanoparticle sensors, Sensors 9 (2009) 8130–8145. [94] S.  Bucak, D.A.  Jones, P.E.  Laibinis, T.A.  Hatton, Protein separations using colloidal magnetic nanoparticles, Biotechnol. Prog. 19 (2003) 477–484. [95] C. Sun, J.S. Lee, M. Zhang, Magnetic nanoparticles in MR imaging and drug delivery, Adv. Drug Deliv. Rev. 60 (2008) 1252–1265.

Multistimuli-responsive magnetic assemblies191

[96] L. Liu, L. Tseng, Q. Ye, Y.L. Wu, D.J. Bain, C. Ho, A new method for preparing mesenchymal stem cells and labeling with ferumoxytol for cell tracking by MRI, Sci. Rep. 6 (26271) (2016) 1–10. [97] M.  de Smet, S.  Langereis, S.  van den Bosch, H.  Grull, Temperature-sensitive liposomes for doxorubicin delivery under MRI guidance, J. Control. Release 143 (2010) 120–127. [98] T.M. Allen, P.R. Cullis, Liposomal drug delivery systems: from concept to clinical applications, Adv. Drug Deliv. Rev. 65 (2013) 36–48. [99] A.M.  Christophe, B.D.  Burnand, B.R.  Rutishauser, M.  Lattuada, A.P.  Fink, Magnetoliposomes: opportunities and challenges, Eur. J. Nanomed. 6 (4) (2014) 201–215. [100] S. Mura, J. Nicolas, P. Couvreur, Stimuli-responsive nanocarriers for drug delivery, Nat. Mater. 12 (2013) 991–1003. [101] L.  Tavano, R.  Muzzalupo, Multi-functional vesicles for cancer therapy: the ultimate magic bullet, Colloids Surf. B: Biointerfaces 147 (2016) 161–171. [102] T.L. Andresen, S.S. Jensen, K. Jorgensen, Advanced strategies in liposomal cancer therapy: problems and prospects of active and tumor specific drug release, Prog. Lipid Res. 44 (2005) 68–97. [103] Y. Barenholz, G. Haran., (1994). Liposomes: efficient loading and controlled release of amphipathic molecules. US Patent No. 5,316,771. [104] Z. Symon, A. Peyser, D. Tzemach, et al., Selective delivery of doxorubicin to patients with breast carcinoma metastases by stealth liposomes, Cancer 86 (1999) 72–78. [105] M.L.  Immordino, F.  Dosio, L.  Cattel, Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential, Int. J. Nanomed. 1 (3) (2006) 297–315. [106] T.M. Allen, E. Brandeis, C.B. Hansen, G.Y. Kao, S. Zalipsky, A new strategy for attachment of antibodies to sterically stabilized liposomes resulting in efficient targeting to cancer cells, Biochim. Biophys. Acta 1237 (1995) 99–108. [107] J.W.  Park, D.B.  Kirpotin, K.  Hong, R.  Shalaby, Y.  Shao, U.B.  Nielsen, J.D.  Marks, D. Papahadjopoulos, C.C. Benz, Tumor targeting using anti-Her2 immunoliposomes, J. Control. Release 74 (2001) 95–113. [108] B. Du, S. Han, H. Li, F. Zhao, X. Su, X. Cao, Z. Zhang, Multi-functional liposomes showing radiofrequency-triggered release and magnetic resonance imaging for tumor multi-mechanism therapy, Nanoscale 7 (2015) 5411–5426. [109] J.P. May, S.D. Li, Hyperthermia-induced drug targeting, Expert Opin. Drug Deliv. 10 (2013) 511–527. [110] A.  Gharib, Z.  Faezizadeh, S.A.  Mesbah-Namin, R.  Saravani, Preparation, characterization and in vitro efficacy of magnetic nanoliposomes containing the artemisinin and transferrin, DARU J. Pharm. Sci. 22 (44) (2014) 1–7. [111] L.  Li, T.L.  ten Hagen, M.  Hossann, R.  Suss, G.C.  van Rhoon, A.M.  Eggermont, D. Haemmerich, G.A. Koning, Mild hyperthermia triggered doxorubicin release from optimized stealth thermosensitive liposomes improves intratumoral drug delivery and efficacy, J. Control. Release 168 (2013) 142–150. [112] P.T.  Wong, S.K.  Choi, Mechanisms and implications of dual-acting methotrexate in ­folate-targeted nanotherapeutic delivery, Int. J. Mol. Sci. 16 (2015) 1772–1790. [113] Y. Li, J. Lin, H. Wu, M. Jia, C. Yuan, Y. Chang, Z. Hou, L. Dai, Novel methotrexate prodrug-trageted drug delivery system based on PEG-lipid-PLA hybrid nanoparticles for enhanced anticancer efficacy and reduced toxicity of mitomycin C, J. Mater. Chem. B 2 (2014) 6534–6548.

192

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications

[114] Y. Guo, Y. Zhang, J. Ma, Q. Li, Y. Li, X. Zhou, D. Zhao, H. Song, Q. Chen, X. Zhu, Light/ magnetic hyperthermia triggered drug released from multifunctional, thermo-­sensitive magnetoliposomes for precise cancer synergetic theranostics, J. Control. Release 272 (2018) 145–158. [115] A. Ito, M. Shinkai, H. Honda, T. Kobayashi, Medical application of functionalized magnetic nanoparticles, J. Biosci. Bioeng. 100 (2005) 1–11. [116] P.  Yi, Y.  Wang, P.  He, Y.  Zhan, Z.  Sun, Y.  Li, Y.  Zhang, Study on β-cyclodextrin-­ complexed nanogels with improved thermal response for anticancer drug delivery, Mater. Sci. Eng. C 178 (2017) 773–779. [117] S. Laurent, A.A. Saei, S. Behzadi, A. Panahifar, M. Mahmoudi, Superparamagnetic iron oxide nanoparticles for delivery of therapeutic agents: opportunities and challenges, Expert Opin. Drug Deliv. 11 (2014) 1449–1470. [118] S.  Laurent, D.  Forge, M.  Port, A.  Roch, C.  Robic, L.  Vander Elst, R.N.  Muller, Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications, Chem. Rev. 108 (2008) 2064–2110. [119] E. Alphandéry, S. Faure, O. Seksek, F. Guyot, I. Chebbi, Chains of magnetosomes extracted from AMB-1 magnetotactic bacteria for application in alternative magnetic field cancer therapy, ACS Nano 5 (2011) 6279–6296. [120] K.H. Bae, M. Park, M. Do, N. Lee, J.H. Ryu, G.W. Kim, C.G. Kim, T.G. Park, T. Hyeon, Chitosan oligosaccharide stabilized ferrimagnetic iron oxide nanocubes for magnetically modulated cancer hyperthermia, ACS Nano 6 (2012) 5266–5273. [121] L. Traikov, I. Antonov, A. Gerou, L. Vesselinova, R. Hadjiolova, J. Raynov, Thermoinduced modifications and selective accumulation of glucose-conjugated magnetic nanoparticles in vivo in rats–increasing the effectiveness of magnetic-assisted therapy– pilot study, Electromagn. Biol. Med. 34 (2015) 228–232. [122] E.C.  Calvaresi, P.J.  Hergenrother, Glucose conjugation for the specific targeting and treatment of cancer, Chem. Sci. 4 (2013) 2319–2333. [123] O. Warburg, On the origin of cancer cells, Science 123 (1956) 309–314. [124] C. Wu, C. Lin, Y. Chen, Using glucose-bound Fe3O4 magnetic nanoparticles as photothermal agents for targeted hyperthermia of cancer cells, J. Nanomed. Nanotechnol. 6 (1000264) (2015) 1–7. [125] F.  Yang, M.  Li, Y.  Liu, T.  Wang, Z.  Feng, H.  Cui, N.  Gu, Glucose and magnetic-­ responsive approach toward in situ nitric oxide bubbles controlled generation for hyperglycemia theranostics, J. Control. Release 228 (2016) 87–95. [126] F. Yang, P. Chen, W. He, N. Gu, X. Zhang, K. Fang, Y. Zhang, J.F. Sun, J. Tong, Bubble microreactors triggered by an alternating magnetic field as diagnostic and therapeutic delivery devices, Small 6 (2010) 1300–1305. [127] Y. Zhang, Y. Liu, L. Su, Z. Zhang, D. Huo, C. Hou, Y. Lei, CuO nanowires based sensitive and selective non-enzymatic glucose detection, Sensors Actuators B Chem. 191 (2014) 46–57. [128] Y. Li, J. Fu, R. Chen, M. Huang, B. Gao, K. Huo, P. Chu, Core–shell TiC/C nanofiber arrays decorated with copper nanoparticles for high performance non-enzymatic glucose sensing, Sensors Actuators B Chem. 192 (2014) 474–479. [129] Z.  Shahnavaz, F.  Lorestani, Y.  Alias, M.  Woi, Polypyrrole–ZnFe2O4 magnetic ­nano-composite with core–shell structure for glucose sensing, Appl. Surf. Sci. 317 (2014) 622–629. [130] Z.  Jiawen, H.  Ritter, Cyclodextrin functionalized polymers as drug delivery systems, Polym. Chem. 1 (2010) 1552–1559.

Multistimuli-responsive magnetic assemblies193

[131] W.  Saenger, J.  Jacob, K.  Gessler, T.  Steiner, D.  Hoffmann, H.  Sanbe, K.  Koiumi, S.M.  Smith, T.  Takaha, Structures of the common cyclodextrins and their larger ­analogues-beyond the doughnut, Chem. Rev. 98 (1998) 1787–1802. [132] D.V.E.M. Martin, Cyclodextrins and their uses: a review, Process Biochem. 39 (2004) 1033–1046. [133] S. Gould, R.C. Scott, 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD): a toxicology review, Food Chem. Toxicol. 43 (2005) 1451–1459. [134] H. Wang, Y. Zhou, Y. Guo, W. Liu, D. Chuan, Y. Wu, S. Li, S. Shaomin, β-Cyclodextrin/ Fe3O4 hybrid magnetic nano-composite modified glassy carbon electrode for tryptophan sensing original research, Sens. Actuators B Chem. 163 (2012) 171–178. [135] S.S. Banerjee, D.H. Chen, Cyclodextrin-conjugated nanocarrier for magnetically guided delivery of hydrophobic drugs, J. Nanopart. Res. 11 (2009) 2071–2078. [136] B. Chertok, A.E. David, V.C. Yang, Brain tumor targeting of magnetic nanoparticles for potential drug delivery: effect of administration route and magnetic field topography, J. Control. Release 155 (2011) 393–399. [137] A.K. Gupta, M. Gupta, Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications, Biomaterials 26 (2005) 3995–4021. [138] R.  Zhang, C.  Wu, L.  Tong, B.  Tang, Q.-H.  Xu, Multifunctional core–shell nanoparticles as highly efficient imaging and photosensitizing agents, Langmuir 25 (2009) 10153–11015. [139] K. Uekama, F. Hirayama, H. Arima, Recent aspect of cyclodextrin-based drug delivery system, J. Incl. Phenom. Macrocycl. Chem. 56 (2006) 3–8. [140] A.M. Badruddoza, M.T. Rahman, S. Ghosh, M.Z. Hossain, J. Shi, K. Hidajat, M. Shahab Uddin, β-Cyclodextrin conjugated magnetic, fluorescent silica core–shell nanoparticles for biomedical applications, Carbohydr. Polym. 95 (2013) 449–457. [141] H. Cao, J. He, L. Deng, X. Gao, Fabrication of cyclodextrin-functionalized superparamagnetic Fe3O4/amino-silane sore–shell nanoparticles via layer-bylayer method, Appl. Surf. Sci. 255 (2009) 7974–7980. [142] N.  Sudha, S.  Yousuf, E.  Israel, M.S.  Paulraj, P.  Dhanaraj, On the accessibility of ­surface-bound drugs on magnetic nanoparticles. Encapsulation of drugs loaded on modified dextran-coated superparamagnetic iron oxide by β-cyclodextrin, Colloids Surf. B: Biointerfaces 141 (2016) 423–428. [143] P.  Zou, Y.  Yu, Y.A.  Wang, Y.  Zhong, A.  Welton, C.  Galbán, S.  Wang, D.  Sun, Superparamagnetic iron oxide nanotheranostics for targeted cancer cell imaging and pH-dependent intracellular drug release, Mol. Pharm. 7 (6) (2010) 1974–1984.

Further reading [144] F. Danhier, N. Lecouturier, B. Vroman, C. Jérôme, J. Marchand-Brynaert, O. da Feron, V. Préa, Paclitaxel-loaded PEGylated PLGA-based nanoparticles: in vitro and in vivo evaluation, J. Control. Release 133 (1) (2009) 11–17.