Oxide and Hybrid Nanostructures For Therapeutic Apps

Advanced Drug Delivery Reviews 63 (2011) 12671281
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Advanced Drug Delivery Reviews

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r
Oxide and hybrid nanostructures for therapeutic applications

Sudeshna Chandra, K.C. Barick, D. Bahadur
Department of Metallurgical Engineering and Materials Science, Indian Institute of Technology Bombay, Mumbai 400076, India
a r t i c l e
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a b s t r a c t
The research on biomedical applications of nanoparticles has seen an upsurge in recent years due to their unique capabilities in treatment of ailments. Though there are ample reviews on the advances of nanoparticles right from their fabrication to applications, comparatively fewer reviews are available for the nanostructured materials particularly on oxides and hybrids. These materials possess unique physicochemical properties with an ability to get functionalized at molecular and cellular level for biochemical interactions. Keeping the enormosity of the nanostructures in mind, we intend to cover only the recent and most noteworthy developments in this area. We, particularly emphasize on iron oxide and its derivatives, zinc oxides, layered double hydroxides, silica and binary/ternary metal oxides and their applications in the area of therapeutics. This review also focuses on the designing of biodegradable and biocompatible nanocarriers and critical issues related to their therapeutic applications. Several representative examples discuss targeting strategies and stimuli responsive nanocarriers and their therapeutics. 2011 Elsevier B.V. All rights reserved.
Article history: Received 2 February 2011 Accepted 8 June 2011 Available online 15 June 2011 Keywords: Nanostructures Hybrid Stabilizers Cancer therapy
Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . Properties of the nanostructures to be used as carriers . . . 2.1. Size and shape . . . . . . . . . . . . . . . . . . 2.2. Surface functionality . . . . . . . . . . . . . . . . 3. Stabilization of oxide and hybrid nanostructures . . . . . . 3.1. Organic stabilizers . . . . . . . . . . . . . . . . 3.1.1. Small molecules . . . . . . . . . . . . . 3.1.2. Macromolecules . . . . . . . . . . . . . 3.2. Inorganic stabilizers . . . . . . . . . . . . . . . . 3.3. Other stabilizers . . . . . . . . . . . . . . . . . . 4. Therapeutic applications of oxide and hybrid nanostructures 4.1. Challenges faced in the drug delivery . . . . . . . 4.1.1. Drug loading and release . . . . . . . . . 4.1.2. Cellular uptake and Imaging . . . . . . . 4.2. Hyperthermia treatment of cancer . . . . . . . . . 4.3. Other therapeutic applications . . . . . . . . . . . 4.4. Towards clinical trials . . . . . . . . . . . . . . . 5. Conclusion and future scope . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1267 1268 1268 1268 1269 1269 1269 1269 1270 1270 1271 1271 1271 1274 1276 1277 1277 1278 1278 1278
1. Introduction
This review is part of the Advanced Drug Delivery Reviews theme issue on Hybrid Nanostructures for Diagnostics and Therapeutics. Corresponding author. E-mail address: dhirenb@iitb.ac.in (D. Bahadur). 0169-409X/$ see front matter 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2011.06.003
Advances in nanotechnology play an important role in designing nanomaterials with specic functional properties that can address the shortcomings in the area of diagnostics and therapeutics. The potential of nanomaterials has sparked enormous interest in the
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drug industry and has envisaged several applications, as can be evidenced by the exponential growth of activities in this eld. The advantages of the nanoparticles are mainly due to their nanoscale size and large surface area with the ability to get functionalized with targeting ligands, therapeutic moieties and biomolecules [1]. The fact that the size of the nanoparticles is quite similar or smaller to the size range of several bio entities makes them a natural companion in the hybrid system. Furthermore, the nanoparticles can easily gain access to various areas of the body without interfering into normal functions and has the requisite potential for diagnostic and therapeutics. The ability to manipulate/bind individual molecules at nanoscale has provided ample opportunity for new therapeutic and diagnostic applications [2]. In this way, either hybrid nanostructures can be obtained or it may be embedded in biocompatible materials to impart new functionalities. Since multifunctional nanostructures are desirable for many applications like chemical and biological sensing and diagnosis [38], sustained drug delivery [9] and hyperthermia [10,11], the fabrication of the nanostructures is signicant for controlling crystalline morphology and surface architecture. Drug delivery is a key technology for the realization of nanomedicine and nanostructured mediated drug delivery systems play an important role in improving the properties of already existing therapeutic and diagnostic modalities. Such systems with controlled composition, shape, size and surface morphology are designed to enhance solubility, biocompatibility, stability of the carrier and cellular uptake. The effectiveness of these has also been improved signicantly as delivery vehicles with increased therapeutic payload [3,4,12]. Ideally, the nanostructured delivery vehicles should be able to efciently load high weight fraction of drugs, and must form a stable suspension in an aqueous medium. These also need to be biodegradable and/or biocompatible. Drugs are usually encapsulated in, conjugated to, or adsorbed onto surface of the nanocarrier and are triggered released by heat, pH or other modes of electromagnetic radiation like ultrasound. The nanoscale drug delivery system also helps in stabilizing drug molecules [6,13,14] which would otherwise degrade rapidly and reduce drug efcacy. These benets have accounted for extensive research in the development of nanostructures and their interactions. Most of these are hybrid nanomaterials and are formed using weak molecular interactions such as Hbonding, van der Waal forces, and other surface forces which require low energy, thereby allowing reversible and subsequent changes that are essential for a bioprocess to take place. Thus, understanding the interactions helps in broadening therapeutic strategies, and designing and improving drug delivery system. In this context, researchers have studied the tunable properties of the nanomaterials by altering the size, shape, and chemical composition and have developed strategies to design biocompatible nanostructures of desired functionality with and without biomolecules [1521]. Quantum dots (QDs) are an archetype of this hybrid material which have gained interest due to their tunable optical properties and have been considered as potential optical probes for biological imaging. They are resistant to degradation than other optical imaging probes and hence, can track cell processes for longer periods and give more information on molecular interactions, drug delivery or locating a tumor and to arm it with toxic therapies. Thus, while this review aims to cover the fabrication, and functionalization/stabilization of various oxide and hybrid nanostructures, it will also attempt to discuss their therapeutic applications. We will emphasize on magnetic nanostructures for drug delivery and magnetic hyperthermia treatment of cancer. After a brief introduction to the nanoparticulates and the hybrids, effective methods for functionalization and stabilization of these structures are discussed. The application of the oxides and hybrid nanostructures in biomedicine is presented in the nal section. In this review, noteworthy and most recent scientic advances dealing with the therapeutic application of a wide variety of oxides and hybrid nanostructures such as silica, iron oxide and its derivatives, zinc oxide,
layered double hydroxides, and binary/ternary metal oxides are reported. We also emphasize here on designing of biodegradable, biocompatible, thermosensitive or pH sensitive nanocarriers for their use in drug delivery and hyperthermia. Some recent advances with respect to sustained and triggered drug release have been delineated. Further, the critical issues related to the therapeutic applications of oxide and hybrid nanostructures have been addressed and several representative examples to highlight these applications have been covered briey in this review. 2. Properties of the nanostructures to be used as carriers The therapeutic applications of oxide and hybrid nanostructures strongly depend on their physicochemical properties such as permeability, stability, morphology (size, shape and functionality) and biocompatibility. These physicochemical properties are dictated by the types, structures and orientations of the materials that comprise the oxide and hybrid nanostructures. The nanoparticles and their hybrids used for therapeutic applications include both porous and non-porous forms of non-toxic oxides having surface functionality to which targeting ligands and additional imaging modalities are anchored. One of the most extensively investigated oxide is iron oxide (-Fe2O3, Fe3O4) and its derivatives [2226]. Therapeutic agents like drugs and biomolecules can then either be physically embedded into the porous matrix or chemically bonded to its surface. Obvious advantages of using magnetic oxides in therapeutic applications include magnetic drug targeting, heating ability for hyperthemia and separation under external magnetic eld. 2.1. Size and shape The size and size distribution, shape and surface functionality of oxide nanocarriers are important parameters related to intracellular uptake and biodistribution to a wider range of biological targets due to their smaller size and relatively higher mobility. The small sized nanoparticles (b 100 nm) have higher effective surface area facilitating easy attachment of ligands, lower sedimentation rates (high stability in colloidal suspension) and improved tissular diffusion. For most of therapeutic applications, the rst signicant challenge is to avoid undesirable uptake of nanoparticles by the reticulo-endothelial system (RES). The next step is to achieve selective targeting of the system to the site of interest for the in-vivo studies. In order to overcome these problems, nanoparticles should be small enough with desired functionality to escape from the RES. These nanoparticles should remain in the circulation for prolonged time after injection into bloodstream and should be capable of passing through the ne capillary systems of organs and tissues avoiding vessel embolism. The size (hydrodynamic size) controls the nanoparticles concentration prole in the blood vessel, affects the mechanism of nanoparticles clearance and mediates the permeability of nanoparticles out of the vasculature [27]. Small sized spherical nanoparticles have higher diffusion rates which increase the concentration of nanoparticles at the center of a blood vessel, thereby limiting the interactions of nanoparticles with endothelial cells and prolonging the nanoparticles blood circulation time [28]. Park et al. [29] reported that anisotropic iron oxide having high aspect ratio shows enhanced blood circulation times over their spherical counterparts. Other than size and shape, the pore size and its distribution have signicant effect on the therapeutic applications due to its enhanced surface area and its ability to contain and release drug [30]. This aspect is discussed in a later section. 2.2. Surface functionality The surface charge (zeta potential) of nanoparticles has an important role to play in their physiological and aqueous colloidal stability as well as in functionalization and designing promising
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nanostructures. It can be easily controlled by the nature of the surface groups in solution at a particular pH. A high positive or negative zeta potential value is an indication of the colloidal stability of nanoparticles due to the electrostatic interaction. It is reported that the surface of the nanoparticles determines their cellular interaction, especially during endocytosis and phagocytosis. A strong correlation between the surface charge and their cellular uptake efciency into different cell lines has been observed. It is further reported that the hydrophobic groups on the surface of nanoparticles induce agglomeration upon injection, leading to rapid removal by the RES [31]. Thus, surface modication with hydrophilic molecules is essential to reduce the opsonization potential through steric repulsion, prolonging the circulation time of nanoparticles. The surface modication of nanoparticles for their aqueous/physiological stabilization is important for most of the therapeutic applications and hence will be discussed in more detail in the following section. 3. Stabilization of oxide and hybrid nanostructures The colloidal stabilization of the nanoparticles in both aqueous and physiological medium is crucial for their therapeutic applications and can be achieved by either charging the surface or conjugating it by macromolecules for steric hindrance. The surface charge can be monitored and ensured by suitable means such as changing pH of the medium or modifying with functional groups. The steric stabilization can be achieved by attaching/grafting of macromolecules such as surfactant [32] or polymer [33] on the surface. The steric stabilization is indeed less sensitive to the ionic strength of the suspension medium and can be easily achieved in both polar and non-polar medium. The oxide nanoparticles may be stabilized either during their synthesis or in a post-synthesis process. The in situ modication during synthesis process has several advantages including reduced agglomeration [34]. These biocompatible layers stabilize the nanoparticles and provides accessible surface for routine conjugation of biomolecules. 3.1. Organic stabilizers 3.1.1. Small molecules The small molecule targeting groups are predominantly attractive for stabilizing oxide nanoparticles due to their ease of preparation and simple conjugation chemistry [35]. The binding afnity of large surfactant molecules or long polymer chains to the nanoparticles may be lost due to steric hindrances, which could otherwise be easily overcome by using small molecules having multiple functional groups such as carboxyl (COOH), amine (NH2), thiol (SH), phosphate and sulfates. These stabilizers can be tailored for dispersibility into aqueous media or other biocompatible uids. The presence of hydroxyl groups on the surface of oxide nanoparticles provides a versatile route for multiple functionalities. Furthermore, the presence of large number of functional groups on the surface of nanoparticles may be used for linkage of various biomolecules as well as drugs. Thus, the stability of the bonding between functional molecules and nanoparticles is crucial for therapeutic applications. Among various small molecules, citrate moiety having multiple carboxylate functionalities has been extensively used for the colloidal stabilization of oxide nanoparticles. The functional groups are chemisorbed on the surface of the oxide nanoparticles by coordinating via one or two of the carboxylate functionalities, depending upon size and shape of the particles and leaving at least one carboxylic acid group exposed to the solvent. The free carboxylic groups render sufcient negative charge on the surface of particles and hence, make them hydrophilic [36]. The short chain amines and aminosilanes are commonly used as stabilizing agent in fabrication of various oxide nanoparticles. Recently, Barick et al. [22,32] demonstrated a single-step facile approach for highly water-stable assembly of amine-functionalized
Fe3O4 nanoparticles using thermal decomposition of Fe-chloride precursors in ethylene glycol medium in the presence of sodium acetate and ethylenediamine for bio-applications and compared their magnetic resonance (MR) contrast behavior. In addition to short chain amine and aminosilanes, various amino acids [37] and peptides [38] having multiple amine molecules have been used as stabilizer for successful design of oxide nanoparticles. Small molecules having thiol functionality achieved great deal of attention due to their higher binding afnity towards metal and metal oxide nanoparticles. The organosulfur compound, 2,3-meso dimercaptosuccinic acid (DMSA) having two carboxylic and two thiol groups have been commonly used as a stabilizing agent for inorganic oxides. MNPs have been stabilized with DMSA for tissue- and cell-targeted delivery of therapeutic drugs in the lung [39]. Specically, the mechanism of the pro-inammatory effects of MNPsDMSA has been investigated. Maurizi et al. [40] developed a convenient method to stabilize free thiols onto the surface of iron oxide nanoparticles by post functionalization using methoxy PEG 2000 silane and observed that thiol functionalized nanoparticles were stable under physiological pH. Furthermore, they have demonstrated that the stability of thiols can be increased signicantly when DMSA is protected by polyethyleneglycol (PEG) chains on the surface of nanoparticles. DMSA stabilized aqueous colloidal Fe3O4 nanoparticles were fabricated by introducing DMSA molecules onto the surface of hydrophobic nanoparticles through ligand exchange process [22]. 3.1.2. Macromolecules A variety of polymer molecules have been used for steric stabilization of oxide nanoparticles in aqueous and high ionic strength media [4143]. The polymer shell improves the stability of nanoparticles in solution and allows the encapsulation of a therapeutic agent. Further, these stabilizers provide a means to tailor the surface properties of nanoparticles such as surface charge and chemical functionality or their thermosensitive properties. Major facts with regard to polymeric stabilizer that may affect the performance of nanocarriers include the chemical nature of the polymer (i.e., hydrophilicity/hydrophobicity, biocompatibility and biodegradation), the molecular weight of the polymer, the manner in which the polymer is grafted or attached (i.e., physically or chemically), the conformation of the polymer and the degree of particle surface coverage. Among various macromolecules, dextran has been widely used for surface modication mostly because of its favorable size (chain length) and biocompatibility, which enables optimum polar interactions (mainly chelation and hydrogen bonding). Dextran coating not only provides a smooth outline and narrow size distribution but also retains the essential superparamagnetic behavior of iron oxide nanoparticles and a signicantly prolonged the storage stability [44]. Pradhan et al. [45] fabricated dextran coated Fe3O4 nanoparticles by co-precipitation method and compared their in vitro cytocompatibility and cellular interactions with mouse broblast and human cervical carcinoma cell lines with lauric acid-coated Fe3O4 nanoparticles. The surface modication was found to play an important role in modulating biocompatibility and cellular interaction of MNPs. PEG is a hydrophilic, water-soluble, biocompatible polymer and extensively used to increase blood circulation times. Xie et al. [42] used controlled PEGylation method and dopamine as a cross-linker to produce monodisperse Fe3O4 nanoparticles. PEG was successfully anchored on the nanoparticles through a covalent bond which showed negligible aggregation in cell culture condition and reduced non-specic uptake by macrophage cells. These MNPs based systems are capable of site-specic targeting and controlled drug release with high biocompatibility. The temperature-sensitive poly N-isopropylacrylamide (PNIPAAm) based MNPs are also of particular interest because of their stimuli (temperature) responsiveness and enhanced drug-loading ability [46]. Wong et al. [47,48] fabricated thermoresponsive
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PNIPAAm microgel through LBL technique possessing both thermoresponsivity and magnetism with high specic absorption rate which could open up new prospects for remotely controlled drug carriers. Other polymers that display some thermosensitivity near physiological or hyperthermic conditions include hydroxypropyl cellulose (HPC) [49], pluronic triblock copolymer surfactants and block copolymers [50]. The formulation of the nanoparticulates can also be realized by using Food and Drug Administration (FDA) approved biodegradable polymers such as poly (lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) and various novel biodegradable copolymers such as poly(lactic acid-coethylene glycol) (PLEA) and copolymer of (lactic acid-D--tocopherol polyethylene glycol 1000 succinate) (PLA-TPGS) [51,52]. Various other polymers used for aqueous stabilization of iron oxide magnetic nanoparticles are sodium alginate [53], L-arginine [54], polyacrylic acid (PAA) [55], poly(allylamine) [56], acrypol 934 [26] and chitosan [57]. 3.2. Inorganic stabilizers Silica (SiO2), gold (Au) and silver (Ag) are extensively used for surface modication of the oxide nanoparticles which forms core shell structures, and provides stability to the nanoparticles in solution and further help in binding various biological molecules and drugs to the surface of nanoparticles through suitable functional groups. The stabilization of oxide nanoparticles by silica can easily be achieved either by Stber process or microemulsion method [58,59]. SiO2 stabilized Fe3O4 coreshell nanoparticles functionalized with phosphorescent iridium-complex has been used for applications in photodynamic therapy [60]. Surface modication with alumina of a substituted garnet system, in an attempt to tune the TC of the magnetic oxides for in vivo control during hyperthermia is also noteworthy [61]. There has been considerable interest in stabilizing oxide nanoparticles with noble metal shells such as Au and Ag. The magnetic oxide nanoparticles with metal coating can be effectively stabilized in corrosive biological conditions and can be readily functionalized through the well-established metal-sulfur chemistry. The magnetic coreshell nanoparticles with tunable plasmonic properties have great potential for nanoparticle-based diagnostic and therapeutic applications [6264]. Dumbbell shaped AuFe3O4 nanoparticles with
controlled plasmonic and magnetic properties were reported to act as target-specic nanocarriers to deliver cisplatin into Her2-positive breast cancer cells with strong therapeutic effects. When compared to conventional single-component iron oxide NPs, the AuFe3O4 NPs were advantageous in facilitating stepwise attachment of an antibody to a platin complex and also for serving as magnetic and optical probe for tracking the drug in the cells [64]. The most signicant advantage of this composite system is that it provides controlled magnetooptical properties, long term stability to the magnetic core and functionality to the nanoparticles. 3.3. Other stabilizers The amphiphilic molecules such as liposomes and micelles have been successfully used to stabilize oxide nanoparticles for therapeutic applications [65,66]. Liposomes have also the ability to encapsulate a large number of nanoparticles and deliver them together to the specic target site. Both hydrophilic and hydrophobic foreign molecules such as drugs and biomolecules can be easily anchored to the amphiphilic liposomes and micelles which can enhance the multifunctionality of a system. Martina et al. [67] developed magnetic uid-loaded liposomes by encapsulating -Fe2O3 nanocrystals within unilamellar vesicles of egg phosphatidylcholine and DSPE-PEG2000. Further, it was also found that phospholipid molecules (egg phosphatidylcholine), which are essential precursors for liposome formation may also inuence the nucleation and growth characteristics of MNPs. The effects of phosphatidylcholine (PC) on the synthesis of MNPs and magnetoliposomes and their properties have been well discussed [68]. Fig. 1 shows a schematic representation of TEM micrographs of various stabilizers used for stabilizing magnetic nanoparticles. Recently, dendrimers a novel class of macromolecules with highly ordered structure has received signicant attention for functionalization and stabilization of oxide nanoparticles. Dendrimer coating alters the surface charge, functionality and reactivity, and enhances the stability and dispersibility of the nanoparticles. Furthermore, the presence of multiple functional groups with symmetric perfection and nanometer scale internal cavities enables dendritic stabilized nanoparticles for incredible biomedical applications including targeting, imaging, and sensing. Magnetic iron oxide nanoparticles have been successfully
Fig. 1. Schematic representation of different stabilizers for stabilizing magnetic nanoparticles along with some selected TEM micrographs: (a) 2,3-dimercaptosuccinic acid (DMSA) functionalized Fe3O4 nanoparticles [22], (b) dopamine-PEG functionalized Fe3O4 nanoparticles [42], (c) iridium-complex functionalized Fe3O4/SiO2 core/shell nanoparticles [60] and (d) doxorubicin-supermagnetic iron oxide (SPION) loaded polymeric micelles [65]. (Reproduced with permission from [22] copyright RSC publications; [42,60] Copyright John Wiley and Sons, Inc. and [65] Copyright 2006 American Chemical Society Publications.)
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stabilized with different generation of polyamidoamine (PAMAM) dendrimers for gene delivery [69]. Chandra et al. [70] demonstrated a facile approach for the preparation of dendrimers coated Fe3O4 nanoparticles for drug delivery application. In this method, dendritic structures were grown on the silane coated iron oxide nanoparticles using methylacrylate and a biocompatible arginine as monomers. Taratula et al. [71] reported a multifunctional superparamagnetic nanoparticles-poly(propyleneimine) G5 dendrimer (SPION-PPI G5) for siRNA delivery system for cancer therapy. PEG coating and LHRH targeting peptide was incorporated into SPIO-PPI G5siRNA complexes to enhance serum stability and selective internalization by cancer cells. Bulte and coworkers labeled human neural stem cells and mesenchymal stem cells with magnetodendrimers through a non-specic membrane adsorption process with subsequent intracellular localization in endosomes. The labeled neural stem-cells derived oligodendroglial progenitors were readily detected in vivo by MR signals. The magnetomers were also used to track the olfactory ensheathing glia grafted into rat spinal cord in vivo [72]. However, there were no specic interaction between the particles and the target cells since the magnetodendrimers did not have any specic surface modication. Modication of the magnetodendrimers with biological receptors or antibodies opens up the possibility of their use for specic application right from targeting to a site, transiting the cell membrane and making intracellular delivery. 4. Therapeutic applications of oxide and hybrid nanostructures Controlled synthesis of individual monodisperse nanoparticles led to the evolution of nanostructures with improved magnetic, conducting, uorescent and targeting properties for potential bio-medical applications. Coreshell nanoparticles, LBL assembly [73] and other nanocomposites encompassing a broad range of materials and various nanostructural morphologies (spherical, cylindrical, star-like etc.) are becoming the main building blocks for next generation of drug delivery systems. 4.1. Challenges faced in the drug delivery Most of the delivery systems have limitations of poor pharmacokinetics and targeting efciency. It is important that the drug molecule is carried only to the affected site without affecting other parts of organs and tissues. In addition, many of these systems need to provide stability, a sustained or burst release, non toxicity, solubility in aqueous media and bio-distribution to suit a particular therapy. These therapeutic agents could be in the form of microcapsules, dispersion, adsorbed entities, as a conjugate to nanoparticulates or loaded to porous or hollow structures. Let us look at some of the potential drug delivery systems which include several oxide systems as well as hybrid structures. Although many organic systems such as liposomes, dendrimers or other macromolecules are used as excellent drug carriers, but we are limiting our discussion only to inorganic oxide/hydroxide systems or their hybrids with organic moieties. In this context, a number of organic/inorganic hybrids have been investigated as delivery vehicles to develop effective therapeutic modalities. So far, only a few therapeutic products have been approved by FDA for clinical use; of these, most are based on nontargeted delivery system. The miniaturization of the materials to nanoscale incorporates new properties within themselves which should be carefully characterized to avoid any un-intended side effects. The increased activity of the nanostructures can either be desirable in terms of therapeutic capacity, cell barrier penetration for drug delivery, induction of oxidative stress or cellular dysfunction or a combine effect of both [74]. The toxicity of the nanoparticles remains a major issue towards fabrication of nanomedicine and it mainly depends on factors like chemical composition, surface chemistry, dose quantication, particle size, biodistribution and biodegradability etc. Fe particles with a uniform epitaxial shell of MgO and the nanoparticles satised all the
technical requirements for clinical use including high biocompatibility in living cells, injection through blood vessels without any clotting, high absorption rate for magnetic hyperthermia and as contrast agent in MRI [75]. The in-vivo animal experiments showed that a total iron dose about 0.6 mg/kg showed no apparent acute toxicity, or side effects over a monitoring period of 3 weeks. Biocompatibility results of PVA coated magnetic nanoparticles on L929 and K562 cells demonstrated acceptable cell viability levels following exposure of upto 20 mM iron concentration and neither apoptosis nor necrosis took place [76]. Kikumori and co-workers [77] developed anti-HER2 magnetoliposomes (HML) for effective targeting of breast cancer cells and cytocidal abilities of the HML has been achieved using cell culture models. Their studies show that the growth of tumor is almost suppressed by just two hyperthermia treatments and no iron accumulation was observed in the organs (e.g. liver, spleen, brain, heart etc.) of the HML-injected mice. Further, in a rat model also, no specic pathologic changes were observed in liver, spleen, heart and brain even after repeated subcutaneous injection of HML. A signicant decrease in glioblastoma cell survival was observed after treatment with epidermal growth factor receptor (EGFRvIII) antibody-conjugated iron oxide nanoparticles. Further, an increase in animal survival was found after convection-enhanced delivery (CED) of magnetic nanoparticles in mice implanted with tumorigenic glioblastoma xenografts [78]. There has to be focus on developing targeted, controlled and sustained drug release systems, which can convey drugs more effectively, increase patient compliance, reduce cytotoxicity to normal cells and extend circulation time. 4.1.1. Drug loading and release The efciency of drug loading and release strongly depends upon the ability to design a biocompatible colloidal nanocarrier that allows high loading of drug molecules without any premature release of drug before reaching the destination. Thus, the carrier should have good biocompatibility properties with higher encapsulation efciency and should exhibit site specic control release of drug molecules. Among a variety of drug carriers, mesoporous silica and zinc oxide nanoparticles have several striking features for use in the drug delivery. These nanoparticles have large surface area and porous interiors that can be used as reservoirs for storing drug molecules. The pore size and surrounding environment can be easily tuned to preferentially store various drug molecules of interest while the size and shape of the nanoparticles can be tailored to maximize the cellular uptake [79]. Mesoporous silica has been successfully used for storing of drug molecules (Ibuprofen) into the pores through hydrogen bond interaction between the ibuprofen and the silanol groups present in the pore wall [80]. It was observed that the release rate of ibuprofen in a simulated body uid solution increased signicantly under the pulsed pressure drop. An interesting photothermal modulated drug delivery system was designed based on silicagold (SiO2Au) nanoshells consisting of a silica core surrounded by a gold shell [81]. The peak extinctions of the nanoshells are easily tuned over a wide range of wavelengths particularly in the near infrared (IR) region of the spectrum and the light in this region is transmitted through tissue with relatively little attenuation due to absorption. Also, irradiation of SiO2Au nanoshells at their peak extinction coefcient results in the conversion of light to heat energy that produces a local rise in temperature. Further, SiO2Au nanoshells were embedded into a temperature-sensitive hydrogels (N-isopropylacrylamide-co-acrylamide (NIPAAm-co-AAm)) for the purpose of initiating a temperature change with light for triggered release of drug molecules. The composite hydrogels had the extinction spectrum of the SiO2Au nanoshells in which the hydrogels collapsed reversibly in response to temperature (50 C) and laser irradiation. Recently, the drug-loading efciency of a highly mesoporous spherical three dimensional ZnO nanoassemblies was investigated using doxorubicin hydrochloride (DOX) as a model drug by our research group [82]. The interaction and entrapment of drug molecules
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Fig. 2. Triggered drug release in presence of various external stimuli such as (a) pH [82], (b) ultrasound [82], (c) temperature [66] and (d) AC magnetic eld [70] (Reproduced with permission from [82,70] copyright RSC publications and [66] copyright Elsevier License.)
with ZnO were evident from the quenching of the uorescence as well as the shift in band positions. The drug release showed strong dependence on the pH of the medium, ultrasound energy (continuous or pulsatile), and the nature of encapsulents (Fig. 2a, b). The drug-loaded ZnO nanoassemblies released about 90 and 65% of loaded drug in acetate buffer-pH 4 and acetate buffer-pH 5 media, respectively, after 33 h. About 26% DOX was released from the DOX-loaded ZnO nanoassemblies under continuous irradiation of ultrasound for 60 min in aqueous media whereas in pulsatile mode (ONOFF condition) about 42.5% of loaded drug was released. Another approach which received great attention is of combining anti-cancer drug therapy with quantum dot technology. Yuan et al. [83] synthesized blue-light emitting ZnO quantum dots (QDs) and then combined them with biodegradable chitosan (N-acetylglucosamine) to use in tumor-targeted drug delivery. The hydrophilicity and cationic surface charge of chitosan enhanced the stability of the QDs. Drug-loading efciency of these carriers was about ~75% with an initial rapid drug release followed by a controlled release. This study has thrown new insight towards the application of water-dispersed ZnO QDs (24 nm) in designing of new drug release carrier with longterm uorescence stability. Recently, Li et al. [84] studied the cytotoxicity and photodynamic effect of different-sized ZnO nanoparticles to cancer cells. They have observed that ZnO nanoparticles exerted time and dose dependent cytotoxicity for cancer cells. The suppression ability of ZnO nanoparticles for cancer cells proliferation was found to be enhanced by UV irradiation. These results suggested that ZnO nanoparticles could play an important role in drug delivery to enhance the accumulation and the synergistic cytotoxicity of daunorubicin in the target SMMC-7721 cells. Thus, the uorescent ZnO nanoparticles could be developed for simultaneous detection and localization of multiple solid cancer biomarkers, enabling the personalization of therapeutic regimens for each patient. These nanoparticles can be easily conjugated with
tumor-specic ligands and used for tumor-selective delivery of chemotherapeutic agents as well as photodynamic cancer therapy. The slight solubilization of the biocompatible ZnO nanocarriers at lower pH can also facilitates the drug release. Such pH-triggered release is advantageous in chemotherapy, since the relatively lower pH in tumors specically stimulate the drug release at the target site. In addition, these systems also work under the ultrasound or UV irradiation (continuous or pulsatile) for controlled and targeted on-demand drug delivery. Targeting is the biggest challenge. Generally, when the drug is administered, it would not have any site of preference and hence may distribute all over the organs, which in many cases are undesirable due to its toxic nature. Active targeting is a preferred modality through the modication of nanoparticles with ligands which has the attributes to enhance the therapeutic efcacy and reduce the side effects relative to conventional therapeutics. Various factors such as delivery vehicles, drugs, and diseases inuence the targeted delivery. It is therefore desired that the delivery system has some moieties attached to the carrier which either gets bound to the diseased site or preferentially overexpress to the target site. Ligand mediated cellular uptake is a valuable pathway for therapeutics. Some of the important targeting ligands are folate, antibodies and their fragments, and different peptides. For diseases like tumor or ination, passive targeting also occurs due to leaky vasculature. Most tumors exhibit pores within their vasculature of typical size between 350 and 400 nm. This facilitates drug concentration in tumor or inated regions by extravasation. Any targeting, however, demands that nanocarriers circulate in blood for extended times. Nanoparticulates, otherwise, exhibit short circulation half lives which can be enhanced by suitable surface modication with long circulating molecules like PEG. Due to its several favorable properties like hydrophilic nature, low degree of immunogenicity and availability of terminal primary hydroxyl groups for functionalization, PEG is most extensively used for this purpose.
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The magnetically targeted-drug delivery system is considered one of the most popular and efcient methods. In this technique, the drug carrying MNPs with a suitable carrier system taken orally or injected through vein may be directed to the diseased area by an external magnetic eld. A novel method for entrapping positively charged drug molecules (DOX) onto the surface of negatively charged citratestabilized 810 nm Fe3O4 magnetic nanoparticles (CA-MNP) through electrostatic interactions is recently developed by Nigam et al. [85]. The drug loading efciency of about 90% (w/w) was achieved by electrostatic interaction of DOX with CA-MNP and the DOX conjugated CA-MNP exhibited a sustained release prole. It has been observed that bound drug molecules are released in appreciable amounts in the mild acidic environments of the tumor. Storage and release of cisplatin using porous hollow nanoparticles (PHNPs) of Fe3O4 were studied [86]. The porous shell (pore size of about 24 nm) was stable in neutral or basic physiological conditions, and cisplatin releases from the cavity through a diffusion-controlled slow process. A composite membrane based on thermosensitive, poly(NIPAAm)based nanogels and magnetite nanoparticles was developed which enabled rapid, and tunable drug delivery upon the application of an external oscillating magnetic eld [87]. Onoff release of sodium uorescein over multiple magnetic cycles has been successfully demonstrated using prototype non-cytotoxic, biocompatible membrane-based switching devices. The total drug dose delivered was directly proportional to the duration of the on pulse. Coreshell nanoparticles of similar composition showed signicantly lower systemic toxicity and DOX encapsulation efciency of 72% [88]. The drug release study indicated that the polymer is sensitive to temperature which undergoes phase change at LCST resulting into the collapse of nanoparticles thereby releasing more drugs. After 72 h, 78% of the encapsulated DOX was released at 41 C, whereas at 4 C and 37 C, ~26% and ~43% was released, respectively. Released drugs were also active in destroying prostate cancer cells and the nanoparticle uptake by these cells was dependent on dose and incubation time. Folate-targeted doxorubicin-containing magnetic liposomes (MagFolDox) shows temperature dependent drug release (Fig. 2c) after 1 h incubation in PBS and FBS medium [66]. In 50% FBS, upto 46% DOX was released from FolDox, but in the presence of magnetic eld, it increased to 52%. Zhang et al. [89] described in vitro drug delivery response of polyethylene glycol (PEG)-functionalized magnetite (Fe3O4) nanoparticles, which were activated with a folic acid and conjugated with doxorubicin. Here, the drug release involved Fickian diffusion through pores in the polymer matrix. The diffusion of drug from biodegradable polymer is often dictated by the excluded volume and hydrodynamic interactions. Other factors that inuenced the drug release response are drug solubility, polymer degradation and polymerdrug interaction. The composites of biocompatible bovine serum albumin (BSA) dextranchitosan nanoparticles were effectively used to load DOX into the nanoparticles after changing the pH of their composite to 7.4 [90]. These nanoparticles exhibited faster release of doxorubicin at pH 5.0 (acetate buffer) than at pH 7.4 (PBS buffer). The protonated doxorubicin decreases the hydrophobic interactions which lead to electrostatic repulsion between the nanoparticles and the doxorubicin thereby releasing at a faster rate. The performance of gelatin coated iron oxide MNPs as drug carrier was evaluated for drug targeting of doxorubicin (DOX) [91] where the drug loading was done using adsorption as well as desolvation/cross-linking techniques. Compared to adsorption technique, desolvation/cross-linking technique improved the efciency of drug loading regardless the type of gelatin used for the coating. The DOX-loaded particles showed pH responsive drug release leading to accelerated release of drug at pH 4 compared to pH 7.4. Recently, dendritic magnetic Fe3O4 nanocarriers (DMNCs) for drug delivery application in presence and absence of AC magnetic eld are explored by Chandra et al. [70]. The pH triggered release prole of DOX loaded DMNCs clearly shows a sustained release over a period of 24 h
with a maximum of 54%. Interestingly, the steady linear release steepens upon application of the AC magnetic eld. About 35% of the drug was released in the rst 45 min in the absence of a magnetic eld whereas the release percentage further increased to 80% under the continuous application of AC magnetic eld over the next 15 min. The enhanced release of the drug molecules in the AC magnetic eld is favorable for combined therapy involving drug delivery and hyperthermia (Fig. 2d). Furthermore, the surface of dendritic magnetic nanocarriers can be easily tailored to provide precise anchoring sites to conjugate various biomolecules. Due to their versatility, the dendritic magnetic nanocarriers can also incorporate both hydrophilic and hydrophobic drugs. Based on the various studies, one may conclude that functional nanoparticles coupled with biological targeting agents and drug molecules is promising as drug delivery vehicles with enhanced imaging and therapeutic efcacy. However, there are many factors which affect the efcacy of a developed system. For example, the presence of target and drug molecules on the nanoparticles may interfere with the targeting capability and cellular uptake of the nanoparticles. Further, coupling of different chemical functionalities on a surface of nanoparticles often leads to a low yield synthetic process. This can be overcome by using multicomponent nanohybrid systems wherein target molecules, imaging probe and a drug can be anchored on different surface functionality on the same system [83,66]. Another concern in the use of hybrid nanostructures of different sizes and shapes is their movement through the systemic circulation as they are intended to experience various uid environments and might behave differently due to the effect of viscous force. Agglomeration of the nanosystems cannot be ruled out as they move through the narrow capillaries which might lead to clogging of blood vessels [92]. Further, the nanohybrid systems may have restricted or indiscriminate movement across the biological barriers which dictates their behavior and fate upon introduction into the body (biodistribution). Functionalization of the nanoparticles with various macromolecules, biopolymers or dendrimers enables the nanoparticles to interact with the biological environment and protect them from degradation [93]. As our knowledge of various multifunctional and hybrid nanostructures grow, the enormity of the
Fig. 3. Confocal laser scanning microscopy images of FMSN taken up by PANC-1 cells incubated at (a) 37 C and (b) 4 C for 30 min [96], and optical images of KB cells treated by ZnO nanoparticles targeted with folic acid after (c) 1 h and (d) 3 h of incubation [100]. (Reproduced with permission from [96] copyright Springer and [100] copyright American Chemical Society Publications.)
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challenges become obvious. Thus, while designing the hybrid nanostructures, one must have to take care of certain features that are essential for effective intracellular targeting. These include (i) clearance from the circulation, (ii) withheld release of drug at non-targeted sites, (iii) delivery of drugnanocarrier and release of drug at targeted site, (iv) removal of drug from the target site and (v) effective elimination of the nanocarrier from the body. 4.1.2. Cellular uptake and Imaging The ability for therapeutic and diagnostic applications depends on the internalization of the nanoparticles within the cells. Thus, the efciency with which cells can be loaded with nanoparticles is a major determinant for imaging sensitivity at the single cell level. Some cells such as macrophages can be readily labeled with adequate quantities of nanoparticles due to their inherent ability to phagocytose material in the extracellular medium, however, there are many other cell lines, including cancer cells which do not readily phagocytose. This challenge can be overcome by direct conjugation of cell-penetrating peptides to the surface of nanoparticles [94]. In-vivo studies in rats showed that magnetic nanoparticles predominantly accumulate in the liver and spleen after intravenous administration. Jain et al. [95] studied the biodistribution, clearance, and biocompatibility of oleic acidpluronic magnetic nanoparticles (MNPs) for in vivo biomedical applications. Changes in levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP) were analyzed over 3 weeks after intravenous administration of MNPs to rats. They found that the serum iron levels gradually increased for up to 1 week and then slowed down. Greater fraction of the injected iron is uptaken in liver and spleen which may be due to the increased hydrodynamic diameter of the nanoparticles. However histological analyses of the organs showed no apparent abnormal changes. The energy-dependent cellular uptake of biocompatible uorescent (uorescein isothiocyanate) mesoporous SiO2 nanoparticles (FMSN) as well as the delivery of hydrophobic anticancer drug paclitaxel to PANC-1 cancer cells were investigated [96]. The cellular uptake was higher at 37 C than at 4 C (Fig. 3(a) and (b)) and metabolic inhibitors such as sodium azide, sucrose and balomycin A impeded the uptake of FMSN into cells. These results suggested that the uptake was an energy-dependent endocytic process. The uptake of nanoparticles through energy-dependent endocytic process was also observed with A549 and HeLa cells [97,98]. In another study, Guo et al. [99] showed that the presence of ZnO nanoparticles enhanced the cellular uptake of daunorubicin for leukemia cell lines. They have observed that the effective anti-drug resistance and anticancer effect of photoexcited ZnO nanoparticles accompanied with the anticancer drug shows synergistic cytotoxicity suppression on leukemia cell lines under UV irradiation. On the other
hand, biocompatible ZnO nanocrystals having a non-centrosymmetric structure was synthesized and used as non-resonant and nonlinear optical probes for in vitro bioimaging applications [100]. The nanocrystals were dispersed in aqueous media using phospholipid micelles and incorporated with the biotargeting folic acid (FA) molecule. The confocal images of KB cells treated with an aqueous dispersion of ZnO and ZnO-FA (targeted by FA), for 1 and 3 h of treatment shows robust intracellular signal (Fig. 3(c) and (d)). In comparison to SiO2 and ZnO, the cellular uptake of iron oxide nanoparticles and their nanocomposites were extensively explored [45,101]. The cellular uptake of protein passivated-Fe3O4 nanoparticles in different types of cancer cells was studied in the absence and presence of serum [102]. It was observed that the serum reduces the cellular uptake of Fe3O4 nanoparticles and the internalization of nanoparticles into cells takes place via endocytosis or by diffusion/ penetration across the plasma membrane. In another study, the cellular uptake and in vitro cytotoxicity of hollow mesoporous spherical nanocomposites of Fe3O4@SiO2 towards HeLa cells was found relatively faster [103]. In an interesting study, Pan et al. [69] reported the development of a nanoscale delivery system composed of MNPs coated with different generation of PAMAM dendrimers (dMNP) and investigated the uptake mechanism with different cell lines after complexing them with antisense survivin oligodeoxynucleotides (asODN). They observed that asODN-dendrimer-MNPs enter into tumor cells within 15 min (endocytosed by cancer cells, Fig. 4(a)) and inhibited cell growth in dose- and time-dependent means. The intracellular uptake rate of G5.0 dMNP (fth generation dMNP) was found to be 60% whereas that of naked MNPs was 10% (Fig. 4(b)). Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely used in magnetic resonance imaging as they can be used as contrast agent and can be incorporated into magnetic eld-guided drug delivery carriers for cancer treatment. However, the hydrophobic nature of some SPION leads to fast reticuloendothelial system (RES) uptake due to which their systemic administration still remains a challenge. Folate targeted NIPAAM-PEGMA composite magnetic nanoparticles with imaging potential were reported [104]. Copolymerisation of the nanocomposites with acrylic acid (AA) and polyethylene glycol methacrylate (PEGMA) led to an increase in the Curie temperature (TC ) of the co-polymer to 44 C enabling hyperthermia coupled drug delivery. The increased binding of the PEGMA and AA with the iron surface caused prolonged circulation time of the nanocomposites, thereby preventing rapid clearance by RES system. The nanocomposites showed high T1 and T2 relaxivities and R1 and R2 increases linearly with increase in iron concentration proving their application for imaging purposes. A dual imaging (optical/MR) of Lewis lung carcinoma tumor by Cy5.5 conjugated
Fig. 4. (a) Schematic representation of endocytosis of dMNP-asODN complexes by cancer cells and (b) intracellular uptake rate of dMNP-asODN (control: without dMNP; null: MNP without dendrimer modication [69]). (Reproduced with permission from [69] copyright American Association for Cancer Research.)
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Fig. 5. T2-weighted images before and after injection of herceptin-nanoparticles. A gray-level MRI; B color-map MRI [107]. (Reproduced with permission from [107] copyright Springer.)
thermally crosslinked SPIONs in mice was studied [105]. High level of accumulation of these nanomagnets within the tumor site was established by T2-weighted magnetic resonance images as well as in optical uorescence images within 4 h of intravenous injection. A multifunctional Herceptin-conjugated Aurods(Fe3O4)n was studied as theranostic platforms for targeting SK-BR-3 cells (by MRI and uorescence) and destroying them (by Au-mediated photothermal ablation) [106]. In another work, when a MRI contrast agent containing targeted herceptindextran coated magnetic nanoparticles were administered to mice bearing breast tumor allograft, the tumor site was detected in T2-weighted MR images as a 45% enhancement drop, indicating a high level of accumulation of the contrast agent
within the tumor (Fig. 5). The potential cytotoxicity of the herceptinnanoparticles indicated inhibition of cells that overexpress HER2/neu receptors (BT-474, SKBR-3, MDA-MB-231, and MCF-7) at high iron concentrations [107]. Yang et al. [108,109] engineered urokinase plasminogen activator receptor (uPAR) targeted biodegradable polymer coated magnetic nanoparticles (ATF-IO) for delivery of doxorubicin and in vivo magnetic resonance and optical imaging in mouse mammary tumors. A strong magnetic resonance imaging contrast detectable by a clinical MRI scanner at eld strength of 3 T was generated when ATF-IO was systemically delivered into the mice bearing mammary tumors. It was also found that the mice administered with ATF-IO nanoparticles
Fig. 6. Targeting and in vivo magnetic resonance tumor imaging of intraperitoneal (i.p). mammary tumor lesions. Top, bioluminescence imaging detects the presence of i.p. tumors on the upper right of the peritoneal cavity of the mouse. MRI reveal two areas located near the right kidney (red dashed lined) with decreased magnetic resonance imaging signals 5 or 30 h after the tail vein injection of 11.2 nmol/kg of body weight [108]. (Reproduced with permission from [108] copyright American Association for Cancer Research.)
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exhibited lower uptake of the nanoparticles in liver and spleen as compared with those receiving nontargeted iron oxide nanoparticles (Fig. 6). 4.2. Hyperthermia treatment of cancer Functionalized MNPs and ferrouids have been extensively used for generating heat for magnetic hyperthermia treatment (MHT) as a promising tool for therapeutics, particularly for cancer. With this, heat may be applied to tumor tissues with no systemic and side effects compared to chemotherapy and radiotherapy. In this application, MNPs are used as effective heating mediator in the presence of an alternating current (AC) magnetic eld. The type and thickness of functional layers used for stabilizing nanoparticles can signicantly inuence heating ability. The heat produced during MHT not only destroys the tumor cells but also boosts the activity of the majority of cytostatic drugs and activates the immunological response of the body. Kim et al. [110] reported that self-heating from MNPs under AC magnetic eld can be used either for hyperthermia or to trigger the release of an anti-cancer drug, using thermo-responsive polymers. The heat generated by applying an AC magnetic eld depends on the properties of MNPs (composition, size, shape and functionalization) as well as the frequency and amplitude of the magnetic eld. In their study, CoFe2O4 nanoparticles were investigated as heating agents for hyperthermia and thermo-drug delivery. Towards this approach, our research group has made signicant contributions in processing functionalized MNPs of different ferrites and their ferrouids. Along with CoFe2O4, we have investigated comparative heating ability as well as biocompatibility of different ferrite based magnetic uids [11,22,24,111114]. It has been observed that CoFe2O4 is rather toxic compared to other Mn-based ferrites. In vitro studies of water-based ferrouids of substituted ferrites Fe1 xMnxFe2O4, [114] with an average particle size of about 1012 nm prepared by the coprecipitation, on BHK-21 cells showed that the threshold biocompatible concentration is dependent on the nature of ferrite and their surface modication. The reports showed that the value of specic absorption rate (SAR) increased by 20% in Fe0.6Mn0.4Fe2O4 as compared to Fe3O4. The higher SAR makes these materials useful for hyperthermia applications. The suspension of nanosized -Fe2O3 [25] and -AlxFe2 xO3 [115] particles in cellulose was successfully
prepared which showed high degree of biocompatibility and was found suitable for hyperthermia treatment of cancer. The mechanism of cell death induced by magnetic hyperthermia with -MnxFe2 xO3 nanoparticles was rst investigated by our research group [26]. The hyperthermia induced by the application of an AC magnetic eld in the presence of the Acrypol 934 stabilized -MnxFe2 xO3 suspension caused the death of HeLa cells. The cells showed varying degrees of membrane blebbing with signicant disruption of the actin and tubulin cytoskeletons (Fig. 7) following MHT which nally led to cell death. The cell death was proportional to the quantity of the particles and the duration of the applied AC magnetic eld. Thermoresponsive polymer-coated magnetic nanoparticles can be used for magnetic drug targeting followed by simultaneous hyperthermia and drug release. Jaiswal et al. [116] reported Poly(NIPAAm)chitosan (CS) based nanohydrogels (NHGs) and iron oxide (Fe3O4) magnetic nanoparticles encapsulated magnetic nanohydrogels (MNHGs) in which it has been observed that CS not only served as a cross linker during polymerization but also plays a critical role in controlling the growth of NHG and enhancement in lower critical solution temperature (LCST) of poly(NIPAAm) which increased with increasing weight ratio of CS to NIPAAm. Also, the presence of CS in the composite makes it pH sensitive by virtue of which, both temperature and pH changes have been used to trigger drug release. Furthermore, the encapsulation of iron oxide nanoparticles into hydrogels also caused an increment in LCST. Specically, temperature optimized NHG and MNHG were fabricated having LCST close to 42 C (hyperthermia temperature). The MNHG shows optimal magnetization, good specic absorption rate (under external AC magnetic eld) and excellent cytocompatibility with L929 cell lines, which may nd potential applications in combination therapy involving hyperthermia treatment of cancer and targeted drug delivery. On a similar line of approach, Meenach and coworkers [117] demonstrated a method for remotely heating the tumor tissue using hydrogel nanocomposites containing magnetic nanoparticles upon exposure to an external alternating magnetic eld (AMF). Swelling analysis of the systems indicated a dependence of ethylene glycol (EG) content and cross-linking density on swelling behavior where greater EG amount and lower cross-linking resulted in higher volume swelling ratios. Both the entrapped iron oxide nanoparticles and hydrogel nanocomposites exhibited high cell viability for murine broblasts, indicating potential biocompatibility. The hydrogels were heated in an AMF, and the heating response was shown to be dependent on both iron
Fig. 7. Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of -MnxFe2 xO3 [26]. (Reproduced with permission from [26] copyright RSC publications.)
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oxide loading in the gels and the strength of the magnetic eld. The thermal therapeutic ability of the hydrogel nanocomposites to selectively kill M059K glioblastoma cells in vitro on exposure to an AMF has been demonstrated. A unique drug delivery system based on mesoporous silica nanoparticles and magnetic nanocrystals was developed [118]. The combined ability of the mesoporous silica nanoparticles to contain and release cargos and the ability of the magnetic nanocrystals to exhibit hyperthermic effects when placed in an oscillating magnetic eld makes the system very promising. Zinc-doped iron oxide nanocrystals were incorporated within a mesoporous silica framework and the surface was modied with pseudorotaxanes. Upon application of an AC magnetic eld, the nanocrystals generate local internal heating, causing the molecular machines to disassemble and allowing the cargos (drugs) to be released. Folic acid (FA) and cyclodextrin (CD)-functionalized superparamagnetic iron oxide nanoparticles, FA-CD-SPIONs, were synthesized by chemically modifying SPIONs derived from iron (III) allylacetylacetonate and the drug was incorporated [119]. Heat generated by MNPs under high-frequency magnetic eld (HFMF) is useful not only for hyperthermia treatment but also as a driving force for the drugrelease. Induction heating triggers drug release from the CD cavity on the particlea behavior that is controlled by switching the HFMF on and off. MNPs coated with materials having unique properties, such as ordered pore structures and large surface areas, hold great potential for multimodal therapies. Recently, it has been reported [120] that composites of maghemite nanoparticles embedded in an ordered mesoporous silica-matrix forming magnetic microspheres (MMS) have great ability to induce magnetic hyperthermia upon exposure to a low-frequency AMF. MMS particles were efciently internalized within human A549, Saos-2 and HepG2 cells, and the MMS treatment did not interfere with morphological features or metabolic activities of the cells, indicating good biocompatibility of the material. The inuence of MNPs combined with short external AMF exposure on the growth of subcutaneous mouse melanomas was evaluated recently [121]. Bimagnetic Fe/Fe3O4 core/shell nanoparticles were designed for cancer targeting after intratumoral or intravenous administration. The inorganic core of the nanoparticles was protected against rapid biocorrosion by organic dopamineoligoethylene glycol ligands. The magnetic hyperthermia results obtained after intratumoral injection indicated that micromolar concentrations of iron given within the modied coreshell Fe/Fe3O4 nanoparticles caused a signicant anti-tumor effect on melanoma with three short 10-minute AMF exposures. Villanueva et al. [122] studied the effect of a high-frequency AMF on HeLa tumor cells incubated with ferromagnetic nanoparticles of manganese oxide perovskite La0.56 (SrCa)0.22MnO3. The application of alternating electromagnetic eld cells induced signicant cellular damage that nally caused cell death by an apoptotic mechanism. Cell death is triggered even though the temperature increase in the cell culture during the hyperthermia treatment is lower than 0.5 C. Another manganite, La1 x AgxMnO3 + has been explored as an alternative to superparamagnetic iron oxide based particles for highly controllable hyperthermia cancer therapy and imaging [123]. Adjusting the silver doping level, it was possible to control the TC in the hyperthermia range of interest (4144 C). The nanoparticles were found to be stable, and their properties were not affected by the typical ambient conditions in the living tissue. When placed in AMF, the temperature of the nanoparticles increased to the denite value near TC and then remained constant if the magnetic eld is maintained. During the hyperthermia procedure, the temperature can be restricted, thereby preventing the necrosis of normal tissue. Recently, we have demonstrated magnetic hyperthermia with biphasic gel of La1 xSrxMnO3 (LSMO) and -Al0.07 Fe1.93O3 [124]. While LSMO could be useful for self regulating the temperature, the latter was used for better biocompatibility and higher SAR values. It has been observed that
SAR increases (time required to reach hyperthermia temperature decreases) with increasing the ratio of Al-substituted maghemite. Such biphasic gel could be very useful for magnetic hyperthermia with in vivo control of temperature. La1 x SrxMnO3 (LSMO) nanoparticles were also stabilized by various polymers for biomedical applications. Prasad et al. [125] fabricated acrypol stabilized Tc-tuned biocompatible aqueous suspension of LSMO for magnetic hyperthermia treatment of cancer with a possibility of in vivo temperature control. 4.3. Other therapeutic applications In recent years, among host-guest hybrid materials, layered double hydroxides (LDH) have received much attention due to their vast applicability and hence are considered to be the new generation materials in areas such as nanomedicine [126]. LDH materials having both cation and anion exchange properties provide an opportunity to design a material with promising applications. Pan et al. [127] established the importance of understanding the microstructure and nature of LDH that could ultimately control the drug release properties. In their study, a series of novel doxiuridine intercalated MgAl-layered double hydroxide (DFURLDH) microhybrids were fabricated and diffusion controlled in-vitro release was observed. An anti-tumor drug podophyllotoxin (PPT) was intercalated into LDH [128] and it was further investigated for in vitro cytotoxicity to tumor cells, the cellular uptake and in vivo antitumor inhibition of PPT-LDH. The in vivo tests reveal that delivery of PPT via LDH nanoparticles is more efcient, but the toxicity to mice is reduced in PPT-LDH hybrids in comparison with PPT alone. These observations imply that LDH nanoparticles are the potential carrier of anti-tumor drugs in a range of new therapeutic applications. The intercalation of sulfobutyl ether -cyclodextrin (SBE7--CD) into MgAl LDH was examined for controlled release of prazosin, a sympatholytic drug used to treat high blood pressure [129]. Anticancer drug podophyllotoxin (PPT) [130] and campothecin [131] were encapsulated in the galleries of MgAl LDH which showed that the druginorganic composites can be successfully used as drug delivery vehicle. Cefazolin, a cephalosporin class antibacterial agent, was also intercalated into LDH in order to improve the drug efciency as well as to achieve the controlled release property [132]. Recently, the formation and intercalation and stability of anti-cardiovascular drugs (pravastatin and uvastatin) in [Fe(CN)6] 3 based Ni 2+/Fe 3+ LDH was studied [133]. Structural characterization techniques revealed that the uvastatin anions are attached with the brucite as a monolayer, whereas the pravastatin anions form a multilayer. In vitro release study of nanohybrid particles suggested that there is a signicant reduction in release rate of uvastatin anions from uvastatin intercalated LDHs which may probably be due to its hydrophobic nature, however, it can be controlled by varying the concentration in physiological medium. The advantage of this method is that the excess divalent metal ions in LDHs can be used as high-temperature inorganic surfactant to restrict the growth and agglomeration of MNPs by forming a divalent oxide protective layer on the surface during heat treatment. 4.4. Towards clinical trials Though cancer is a pervasive problem, the improvement in technologies in diagnosis and treatments has signicantly decreased the mortality rates all over the world. It may be possible to detect the cancer at an early stage with the use of nanodevices when the initial molecular changes start occurring at the nanoscale level inside the cells. Thus the scenario for treatment of cancer is completely changed in most of the cancers if detected early. After diagnosis, nanoscale devices can potentially improve cancer therapy over conventional chemotherapy and radiotherapy. Cancer drugs being mostly cytotoxic to both healthy and cancer cells cause severe side effects,
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thereby limiting the efcacy of chemotherapy [134]. Therefore, it becomes necessary to develop drug formulations which can transport the toxic drug specically to the cancer cells, and release them in a timely and controlled manner. Advancement in nanotechnology has opened up opportunities to nanodevices especially in developing new therapeutic formulations for improved cancer drug delivery. The nanodevices cannot only be used in the area of multifunctional therapeutics (i.e., to create therapeutic devices which control the release of cancer drugs and deliver medication optimally), but also to cancer prevention and control, early detection and imaging diagnostics. Several engineered nanoparticulates involving dendrimers, liposomes or other macromolecules are targeted to cancer cells which increase the selectivity of the drug towards cancer cells thereby reducing toxicity to the normal cells. This is normally done by attaching monoclonal antibodies or receptor ligands that specically bind to the cancer cells. Research on folate conjugated nanoparticles showed high specicity for human cancer cells and an improved drug uptake [135]. Conjugation of FITC (imaging agent), folic acid (targeting molecule) and paclitaxel (drug) to a dendrimer and their in vitro targeted delivery to cancer cells has been discussed [136]. It was found that the cells containing the folic acid receptor took up the dendrimer which had a toxic effect while the dendrimers had no effect on the cells without folic acid receptor. Liposomal nanodevices are extensively investigated as harmless drug delivery carriers which not only carry xed dose of anti cancer drug combinations but also circulate in the blood stream for a longer time [137,138]. Substantial improvements in using the magnetic nanoparticles for clinical applications such as drug delivery, MRI, magnetic drug targeting and hyperthermia has been made in the recent past. However, the clinical breakthrough was achieved by Maier-Hauff et al. [139] in 2007 when deep cranial thermotherapy using magnetic nanoparticles was safely applied to 14 glioblastoma multiforme patients. The patients were intratumorally injected with the iron oxide nanoparticles and exposed to an AC magnetic eld to induce particle heating. MRI was followed to evaluate the amount of uid and spatial distribution of the depots and the actually achieved magnetic uid distribution was measured by computed tomography. Patients were tolerant to thermotherapy and minor or no side effects were observed. In a recent clinical trial [140], insterstitial heating of tumors following direct injection of magnetic nanoparticles has been carried out for the treatment of prostate cancer. However, patient discomfort at high magnetic eld and irregular intratumoral heat distribution remained the limiting factor of the trials. Johannsen et al. [141] reported the results of phase I clinical trial using magnetic nanoparticles involving 10 patients with locally recurrent prostate cancer. No systemic toxicity was observed at a median follow-up of 17.5 months, and prostate specic antigen (PSA) were found to reduce, however, acute urinary retention occurred in four patients with previous history of urethral retention. Although there are a number of successful phase I clinical trials based on therapeutic magnetic targeting, very little successful clinical translations has come up [142,143]. Landeghem et al. [144] demonstrated the tolerability and anti-tumoral effect of thermotherapy using magnetic nanoparticles and the efcacy of magnetic uid hyperthermia (MFH) in murine model of malignant glioma, which is under evaluation for phase II study. From brain autopsies, it was found that the instillation of magnetic nanoparticles for MFH in patients result in uptake of nanoparticles in glioblastoma cells to a minor extent and in macrophages to a major extent as a consequence of tumor inherent and therapy induced formation of necrosis with subsequent inltration and activation of phagocytes. Intracranial thermotherapy using aminosilane magnetic nanoparticles were performed on 14 patients who were then exposed to an AC magnetic eld. All the patients tolerated instillation of the nanoparticles without any complications and the efcacy of the treatment is under evaluation in phase II study [145].
5. Conclusion and future scope The developing market in this decade has already seen the use of nanotechnology to develop efcient drug delivery system. The next evolution will be using nanotechnology for in vivo uses such as implanting multifunctional particles in biological tissue to deliver medicine, destroy tumors and stimulate immune responses. Some of these multifunctional nano-sized assemblies can act as biological systems working together and holds immense potential for cancer therapy and diagnostics. These approaches will encompass the desired goals of early detection, tumour regression with limited collateral damages, and efcient monitoring of response to chemotherapy. In the foreseeable future, the most important clinical application of nanotechnology will probably be in pharmaceutical development. These applications take advantage of the unique properties of nanoparticles as drugs or constituents of drugs or are designed for new strategies to stabilize drugs and their control release, drug targeting, and salvage of drugs with low bioavailability. Although the nanosized materials can be useful in medicine, but they can be potentially dangerous to human body as far as the toxicity of the nanocarriers/nanocomposites is concerned. The nanomaterials have unrestricted access to the human body and have the ability to pass through the blood brain barrier, thereby evading their detection by the body's immune system. Usually, foreign substances are absorbed by phagocytes once they enter the blood stream, however, any substance in the nanoscale range is no longer absorbed by the phagocytes and thus, they travel though the blood and move randomly throughout the body. Within this physiological compartment, the nanomaterials may interact with cell population resulting in internalization through receptor-mediated endocytosis, phagocytosis and pinocytosis. The materials remain in the endosomes and accumulate within the organs and its eventual localization dictates their toxicity. Despite immense impact of nanomedicines in cancer, societal implications cannot be overlooked. The danger of derailing nanomedicines always exists if the science leaps ahead of the ethical, legal and social implications. It is of utmost importance that the area of nanotechnology pays attention not only to the making of devices and processes, but also to the psychological and social aspect as a part of any development. Futuristic nanotechnology will also see medical implants as another sector for better biomedical implants such as a small active pacemaker. Besides all the developments, the exciting milestones made in these areas need to be paralleled with safety evaluations of the platforms before they are translated to the clinics. Nevertheless, we believe that the next few years are likely to see an increasing number of nanotechnology-based therapeutics and diagnostics reaching the clinic.
Acknowledgements The nancial support by Nanomission of Department of Science and Technology and Department of Information Technology, Govt. of India is gratefully acknowledged.
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Oxide and Hybrid Nanostructures For Therapeutic Apps

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Advanced Drug Delivery Reviews 63 (2011) 12671281

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Advanced Drug Delivery Reviews

Oxide and hybrid nanostructures for therapeutic applications

S. Chandra et al. / Advanced Drug Delivery Reviews 63 (2011) 12671281

S. Chandra et al. / Advanced Drug Delivery Reviews 63 (2011) 12671281

S. Chandra et al. / Advanced Drug Delivery Reviews 63 (2011) 12671281

S. Chandra et al. / Advanced Drug Delivery Reviews 63 (2011) 12671281

S. Chandra et al. / Advanced Drug Delivery Reviews 63 (2011) 12671281

S. Chandra et al. / Advanced Drug Delivery Reviews 63 (2011) 12671281

S. Chandra et al. / Advanced Drug Delivery Reviews 63 (2011) 12671281

S. Chandra et al. / Advanced Drug Delivery Reviews 63 (2011) 12671281

S. Chandra et al. / Advanced Drug Delivery Reviews 63 (2011) 12671281

S. Chandra et al. / Advanced Drug Delivery Reviews 63 (2011) 12671281

S. Chandra et al. / Advanced Drug Delivery Reviews 63 (2011) 12671281

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