COREL-07158; No of Pages 34 Journal of Controlled Release xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel

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Review

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Laxmi Upadhyaya a,⁎, Jay Singh b,⁎, Vishnu Agarwal c, Ravi Prakash Tewari a a

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Article history: Received 10 February 2014 Accepted 23 April 2014 Available online xxxx

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Keywords: Carboxymethyl chitosan Drug delivery Tissue engineering Formulation of drug

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Department of Applied Mechanics, MotiLal Nehru National Institute of Technology, Allahabad 211004, India Department of Applied Chemistry & Polymer Technology, Delhi Technological University, Shahbad Daulatpur, Main Bawana Road, Delhi 110042, India Department of Applied Mechanics (Biotechnology), MotiLal Nehru National Institute of Technology, Allahabad 211004, India

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Over the last decade carboxymethyl chitosan (CMCS) has emerged as a promising biopolymer for the development of new drug delivery systems and improved scaffolds along with other tissue engineering devices for regenerative medicine that is currently one of the most rapidly growing fields in the life sciences. CMCS is amphiprotic ether, derived from chitosan, exhibiting enhanced aqueous solubility, excellent biocompatibility, controllable biodegradability, osteogenesis ability and numerous other outstanding physicochemical and biological properties. More strikingly, it can load hydrophobic drugs and displays strong bioactivity which highlight its suitability and extensive usage for preparing different drug delivery and tissue engineering formulations respectively. This review provides a comprehensive introduction to various types of CMCS based formulations for delivery of therapeutic agents and tissue regeneration and further describes their preparation procedures and applications in different tissues/organs. Detailed information of CMCS based nano/micro systems for targeted delivery of drugs with emphasis on cancer specific and organ specific drug delivery have been described. Further, we have discussed various CMCS based tissue engineering biomaterials along with their preparation procedures and applications in different tissues/organs. The article then, gives a brief account of therapy combining drug delivery and tissue engineering. Finally, identification of major challenges and opportunities for current and ongoing application of CMCS based systems in the field are summarised. © 2014 Published by Elsevier B.V.

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The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . Scope of the present review . . . . . . . . . . . . . . . . . . . Limitations with the use of chitosan in drug delivery . . . . . . . . Biopharmaceutical and toxicological profile of CMCS . . . . . . . . Synthesis of various carboxymethyl chitosans (CMCS) . . . . . . . 5.1. Synthesis of O-carboxymethyl chitosans (O-CMCS) . . . . . 5.2. Synthesis of N-carboxymethyl chitosans (N-CMCS) . . . . . 5.3. Synthesis of N,O-carboxymethyl chitosans (N,O-CMCS) . . . 5.4. Synthesis of N,N-dicarboxymethyl chitosans (N,N-di-CMCS) . Preparation techniques of CMCS based formulations for drug delivery

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Abbreviations: ADR, adriamycin; AQCOM, alginate-Q-CMCS-organic montmorillonite; bFGF, basic fibroblast growth gactor; BSA, bovine serum albumin; BMSCs, bone marrow stromal cells; CPT, camptothecin; CMC, critical micelle concentration; CMCS, carboxymethyl chitosan; O-CMCS, O-carboxymethyl chitosans; N-CMCS, N-carboxymethyl chitosans; N,O-CMCS, N,Ocarboxymethyl chitosans; N,N-di-CMCS, N,N-di-carboxymethyl chitosans; CMHC, carboxymethylhexanoyl chitosan; CMCPEG, methoxy poly(ethylene glycol)-grafted carboxymethyl chitosan; CMCS-g-D-GA, CMCS-graft-D-glucuronic acid; CD, cyclodextrin; DD, degree of deacetylation; DS, degree of substitution; DA, deoxycholic acid; DOX, doxorubicin; EPR, enhanced permeability and retention; EDC, 1-ethyl-3(3-dimethylaminopropyl) carbodiimide hydrochloride; FA, folic acid; 5-FU, 5-fluorouracil; GA, glutaraldehyde; GL, glycyrrhizin; GFLX, gatifloxacin; HAP, hydroxyapatite; IPN, interpenetrating; iPSCs, induced pluripotent stem cells; LA, linoleic acid; mPEG-g-CMC, methoxy poly (ethylene glycol) grafted carboxymethyl chitosan; MW, molecular weight; MTA, mineral trioxide aggregate; MIC, minimum inhibitory concentration; MMA, methyl methacrylate; N-CECS/nano-HAP, N-carboxyethyl chitosan/ nanohydroxyapatite; OCT, octreotide; OCC, N-octyl-O,N-carboxymethyl chitosan; OD, ornidazole; OMMT, organic montmorillonite; PTA, Cis-3-(9H-purin-6-ylthio)-acrylic acid; PTX, paclitaxel; PNIPAM, poly(N-isopropylmethacrylamide); PBS, phosphate buffer saline; PEG, polyethylene glycol; PAMAM, poly(amidoamine); PVA, poly-vinyl alcohol; QCMCS, quaternised carboxymethyl chitosan; SA, stearic acid; SMCs, smooth muscle cells; TLAC, thiolated lactosaminated; VEGF, vascular endothelial growth factor. ⁎ Corresponding authors. Tel.: +91 11127871045 (office), +91 9871765453 (mobile). E-mail addresses: [email protected] (L. Upadhyaya), [email protected] (J. Singh).

http://dx.doi.org/10.1016/j.jconrel.2014.04.043 0168-3659/© 2014 Published by Elsevier B.V.

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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1. Introduction

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Natural polysaccharides, due to their non-toxicity, biocompatibility and biodegradability, are widely being studied as biomaterial for drug delivery and tissue engineering applications. Among them, chitosan, which is known to be biocompatible, biodegradable, non-toxic, mucoadhesive and antimicrobial, has been exhaustively exploited for developing different formulations for controlled delivery of biotherapeutics and in regenerative medicine. But limited solubility of chitosan in water and other organic solvents has prevented its full exploitation in drug delivery and tissue repair and reconstruction [1,2]. In addition to this, the limited colloidal stability of chitosan based particulate drug delivery systems are known to exhibit immunogenicity [3] and degradability of chitosan based formulations in tissue regeneration and drug delivery is uncontrollable [4]. Therefore derivatisation of chitosan seems a promising way to get rid of these limitations of chitosan and widening range of drug delivery and tissue engineering applications. In fact, life sciences and bio-technologies is the realm where chitosan and chitosan derivatives have raised greater scientific interest because of their remarkable structural and functional properties. Among them, carboxymethyl chitosan (CMCS), a water soluble derivative of chitosan, has attracted booming interests in several fields such as in vitro diagnostics [5–7], theranostics [8] bioimaging [9], biosensors [10,11], wound healing [12], gene therapy [13–16] and food technology [17,18] but its greatest impact has been in the area of drug delivery and tissue engineering. CMCS is potentially biologically compatible material that is chemically versatile (– NH2 and –COOH) groups and various molecular weight, (MW). The positive facets of increased water solubility, excellent biocompatibility [19], admirable biodegradability, high moisture retention ability [20], improved antioxidant property [21], enhanced antibacterial [22] and antifungal [23] activity and non-toxicity as compared to chitosan has provided ample opportunities to the drug delivery and tissue engineering scientists to create a plethora of formulations and scaffolds. In addition, it is also known to be more bioactive [24], promotes osteogenesis

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CMCS formulations for drug delivery applications . . . . . . . . . . . . 7.1. CMCS hydrogels . . . . . . . . . . . . . . . . . . . . . . . . 7.2. CMCS microspheres. . . . . . . . . . . . . . . . . . . . . . . 7.3. CMCS micelles/aggregates . . . . . . . . . . . . . . . . . . . . 7.4. CMCS nanoparticles. . . . . . . . . . . . . . . . . . . . . . . 7.5. CMCS films and fibers . . . . . . . . . . . . . . . . . . . . . . 7.6. CMCS composites. . . . . . . . . . . . . . . . . . . . . . . . 8. CMCS based targeted drug delivery . . . . . . . . . . . . . . . . . . . 8.1. Cancer-specific drug delivery based on CMCS . . . . . . . . . . . 8.2. Organ-specific drug delivery based on CMCS . . . . . . . . . . . 8.2.1. Colon-specific drug delivery using CMCS . . . . . . . . . 8.2.2. Liver targeted drug delivery using CMCS . . . . . . . . . 8.2.3. Ocular drug delivery using CMCS . . . . . . . . . . . . 8.2.4. Others . . . . . . . . . . . . . . . . . . . . . . . . 9. Tissue engineering: origin and strategies . . . . . . . . . . . . . . . . 10. Preparation techniques of CMCS based biomaterials for tissue engineering . 11. CMCS based biomaterials for tissue engineering and regeneration . . . . . . 11.1. CMCS scaffolds . . . . . . . . . . . . . . . . . . . . . . . . . 11.2. CMCS hydrogels . . . . . . . . . . . . . . . . . . . . . . . . 11.3. CMCS composites. . . . . . . . . . . . . . . . . . . . . . . . 11.4. CMCS injectable gels, films and membranes . . . . . . . . . . . . 12. CMCS applications in different tissues/organs . . . . . . . . . . . . . . 12.1. CMCS in bone tissue engineering . . . . . . . . . . . . . . . . . 12.2. CMCS in cartilage tissue engineering . . . . . . . . . . . . . . . 12.3. CMCS in nerve tissue engineering . . . . . . . . . . . . . . . . 12.4. CMCS in wound healing . . . . . . . . . . . . . . . . . . . . . 13. Tissue engineering application is often combined with drug delivery strategy 14. CMCS based systems: current challenges and opportunities . . . . . . . . 15. Summary and future remarks . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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[25] and its safety evaluation on compounds [26], in vitro models, blood systems [27] and tumor application [28] has been well established. All these favorable physical, chemical and biological properties of CMCS make it a promising biomedical material for drug delivery and tissue engineering applications in several formulations. Recently numerous experimental results have been reported on the potential therapeutic applications of CMCS in reduction in post surgical adhesion formation [29], antibacterial biomaterial [30] and accelerated wound healing [31]. The most exhaustively investigated CMCS based drug delivery formulations include hydrogels [32], microspheres [26], beads [33], micelles [34], aggregates [35], nanoparticles [36,37], films [38] and membranes [39]. Similarly, repairing and reconstruction of tissues like bone, cartilage, and nerve by CMCS based tissue engineering devices like scaffolds [40], injectable gels [41], and biocomposites has been reported by various researchers in recent years.

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In consideration of the above, the scope of the present review is to identify the lines of applied research that are now consolidating major advances made with the CMCS during the last decade in the field of drug delivery and tissue engineering. The novelty of these facts is underlined by the fact that a previous attempt to review the literature on CMCS has focused primarily on the general biomedical applications of CMCS with only a minor part dealing with drug delivery and tissue engineering applications [42]. While another review article authored by Mourya et al. [43] mainly covers literature regarding the synthesis and characterisation of CMCS along with its pharmaceutical applications. CMCS being inherently bestowed with astonishing physical, chemical and biological features, emerging trends show that it is highly suitable for the delivery of numerous bioactive and therapeutic compounds and for the repair and reconstruction of damaged and/or diseases tissues. Excellent biocompatibility, improved biodegradability, enhanced antimicrobial activity, better chelating ability, moisture

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The drug absorption enhancing property of chitosan due to its bio/ mucoadhesive nature (i.e. delayed clearance of the formulation from the absorption site) and the transient opening of the tight junctions between the epithelial cells of the mucosal membrane are well experimentally demonstrated and reported in literature. But the major limitation associated with the use of chitosan in efficaciously increasing mucosal drug absorption is its poor solubility at pH higher than its pKa (∼pH 5.5–6.5). Chitosan is soluble in aqueous dilute acid such as hydrochloric acid and aqueous organic acid such as formic, acetic, oxalic and lactic acids when the degree of deacetylation (DD) of chitin reaches about 50%. While it remains insoluble at neutral and alkaline pH values. The main mechanism involved in the solubilisation of chitosan is protonation of the –NH2 function on the C-2 position of the Dglucosamine monomeric unit of chitosan, whereby the polysaccharide is converted to a polyelectrolyte in acidic media. The main factors governing the solubility of chitosan are DD, the ionic concentration, the pH, the MW, the nature of the acid used for protonation, the distribution of acetyl groups along the chain and the conditions of the method of isolation and drying of the polysaccharide. Highly deacetylated chitosans (N85%) are soluble only up to a pH of 6.5. The dependence of the degree of ionisation on the pH and the pKa of the acid have been experimentally displayed by examination of the role of protonation in the presence of acetic acid and hydrochloric acid on solubility of chitosan [44]. The decrement of intermolecular interactions and the lower crystallinity causing change in the microstructure of chitosan, which facilitate the permeation of water, LiOH hydrates and urea hydrates, thereby enhancing chitosan dissolution in an aqueous solution of LiOH/urea [45]. It is a well known fact that the pH of the small intestines increases from the duodenum to the terminal ileum from pH about 4.5 to 7.4. Therefore, in the lower part of intestine, chitosan will not be soluble. And in order to achieve higher oral bioavailability of drugs through the use of chitosan as an absorption enhancing delivery system, dissolution of chitosan at the pH values present in the lumen of small and large intestines is must. In consideration of the above facts, several attempts have been made and a large body of research exists on chemical modification of chitosan through derivatisation of the amine and/or hydroxyl groups to enhance the water solubility of chitosan. These derivatives mainly include sulfonation [46], quaternarisation [47], carboxymethylation [48], N- and O-hydroxyalkylation [49] and different grafted copolymers of chitosan [50–52]. Among these, chitosan derivatives, CMCS has drawn significant attention of the researchers for drug delivery applications due to its outstandingly enhanced water solubility, superior bio/mucoadhesive property, ease of preparation and numerous other admirable physicochemical and biological characteristics that are elaborated in Fig. 1 which make it highly suitable for fabricating different drug delivery formulations and tissue engineering biomaterials.

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As a result of the research undertaken over the last decade there is an acceptable understanding of suitability of CMCS as a versatile functional biomaterial for delivering different therapeutic moieties and tissue engineering applications. Among the water soluble chitosan derivative, CMCS is an amphiprotic ether derivative containing carboxyl and amine groups in the molecule. Chemically, chitosan is poly-1,4linked β-D-glucosamine, a cationic polysaccharide prepared by alkaline N-deacetylation of chitin. The inherent properties of chitosan itself like biocompatibility, non-toxicity, biodegradability and antimicrobial characteristic makes it suitable for various drug delivery [53,54] and tissue engineering applications [55,56]. But the limited solubility of chitosan in common solvents including water hinders its full potential exploitation in biomedical and pharmaceutical industry. Therefore introducing carboxymethyl group into the chitosan polymer chain endows it with some outstanding physical, chemical and biological properties suitable for delivery of therapeutic compounds and tissue repair and reconstruction purpose. The water solubility property of CMCS at various pH and different preparation conditions has been experimentally demonstrated. The study showed that degree of carboxymethylation has critical effect on aqueous solubility of CMCS. The study demonstrated that the water insolubility of CMCS at different pHs varied with the degree of carboxymethylation. The experiment also showed that the increase in the reaction temperature increased the fraction of carboxymethylation and thereby increased the insolubility at lower pHs. Also the decrease in the fraction of carboxymehylation increased the insolubility at higher pHs [57]. Similarly, DD and degree of substitution (DS) are known to have critical effect on the moisture-absorption and moisture-retention abilities of CMCS. The study revealed that under conditions of high relative humidity, the maximum moisture absorption and moisture retention were obtained at DD values of about 50%. Also when the DD values deviated from 50% moisture absorption and moisture retention decreased. While both moisture absorption and moisture retention increased with the increase in DS value [58]. Currently, a quantitative study of the acid base equilibrium of CMCS has been carried out by a group of researchers which can be useful for many biomedical applications. The study investigated the effect of metal ion properties on the stability of the complexes. The results showed that the study of complexes can be ordered as Mn(N,O-CMCS) b Co(N,O-CMCS),Ni(N,OCMCS) b Cu(N,O-CMCS) b Zn(N,O-CMCS) [59]. Apart from these, the antibacterial characteristics of CMCS [60], its fungistatic activity [61], antimicrobial properties of modified forms of CMCS [62–64] and CMCS based composites [65,66] have been well reported in literature. CMCS has been known to be highly biocompatible and is also known to promote the proliferation of the normal skin fibroblast significantly but inhibited the proliferation of keloid fibroblast [19]. Tao et al. prepared CMCS characterised with different sulfate content and concentration. MTT method was applied to evaluate effect of CMCS on fibroblast proliferation. The results of the study demonstrated that CMCS with sulfate content 26.26% at the concentration of 100 μg/mL shows best potential for skin fibroblast proliferation [67]. Currently, it is also shown that oligo-chitosan, N,O-CMCS and N-CMCS in sheets and pastes are cytocompatible with potential of wound healing when cytotoxicity was evaluated using primary normal human dermal fibroblast cultures and hypertrophic scars [68]. The biological safety of CMCS in blood systems of rats has been experimentally established [27]. Moreover, CMCS is known to be safe in vivo and slightly inhibited growth of sarcoma 180 and enhanced body immunity via elevation of serum IL-2 and TNF-α level in treated mice [28]. Apart from this, the excellent biodegradability of CMCS by in vitro and in vivo evaluation has been experimentally demonstrated in rats. This study revealed that liver played central role in biodegradation of CMCS [69]. The better biodegradability of 1-ethyl3(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) cross linked CMCS films in lysozyme solution (pH 7.4, 37 °C) has been reported. Also, these films enhanced the spread of Neuro-2a cells and provided

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4. Biopharmaceutical and toxicological profile of CMCS

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absorption and retention capacity, increased antioxidant property, and higher bioactivity of CMCS compared to its parent polymer chitosan has contributed to the exhaustive usage of this biopolymer in drug delivery and tissue engineering applications both in vitro and in vivo. This review therefore intends to convey to the reader the detailed information on various CMCS based formulations for drug delivery and tissue engineering and their preparative techniques along with applications in tissues like bone, cartilage and nerves in last few years. The review gives an overview of CMCS based formulations for targeted delivery focusing cancer specific and organ specific drug delivery. The article also gives a brief discussion about the fact that tissue engineering applications are often combined with drug delivery strategy. In this regard, it is very important to understand the basic anatomy of a drug delivery vehicle which is elucidated in the section discussed later.

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Synthesis of different types of CMCS by different chemical routes and effects of DD and DS along with relationship between molecular structure and moisture absorption and moisture retention abilities of CMCS has been well described earlier by several researchers [85–89]. The effect of various parameters like acid, pH, ionic concentration on the aggregation behavior of the polymer in aqueous systems has also been reported [90,91]. In fact, recently, Kong and coworkers developed a novel method for simultaneously determining DD, DS, and the distribution factor of –COONa or –COOH in CMCS by potentiometric titration [92]. Fig. 3 shows the preparative methods of different types of CMCS

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5.1. Synthesis of O-carboxymethyl chitosans (O-CMCS)

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Among the water soluble derivatives of CMCS, O-CMCS is known to be an amphiprotic ether derivative which contains –COOH groups and – NH2 groups in the molecule. The reaction medium used for preparation of O-CMCS is strongly alkaline. O-CMCS is prepared by suspending chitosan, sodium hydroxide and solvent isopropanol into flask and stirring the alkaline slurry at room temperature for 1 h. Subsequently, monochloroacetic acid dissolved in isopropanol is added to reaction mixture drop wise within 30 min. The whole reaction mixture is reacted for 4 h at 55 °C. Finally, the solid is filtered and washed with ethyl alcohol and dried in vacuum. The preparation conditions and degree of carboxymethylation govern water solubility of O-CMCS as experimentally demonstrated by Chen at al. [58].

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5.2. Synthesis of N-carboxymethyl chitosans (N-CMCS)

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Synthesis of N-CMCS takes place in slightly acidic medium. To prepare N-CMCS, free amino group of chitosan is reacted with glyoxylic acid to give soluble aldimine and then aldimine is reduced with reducing agent sodium cyanoborohydride. The reaction neither requires warming, nor cooling. The proportions of acetyl, carboxymethyl and free amino groups are determined by DA and MW of the chitosan used and the quantity of glyoxylic acid used [42].

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5. Synthesis of various carboxymethyl chitosans (CMCS)

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a good proliferation substratum for Neuro-2a cells, as compared to chitosan films [70]. The biodegradation study on CMCS-g-medium chain length polyhydoxyalkanoates by Bhatt and coworkers showed that depends on several factors such as temperature, pH, water potential, oxygen content, stereo regularity and crystallinity of the polymer, and its material processing [71]. The spontaneous degradation of CMCS in soil and by enzymes with satisfactory results has been earlier reported in literature [72]. In this view, controlling the degradation of covalently cross-linked CMCS utilizing bimodal MW distribution as reported by Guangyuan and coworkers is worth mentioning [73]. Recently, a study demonstrating the significant effect of MW of CMCS on its uptake from the lumen of abdomen and blood vessels to peripheral tissues, the distribution of this chemical and urinary excretion after intraperitoneal administration has been carried out [74]. The earliest study establishing the low toxicity of CMCS dates back to early 1990s when Tokura et al. [75] studied the biological activities of different biodegradable polysaccharides. With regard to the in vivo toxicity, no acute toxicity was detected in blood systems of rats after CMCS was absorbed in the abdominal cavity and degraded gradually in the blood [76]. Finally a recent study exploring the in vitro cytotoxicity profile of chitosan, O-CMCS and N,O-CMCS nanoparticles to breast cancer cellsMCF-7 showed less toxicity (almost 98% viability was found) [77]. In this context, the cytocompatibility of some of the modified CMCS formulations like CMCS-2, 2′ ethylenedioxy bisethylamine-folate [78], CMCSPolyamidoamine dendrimer nanoparticles [79] and N-octyl-N,O-CMCS [80] demonstrated currently is worth mentioning. In addition to the toxicological profile of CMCS in different forms, the ability of CMCS in prevention and reduction of postsurgical adhesion formation [81–83] and in vivo wound healing ability [84] have been experimentally demonstrated. Finally, the inherent excellent mucoadhesive and absorption enhancing property of chitosan are retained in CMCS which is favorable for drug delivery applications. Therefore, this interesting biopharmaceutical and toxicological profile of CMCS has encouraged its application as drug delivery and tissue engineering biomaterial. Fig. 2 illustrates different outstanding and astonishing physicochemical and biological properties of CMCS that contribute for its suitability in numerous drug delivery and tissue engineering applications.

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Fig. 1. Represent desirable property of CMCS and which makes it highly suitable for fabricating different drug delivery formulations and tissue engineering biomaterials nanosystem.

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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Fig. 2. Illustrates the different outstanding and astonishing physicochemical and biological properties of CMCS that contribute for its suitability in numerous drug delivery and tissue engineering applications.

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N,O-CMCS is hydrophilic and amphoteric polyelectrolyte which bears carboxymethyl substituents at some of the amino and primary hydroxyl

sites of the glucosamine units of the chitosan structure. The main attractive features of N,O-CMCS are moisture retention, gel formation and good biocompatibility along with increased water solubility and enhanced antibacterial property that makes this polymer derivative highly

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Fig. 3. Preparative methods of different types of CMCS.

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CMCS based formulations for drug delivery applications have been prepared by different techniques and methods by various researchers as per the requirement of the host tissue/organ and the type of drug being delivered. CMCS based hydrogels are one of the major formulations for drug delivery applications and can be prepared by different methods. In each process, CMCS is either physically associated or chemically cross-linked. The major schemes of physical interactions that lead to gelation of CMCS solution in hydrogels are ionic interaction, polyelectrolyte complex; inter polymer complex, and hydrophobic associations. Moreover the physically cross linked hydrogels have the advantage of gel formation without the use of cross-linking moieties. But they have certain limitations like difficulty in accurately controlling the physical gel pore size, chemical functionalisation, dissolution and degradation, thereby providing inconsistent in vivo performance. Cross linked hydrogels often possess better mechanical properties where cross links can be incorporated either chemically or through irradiation. But chemical cross linking method for preparation of hydrogels suffers from disadvantage of having toxic residues of cross linking chemicals. On the other hand preparation of microspheres, nanoparticles and micelles/aggregates can be carried out by different methods like emulsion cross linking, sonication, coacervation/precipitation, spray drying, ionic gelation, sieving, emulsion droplet-coalescence and reverse micellar methods. Each method has its own advantage and certain limitations and therefore the choice of preparative technique depends on the type of particulate being synthesised, its size range, composition, the drug being loaded or encapsulated and the target tissue/organ where drug is to be delivered. Similarly, layer-by-layer assembly and cross linking are the main preparative methods for the synthesis of composites and blending, casting and drying methods are the most popular preparative techniques for films and fibers for the purpose of delivery of different drugs. Table 1 shows preparation techniques of CMCS based formulations for drug delivery.

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7.1. CMCS hydrogels

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In the recent few decades, the pharmaceutical industries have witnessed the emergence of drug delivery technologies as a powerful and efficient tool in order to effectively use the existing drugs and develop new drug candidates successfully [131]. A hydrogel can be defined as cross linked network formed from a macromolecular hydrophilic polymer capable of absorbing large amount of water. The volume of water

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The most crucial parameters for preparing N,N-di-CMCS are the concentration of chitosan, water, glacial acetic acid, glyoxylic acid, and sodium borohydride. In order to synthesise N,N-di-CMCS, to a fixed concentration of chitosan (30 g) suspended in demineralised water (3 l), 27 g of glacial acetic acid is added and stirred for 20 min. After this glyoxylic acid is added (178 mL 50% v/v corresponding to 119 g of glyoxylic acid) and the molar ratio of amine/glyoxylic acid is set to 1:9 at pH 2–3. Finally, with the help of peristaltic pump (1.2 ml min−1), sodium borohydride (90 g) in water (2.5 l) is delivered as a 3.6% solution to the reaction vessel. The N,N-di-CMCS prepared by this method exhibits good film forming ability, good capacity to chelate metal ions and also possesses excellent osteoinductive properties with calcium phosphate [89].

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absorbed by hydrogels may range from 10% to thousands of times of its own volume. The high water content makes hydrogels biocompatible while coherence of their mechanical properties with the soft tissues assists and enhances healing phenomenon. The compatibility of mechanical properties of hydrogels with the soft tissues also mimics morphological and functional characteristics of organ tissue. The viscoelastic property of hydrogels causes minimised damaged to the surrounding tissues in the host. Natural polymer based hydrogels have also attracted the attention of scientists and researchers because of their improved biocompatibility, biodegradability and notable capability of controlled delivery of bioactive molecules [132–134]. As far as covalent cross linking is concerned, it leads to the formation of hydrogels with permanent network structure because irreversible chemical links are formed. Therefore, this type of linkage not only allows absorption of water and/or bioactive compounds without dissolution but also permits drug release by diffusion. Broadly covalently crosslinked chitosan hydrogels can be divided into three categories: chitosan cross linked with itself, hybrid polymer network (HPN) and semi or full interpenetrating networks (IPN). In chitosan cross linked with itself, crosslinking involves two structural units that may or may not belong to the same chitosan polymeric chain [135]. The overall final structure of this type of hydrogel can be considered as a crosslinked gel network dissolved in a second entangled network formed by chitosan chains with restricted mobility [136]. In hybrid polymer networks (HPN) based hydrogels the crosslinking reaction occurs between a structural unit of chitosan chain and a structural unit of polymeric chain of another type. Although crosslinking of two structural units of the same type and/or belonging to the same polymeric chain cannot be excluded. Finally semi or full IPNs contain a non reacting polymer which is added to the chitosan solution before crosslinking. Thus cross linked polymer network in which the non reacting polymer is entrapped (semi-IPN) are thus formed. This additional polymer can further be crosslinked in order to have two entangled crosslinked networks forming a full IPN whose microstructure and properties can be quite different from its corresponding semi-IPN [137]. Ionically cross linked hydrogels leads to the formation of non permanent network structure since reversible links are formed [138]. Ionically cross linked hydrogels show higher swelling sensitivity to pH changes as compared to hydrogels having covalent cross linking. The entities reacting with chitosan are ions or ionic molecules with well defined MW in ionically crosslinking. It is different from polyelectrolyte complexation as the entities reacting with chitosan are polymer with a broad MW distribution [139]. In contrast to covalent crosslining ionic cross linking is a simple and mild procedure as no auxillary molecules such as catalyst are required [140]. Ionic cross linking can be assured by the classical method of preparing a cross linked network namely by the addition of crosslinker either solubilised [141] or dispersed [142,143] to the chitosan solution. Superporous hydrogels containing poly (acrylic acid-co-acrylamide)/ O-CMCS IPNs were prepared by cross-linking O-CMCS with glutaraldehyde (GA) after superporous hydrogel was synthesised by Yin et al. An enhanced capacity of loading insulin was reported for the superporous hydrogels as compared to the non-porous hydrogels. Due to improved mechanical properties, in vitro muco-adhesive force and loading capacities, these IPNs showed potential of muco-adhesive system for peroral delivery of peptide and protein drugs [97]. Similarly, Chen et al. prepared a novel type of IPN hydrogel membrane of poly (N isopropylacrylamide)/ CMCS and systematically studied the effects of the feed ratio of components, swelling medium and irradiation dose on the swelling and deswelling properties of the hydrogel. The results showed that a combination of pH and temperature can be coupled to control the responsive behavior of poly(N-isopropylmethacrylamide (PNIPAAM)/CMCS hydrogels [95]. There are several CMCS based semi-IPNs reported in literature prepared by crosslinking with genipin [20], GA or cross-linked/ grafted with ethylene glycol diglycidyl ether [102], and N,N′methylenebisacrylamide [99]. Min Wang and coworkers synthesised

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suitable for wide variety of biomedical applications. N,O-CMCS can be prepared by using chitosan, sodium hydroxide, isopropanol and chloroacetic acid [93,94].

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Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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Table. 1 Preparation techniques of CMCS based formulations for drug delivery. Composition of formulation

Method of preparation

Refs.

Hydrogel Hydrogel Hydrogel Hydrogel Hydrogel Hydrogel Hydrogel Hydrogel Hydrogel Hydrogel Hydrogel Hydrogel Hydrogel Hydrogel Hydrogel Nanoparticles Nanoparticles Nanoparticles Nanoparticles Nanoparticles Nanoparticles Nanoparticles Nanoparticles Nanoparticles Microspheres Microcapsules and microparticles

Physical cross linking Chemical cross linking Physical cross linking Chemical cross linking Chemical cross linking Chemical cross linking Chemical cross linking Chemical cross linking Chemical cross linking Radiation cross linking Radiation cross linking Radiation cross linking Radiation cross linking Radiation cross linking Radiation cross linking Ionic gelification Ionic gelation Microemulsion Sonication Spraying co-precipitation Coprecipitation Ionic cross-linking Self-assembly Oil in water emulsification Precipitation Self-assembly

[95] [20] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] [119]

t1:30

Microspheres

CMCS/poly(N-isopropylacrylamide) (PNIPAAM) N,O-CMCS & alginate N,O-CMCS CMCS Poly(acrylic acid-co-acrylamide)/O,CMCS CMCS/poly(N-isopropylacrylamide) CMCS 6-O,CMCS/polyurethane CMCS/poly(acrylonitrile) CMCS CM-cellulose/CMCS CMCS CMCS/gelatin Nano-Ag/gelatin/CMCS N-isopropylacrylamide/CMCS Cross linked lactosaminated CMCS O,CMCS Amphiphilic octadecyl Q-CMCS Cholesterol modified O-CMCS CMCS bound Fe3O4 CMCS/poly(amidoamine) O-CMCS Oleoyl-CMCS Oleoyl-CMCS CaCO3/CMCS CMCS & CMCS graft-poly(N,N-diethylacrylamide) (CMCTS-g-PDEA) O-CMCS bound with iron oxide

[120]

t1:31 t1:32 t1:33 t1:34 t1:35 t1:36 t1:37 t1:38 t1:39 t1:40 t1:41

Microspheres Microspheres Microspheres Micelles Micelles Composite Composite Composite Composite Film Fibers

Alginate/Q-CMCS/clay nanocomposite Alginate & chemically modified CMCS Ambroxol hydrochloride CMCS Linoleic acid modified CMCS PEG-grafted-CMCS CMCS/TMCS Folate conjugated CMCS/Fe3O4/CdTe O-CMCS/β cyclodextrin FA–CMCS–ZnS:Mn Poly-vinyl alcohol/CMCS Ag nanoparticles/poly vinyl alcohol/CMCS

In situ coprecipitation and incorporation Ion-crosslinking Ionotropically-crosslinked Emulsion chemical cross-linking Sonication Ion complex formation Direct crosslinking Layer-by-layer assembly technique Crosslinking method Ionic crosslinking Blending/casting Electrospinning technique

480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503

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CMCS hydrogels by gamma rays induced cross linking where adsorption kinetics study showed fast adsorption of Fe (III) ions onto CMCS gels. This was primarily due to the coordination of Fe (III) ions with amino, hydroxyl and carboxyl groups of CMCS molecules [105]. Also an ESR study on CMCS radicals in a highly concentrated CMCS aqueous solution which forms hydrogels by ionizing radiation was performed by Seiichi Saiki et al. [103]. Physically cross linked alginate-N,O-CMCS hydrogels with calcium for oral delivery of protein drugs was prepared by Lin and coworkers [96]. Substantial research has been done in chemically cross-linked hydrogels also. Currently, pH sensitive hydrogels composed of CMCS, chemically cross linked by GA was prepared and evaluated in vitro as a potential carrier for colon targeted drug delivery of ornidazole [100]. In this regard, the synthesis of novel polyampholyte hydrogels based on CMCS of varying DD and DS cross linked with GA by Chen et al. [97] is worth mentioning. With increasing DD or DS value, the hydrogel changed from polyampholyte into polycations or polyanions, respectively. The release of bovine serum albumin (BSA) was much quicker at pH 7.4 buffer than pH 1.2 solutions. In recent years radiation cross linking has proved to be safer, clean and effective method of hydrogel synthesis. The products formed are free of toxicity additives as neither initiator nor cross linker is required as in conventional chemical routines. The synthesis of CMCS using γ-rays radiation [104, 105] and ionizing radiation [103] has been reported in the literature. Yang et al. [144] have in situ synthesised dark bluish coloured 5fluorouracil (5-FU) loaded CMCS hydrogels using genepin as the cross linker and it was speculated that the dark bluish colour of the hydrogels prepared resulted from the cross linking reaction between genipin and the amino groups of CMCS (Fig. 4A). The possible cross linking

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CMCS based formulation

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[121] [22] [122] [123] [124] [125] [126] [127] [128] [129] [130]

mechanism for the reaction of CMCS with genepin was speculated as illustrated in Fig. 4B [144]. Similarly, Yang et al. [145] prepared hydrogel beads based on methoxy poly (ethylene glycol) grafted carboxymethyl chitosan (mPEG-g-CMC) and alginate in order to construct interpenetrating polymeric matrix. Fig. 5 [145] illustrates the synthesis of mPEG-g-CMC copolymer using Schiff's base method. Some of the CMCS based hydrogels for delivery of different therapeutics are summarised in Table 2.

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Microspheres are spherical free flowing particles having size range between 50 μm and 2 mm with drugs entrapped inside them. While in matrix type microspheres drug is mainly released by erosion mechanism, release of drug takes place by diffusion and erosion in matrix and reservoir type microspheres [152]. In general drug release rate depends upon solubility, diffusion, biodegradability of the matrix, drug loading efficiency, and size of the microspheres. Therefore the drug release mechanism can be altered by varying polymer employed and its properties. Microspheres are mainly exploited in controlled drug delivery but by derivatisation and surface modification they can also be used for drug targeting purpose. The partition coefficient determines the drug distribution within the microspheres. CMCS based microspheres have emerged as efficient drug carriers due to their ability to encapsulate a variety of drugs, biocompatibility, protection of fragile drugs, high bioavailability and sustained drug release characteristics. Currently, carboxymethyl cellulose and CMCS based biodegradable and highly porous microspheres were prepared with an inverse emulsion-cross-

513 514

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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crosslinking with CaCl2 and the drug-controlled release was evaluated by using BSA as model drug. The AQCOM microsphere displayed more excellent encapsulation and controlled release capacities than the microsphere without OMMT and in vitro active cutaneous anaphylaxis test on Guinea pigs did not cause anaphylaxis [121]. Fig. 6 shows the pictures of Guinea pigs after ACA test of AQCOM-3 microspheres. Significant anaphylaxis such as swelling and even ulcerated induced by 2,4-dinitrophenol was observed (as shown in Fig. 6f). Again the induce contact and even challenge exposure on Guinea pig treated by

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linking method without incorporating any extraneous cross-linking agents capable of loading anticancer drug doxorubicin (DOX) whose release profile was adjustable. The in vitro and in vivo studies indicated that these microspheres can be used as biocompatible and biodegradable embolic agents for transarterial embolisation [153]. Recently, quaternised carboxymethyl chitosan (QCMCS) was intercalated into the interlayer of organic montmorillonite (OMMT) to obtain the QCMCS/OMMT nanocomposites. The cross linked alginate-Q-CMCS-organic montmorillonite (AQCOM) microspheres were prepared by

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Fig. 4. Possible representations for (A) in situ synthesis of the drug loaded CMCS hydrogel and its photo and (B) cross linking mechanism between CMCS and genipin (Reproduced with permission from [144]).

Fig. 5. Synthesis of the methoxy poly (ethylene glycol) grafted carboxymethyl chitosan (mPEG-g-CMC) copolymer (reproduced with permission from [145]).

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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Table. 2 Summarizes different CMCS based hydrogels for delivery of different therapeutics in drug delivery applications.

t2:3

Composition of hydrogel

t2:4

Photocrosslinked methacrylated O-CMCS & PEG diacrylate OCMCS-based hydrogels with varying concentrations of carboxy and methacrylate groups are envisaged as attractive and versatile synthetic extracellular matrices that can effectively sequester, protect and controllably release basic proteins. Varying the carboxyl and methacrylate groups respectively allows variation of charge and water content/pore size which ultimately allows control of the absorption and dynamic release, via substrate biodegradation, of basic proteins. Covalently crosslinked N,O-CMCS and oxidized alginate Good cytocompatibility against NH3T3 cells by in vitro test and no obvious cytotoxicity for major organs during hydrogel the period of 21-day intraperitoneal administration was observed by acute toxicity test. The hydrogels developed also showed good hemocompatibility. Nanocomposite hydrogel composed of Curcumin, Nano curcumin with improved stability by using methoxy poly(ethylene glycol)-b-poly( -caprolactone) N,O-CMCS and oxidized alginate copolymer as carrier was slowly released from the hydrogel with the diffusion controllable manner at initial phase followed by the corrosion manner of hydrogel at terminal phase. In vivo wound healing study showed that the hydrogel could significantly enhance there-epithelialisation of epidermis and collagen deposition in the wound tissue. CMCS and carbopol 934 hydrogel for delivery of In vitro swelling studies have shown little swelling in acidic pH 432% at the end of 2 h and 1631% in basic pH at the theophylline end of 12 h. The pH-sensitive hydrogel of CMCS can be used for extended release of theophylline in intestine and can be highly useful in treating symptoms of nocturnal asthma. CMCS hydrogel A simple and economical method with no toxic chemicals involved was introduced. The steam-induced crosslinking of CMCS sodium salt was observed to be quite efficacious. Depending on the harshness of steaming conditions used, the DS of the hydrogels was found to be up to 36. The increasing temperature and duration of steam exposure changed the coloration of the samples from light beige to brown. In situ gelable hydrogel composed of N-CMCS and oxidized The rate of gelation was directly related to the degree of oxidation of Odex and the hydrogels underwent fast mass dextran (Odex) loss in the first 2 weeks, followed by a more moderate degradation. The in vivo studies in mice full-thickness transcutaneous wound models showed its ability of enhanced wound healing ability. With the increase in the interaction of component polymers, the swelling and drug release rate of hydrogels Physically crosslinked hydrogels of CMCS with cellulose decrease. Component polymer ratio controlled the swelling and drug release from hydrogels. ethers including hydroxyethylcellulose and methylcellulose 5-FU or bevacizumab loaded N,O-CMCS hydrogels The in vitro drug release experiments showed that nearly 100% of −5-FU was released from the drug-loaded crosslinked with genepin hydrogels within 8 h, but less than 20% bevacizumab was released after 53 h. The hydrogels provided great opportunity to increase the therapeutic efficacy of glaucoma filtration surgery.

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[149]

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Fig. 6. Photos of Guinea pigs by ACA test: (a) experimental procedure, (b) the first day after treating by AQCOM-3 microsphere, (c) the seventh day after treating by AQCOM-3 microsphere, (d) the eighth day after treating by AQCOM-3 microsphere, (e) the eighth day after negative control, and (f) the eighth day after positive control (reproduced with permission from [121]).

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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When polar or non-polar ends of amphiphilic polymer self assemble by hydrophobic or ion-pair interaction in a monophasic or biphasic liquid, nanosised (200 nm to 0.5 μm) structures are formed which are referred to as micelles. In an aqueous environment, the amphiphilic polymers form hydrophobic core by assembly of lipophilic parts and vice versa. The repositioning of hydrophobic and hydrophilic drug within the hydrophobic or hydrophilic core of micelles improves the solubility of drugs in monophasic non-solvent medium often referred to as micellar solubilisation. In biphasic medium, polymeric segments distribution takes place according to their physicochemical characteristics. In general, the hydrophobicity of the drug and the type of polymer determines the preparative method of micelle. In fact the experimental evidences have led to the conclusion that polymeric micelles exhibit numerous promising properties for oral delivery of lipophilic drugs [155]. Nano precipitation technique, dialysis method and sonication are some

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of the preparative methods of micellar structures. Formation of micelles by self-assembly is the most popular preparative methodology in case of CMCS based or modified CMCS micelles designed and developed for drug delivery purpose. The nanoscopic dimension, segregated core/ shell structure, sheltering effect of hydrophobic core on drugs entrapped and stealthy characteristics by their hydrophilic shells makes polymeric micelles suitable for tumor targeting [156,157]. CMCS has been extensively exploited by several researchers for developing micelle based nanoformulations for model anticancer drug DOX [158,30]. Aifeng et al. synthesised and characterised DOX loaded octreotide-modified N-octyl-O,N-CMCS micelles which proved to be promising carrier for efficient intracellular targeting of antitumor drugs [159]. Similarly self-aggregated nanoparticles from linoleic acid (LA) modified CMCS were prepared by Yu-long Tan and coworkers for delivery of hydrophobic anticancer drug adriamycin (ADR). The critical aggregation concentration determined by measuring the fluorescence intensity of the pyrene as a fluorescent probe, was in the range of 0.061–0.081 mg/mL [123]. Gong and coworkers grafted Cis-3-(9Hpurin-6-ylthio)-acrylic acid (PTA) on primary amino of CMCS, under the catalysis of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EDC·HCl and N-Hydroxysuccinimide (NHS) i.e. the reaction took following two steps: synthesis of PTA (Fig. 8A) and synthesis of PTA grafted CMCS (PTA-g-CMCS) Fig. 8B [160]. Amphiphilic polymeric prodrug PTA-g-CMCS designed and synthesised could self-assemble into spherical micelles with a size ranging from 104 to 285 nm with 6mercaptopurine loaded into it. The result demonstrated that nanocarrier was found suitable for controlled drug delivery. Fig. 8C shows 6-methoxy propyl release from PTA-g-CMCS in the presence of glutathione, which follows a Michael addition–elimination reaction [160]. Jeong et al. [124] synthesised methoxy poly(ethylene glycol)-grafted carboxymethyl chitosan (CMCPEG) copolymer using a water-soluble carbodiimide. In addition, DOX-incorporated nanoparticles using CMCPEG were prepared by ion complex formation between the amine groups of DOX and the carboxyl group of CMCPEG. The self assembled N-phthaloyl-CMCS based micelles for drug delivery of levofloxacine hydrochloride and BSA have also been earlier prepared by Peng et al. [161]. Another technique of nano-precipitation was employed for the preparation of copolymer polylactide-polyethylene glycol succinate, 1,3-beta-glucan (Glu), O-CMCS and folate-conjugated O-CMCS micelles for efficient encapsulation of herbal anticancer drug curcumin. The nanoformulation displayed better aqueous solubility and biodegradation along with significantly enhanced the cellular uptake by cancer cell HT29 and HeLa. The anti-tumor-promoting effect of the curcumin encapsulated by copolymer in Hep-G2 cell lines after

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AQCOM-3 microspheres did not induce the anaphylaxis (b–d) which illustrated that AQCOM-3 microspheres did not induce the anaphylaxis [121]. Similarly, clozapine loaded spherical microspheres of chitosan and CMCS within size range of 100 ± 0.25 μm to 140 ± 0.25 μm were prepared by spray drying technique. The in vitro drug release study showed that CMCS microspheres released most part of the drug in the intestine compared to chitosan microspheres hence controlled drug release was achieved [154]. Ma et al. [119] developed a simple method to fabricate BSA loaded self-assembled CMCS and CMCS-graft-poly (N,Ndiethylacrylamide) microcapsules and microparticles whose in vitro drug release rate and encapsulation efficiency depended on pH value. The microspheres were found to be non-cytotoxic against L02 human hepatic natural cell and release of BSA could be sustained. Also sustained release of BSA from microspheres based on mixtures of ionotropically cross linked sodium alginate and chemically modified CMCS and coated through polyelectrolyte complexation with chitosan grafted with poly (ethylene glycol) has been reported in literature. Fig. 7 [26] illustrates the carboxymethylation of chitosan and synthesis of CMCS grafted sodium acrylate copolymer. Again, high encapsulation efficiency and sustained release of model anticancer drug DOX has been achieved by preparing CMCS-CaCO3 microspheres by Wang and coworkers [118]. There is also information regarding preparation of two kinds of OCMCS bounded with iron oxide particles by in situ co-precipitation and incorporation methods reported in literature. The magnetic properties of these microspheres were studied to evaluate its potential in drug delivery applications [120].

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Fig. 7. Scheme of carboxymethylation of chitosan and synthesis of CMCS grafted sodium acrylate copolymer (reproduced with permission from [26]).

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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The emerging trends and recent advances in nanotechnology has made a significant impact on the development of drug delivery systems, after the liposomes were first described in the 1960s as carriers of proteins and drugs for disease treatment [171]. Most of the front-line drugs are toxic entities that act in unspecific fashion being untargeted, often eliciting unwanted, dose limiting and debilitating side effects. Compared to conventional drug delivery systems, nanoscale drug delivery vehicles are capable of enhancing therapeutic activity by prolonging drug half-life, improving solubility of hydrophobic drugs, reducing potential immunogenicity, and/or releasing drugs in a sustained or stimuli-

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R

641 642

N C O

639 640

U

637 638

T

658 659

two weeks of cell growth is shown in (Fig. 9). The sudy showed that in the cytotoxicity assay there were no distinct differences in the cell survival. Also in the anti-tumor promoting assay, the ration of tumor promotion with the Cur, Glu, PLA-TPGS alone was comparable to the control. But contrary to this clear changes in the size and morphology of tumor between the control and all the tested samples particularly curcumin encapsulated with glucan copolymer. It was observed that in comparison to the tumor on the tested wells, in control the tumor size was much larger and their surface was very rough (Fig. 9). [162]. Wang and coworkers prepared Ca–P/CMCS/KALA nanoparticles by self assembly via electrostatic interaction between positively charged peptide KALA and negatively charged Ca–P/CMC nanoparticles in an aqueous solution after loading anticancer drug DOX·HCl onto the Ca–P/ CMCS hybrid nanoparticles. The investigation results showed that DOX·HCl could be encapsulated with high efficiency and the presence of KALA peptide significantly enhanced the cell inhibition effect [163]. Dialysis method was employed for the preparation of methotrexate conjugated O-CMCS micelles where methotrexate exhibited significant sustained release behavior in PBS solutions (pH 4.0, 7.2 and 9.0). The critical micelle concentration (CMC) of O-CMCS–methotrexate conjugates determined in aqueous media was in the range of 0.0084– 0.0424 mg/mL [164]. In addition, sonication method has also been utilised for the designing and development of CMCS based nanocarriers for delivery of anticancer drugs like DOX [165] and paclitaxel (PTX) [166]. Table 3 shows different CMCS based self aggregates and the drugs delivered by these fabrications.

635 636

triggered fashion. Thus, the toxic side effects and administration frequency of the drugs can be reduced [172]. In addition, nanoscale particles can passively accumulate in specific tissues (e.g., tumors) through the enhanced permeability and retention (EPR) effect [173]. Polymers like CMCS have emerged as a promising drug delivery nanovehicle due to inherent increased water solubility, biological functionality, compatibility, safety, biodegradability, and antimicrobial nature. In the context of drug encapsulated CMCS based nanoparticles, nanoprecipitation, dialysis, micro emulsion, emulsion-solvent diffusion technique, solvent evaporation and ionic gelation methods have been employed so far. The preparation of self-aggregated cholesterol modified O-CMCS nanoparticles by sonication method were prepared to be used as a novel carrier for PTX has been reported by Wang et al. [174]. These results suggest that cholesterol modified O-CMCS self-assembled nanoparticles can effectively solubilise PTX and modify its tissue bio-distribution, which may be advantageous in enhancing the therapeutic index and reducing the toxicity of PTX. Similarly Zhang et al. [113] reported synthesis of magnetic Fe3O4 nanoparticles functionalised with CMCS by spraying co-precipitation method and these magnetic nanoparticles are suitable for use as nanomagnetic carriers of drugs formulation. In this context, the preparation of vincristine loaded polymeric ethosomes; formed from amphiphilic octadecyl Q-CMCS with different DS by micro emulsion method is worth mentioning [175]. Biocompatible ciprofloxacinloaded CMCS nanoparticles by ionic cross-linking method and optimised by using Box–Behnken response surface method by Zhao et al., demonstrated, stronger antibacterial activity against Escherichia coli than the free ciprofloxacin because they can easily be uptaken by cells. Still fabrication of CMCS based nanostructure delivery vehicles by ionic gelation is the most popular method employed till date [108,109]. A number of CMCS based nanoscale carriers have been constructed in recent years for the efficient delivery of different anticancer, antiinflammatory drugs, antibiotics, proteins, peptides and vaccines. Model anticancer drug DOX has been encapsulated into a number of modified CMCS nanosystems like FA modified CMCS nanoparticles [176] amphiphatic carboxymethyl–hexanoyl chitosan nanocapsules [158], and acylated CMCS nanoaggregates [35]. Also, liposomes modified with CMCS [177] and CMCS capped magnetic nanoparticles [168] have also been exploited for DOX delivery. The drug release profile of DOX loaded-CMCS-capped-MNP/MMT was tested at pH 7.4 and

E

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Fig. 8. (A) Synthesis of PTA, (B) synthesis of PTA-g-CMCS, (C) 6-MP release from PTA-g CMCS in the presence of glutathione (GSH), which follows a Michael addition–elimination reaction: GSH attacks the β-C of the unsaturated bonds, leading to the cleavage of the unsaturated bonds (reproduced with permission from [160]).

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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significant difference in the cellular uptake of curcumin-O,CMCS NPs comparing normal and cancer cell lines [179] Another multifunctional nanodrug system containing Fe3O4, O-CMCS and curcumin has been recently fabricated by Thu et al. [180]. Similarly, Shen et al. [126] prepared CMCS-ferroferric oxide doped cadmium telluride quantum dot nanoparticles with folate receptors affinity, magnetic responsiveness and luminescent property via layer-by-layer assembly technique in situ surface as shown in Fig. 12. The results indicated that the novel multifunctional folate conjugated carboxymethyl chitosan-ferroferric oxide doped cadmium telluride quantum dot nanoparticles synthesised exhibit a high drug loading efficiency, minimised cytotoxicity and desirable cell compatibility, and are potential candidates for CMCS-based targeted drug delivery and cellular imaging. In addition to this, nanoformulations of other anticancer drugs like vincristine, camptothecin, PTX, and ADR have been developed by different modifications of CMCS such as amphiphilic carboxymethyl–hexanoyl chitosan [181], PEGylated O-CMCS nanoparticles grafted with cyclic Arg-Gly-Asp (RGD) peptide [182] and LA modified CMCS nanoparticles [166] respectively. Apart from these drugs, CMCS based nanoparticles mediated vehicles have been prepared for delivery of anti-inflammatory compounds [183], proteins/peptides [184] and vaccines [185] along with poorly water soluble drugs like triamcinolone [186] and vitamin D3 [187]. Table 4 describes various nanoformulations for delivery of different drugs along with brief method and their outcome.

726 727

7.5. CMCS films and fibers

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R O

O

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12

O

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R

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In the recent years, drugs and polymers are manufactured into various film configurations, like coating of some precarious drugs or proteins by thin polymer films or generating drug–polymer matrix films. These different matrices are suitable for facilitating diffusion mediated drug delivery or adaptable for accomplishing transdermal drug delivery. The parameters that determine the efficacy of polymeric films in delivery of therapeutic compounds are thickness, surface morphology, degree of swelling, degradation behavior, drug release and therapeutic effect. The drug release pattern and rate of drug release from the film coating systems depend on the coating material, thickness of the film and circumstance of the applied site. Polymeric films have also gained importance as promising drug delivery formulation as its thin layer resists change in crystallinity and segmental motions. As CMCS shows inherent excellent biocompatibility, improved biodegradability, antimicrobial strength and easily film forming ability, it has emerged as a suitable biopolymer for films fabrication for drug delivery. The ornidazole (OD) loaded poly-vinyl alcohol PVA/CMCS films prepared by blending/ casting method demonstrated excellent antibacterial and biocompatibility characteristics which were enhanced with increasing CMCS content in the films. The process of preparing the placebo films and their corresponding drug OD loaded films (loaded OD) via blending/casting is shown in Fig. 13 [38]. The results from in vitro and in vivo study demonstrated the blend films as an excellent candidate for local drug delivery system. A similar study was carried out where PVA/CMCS blend films prepared by casting and drying method were evaluated as coating material for site specific drug delivery. The drug release kinetics study by salicylic acid, theophyline, and OD also revealed that a desired rate of drug release could be obtained by controlling the content of CMCS in the blend film, type and MW of drugs, pH of the medium and thickness of the film. As pH of the buffer increased the permeability of OD with a maximum at pH 7 as shown in Fig. 14. The reason for this phenomenon can be attributed to the fact that as pH increased, deprotonation of the charge groups of CMCS takes place. CMCS molecules became uncoiled and assumed to be elongated thereby causing the expansion of the bulk of films. It caused the enhanced water absorption ability and lead to the increase of permeability [129]. A study on the BSA and bovine fibrinogen equilibrium adsorption amount on the PVA/CMCS films prepared by mechanical blending showed the influence of CMCS content and pH and ionic strength of protein solutions

711 712 713 714 715 716 717 718 719 720 721 722 723 724 725

pH 5.0 respectively and the released DOX concentration was determined by UV–vis measurement. From the drug release curve (Fig. 10) it is clear that the release of DOX from DOX loaded-CMCS-cappedMNP/MMT is pH triggered and the release rate of DOX was higher at pH 5.0 than pH 7.4. It is well known fact that the pH of tumor tissue is lower than normal cells. Thus this delivery system will exhibit smaller toxicity towards normal cells as compared to tumor cells thereby illustrating its advantage of safety [178]. Recently, researchers have also developed O-CMCS [179] and folate conjugated O-CMCS nanosystems [162] for efficient delivery of another anticancer compound: curcumin. The cellular uptake study of curcumin-O,CMCS NPs by normal L929 cells and cancer cell line MCF-7 cells using flow cytometry showed (Fig. 11) that the nanoformulation uptake was concentration dependent and non specific. This meant that both the cell line showed increasing uptake of the nanoformulation with the increase in the concentration of the curcumin-O-CMCS nanoformulation. Also there is not much

U

710

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Fig. 9. Anti-tumor-promoting effects of the curcumin encapsulated by copolymer in HepG2 cell lines after two weeks of cell growth on agar: control (a), Cur (b) and Cur-PLA-TPGS (c) under inverted microscope × 100 (reproduced with permission from [162]).

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749

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L. Upadhyaya et al. / Journal of Controlled Release xxx (2014) xxx–xxx t3:1 t3:2

13

Table. 3 Different CMCS based self aggregates. CMCS based formulation

Size range of self-aggregates

Brief method and outcome

Refs.

t3:4

O-CMCS aggregates



[167]

t3:5

Cholesterol modified O-CMCS aggregates

234.9–100.1 nm

t3:6

LA-modified CMCS self-aggregates

222.8–1028 nm

t3:7

LA-modified CMCS aggregates

417.8 ± 17.8 nm

t3:8

Deoxycholic acid-O-CMCS-folic acid conjugates

179–212 nm

t3:9

CMCS nanoclusters

301 nm

Not only the aggregates but also the unimers of O-CMCS enhanced the solubility of camptothecin. The aggregates showed good drug loading capacity and sustained drug release demonstrating potential for localised drug delivery. A series of cholesterol modified O-CMCS conjugates with different DS of cholesterol were synthesised and self-aggregates were prepared by probe sonication in water. The relationships between the chemical structure, the amphiphilic property and the morphological characteristics of O-CMCS self-aggregated nanoparticles were investigated in this study. Covalently conjugated LA to CMCS via EDC mediated reaction to generate self-aggregated nanoparticles by sonication method. Physically entrapped ADR showed slow release which can be adjusted by change in medium pH. The LA modified CMCS self aggregates prepared by sonication method exhibited increased loading capacity and loading efficiency and decreased sustained release for ADR with increasing DS of LA in CMCS with critical aggregation concentration values in the range of 0.061–0.081 mg/mL. Deoxycholic acid and FA modified O-CMCS self-aggregates were prepared by sonication method and the mean diameter and critical aggregation concentration value changed with change in DS and pH values. The results showed that demonstrated that Box–Behnken design methodology was an effective way to obtain the optimal formulation of tea polyphenols-loaded chitosan nanoclusters, and the nanoclusters complexation synthesizing through ionic gelation between CMCS and chitosan hydrochloride was good biomaterials, which could be successfully used to encapsulate tea polyphenols

O

R O

803

Composites are biomaterials that are composed of more than one constituent of different physical and chemical properties that are blended to form macroscopic, microscopic or nano structure. In case of composites for delivery of drugs, usually the polymers are modified either to

805 806

C

E

R

R

804

N C O

799

U

797 798

Fig. 10. Release profiles of DOX from CMCS-capped-MNP/MMT at different pH. The lines are based on the fitting with the empirical Peppas's model (reproduced with permission from [178]).

[123]

[169]

[170]

P

7.6. CMCS composites

795 796

[168]

attenuate the degradation or release behavior of the incorporated drugs or to enable targeted delivery by magnetic or surface modification. The alginate/chitosan/CMCS composite microcapsules prepared by extrusion method encapsulating Lactobacillus casei ATCC 393 proved to be useful for the delivery of probiotic cultures to the human gastro-intestinal tract [202]. Geisberger et al. [125] prepared polyoxometalates-trimethyl chitosan nanoparticles which are obtained from the direct electrostatic interaction of positively charged trimethyl chitosan with negatively charged polyoxometalates as shown in Fig. 15. Table 5 shows different CMCS based composites synthesised for delivery of different drugs.

807

8. CMCS based targeted drug delivery

817

Discovery and development of a new drug is a highly challenging, labor intensive and expensive process. On an average development process of each new drug takes approximately 15 years with an estimated cost of about US$802 million. And, this estimated cost has been reported to markedly increase at an annual rate of 7.4% above general price inflation [203]. Due to their inability to reach the target site of action, most of the drugs in the clinical phase fail to achieve desired clinical outcomes. In fact a considerable amount of drug administered gets distributed over normal tissues or organs, which are not involved in the pathological processes causing severe side effects. An effective approach to overcome this critical problem is the development of targeted drug delivery system that can release bioactive compound at the desired site of action. The main advantages of targeted drug delivery include the accumulation of drug in the action site, increase in therapeutic efficacy, reduction of therapeutic dose and toxicity, etc. [204]. The concept of developing a drug that could selectively destroy diseased cells without harming healthy cells was proposed by Paul Ehrlich almost a century ago. He gave this hypothetical drug name of the “magic bullet” [205]. Since then, out of several polymers that have been exploited in targeted drug delivery till date, CMCS has received significant attention due to its active functional groups which can easily attach targeting ligands like FA. It can protect therapeutic agents from hostile conditions in body and can release the entrapped agents selectively at desired site in a controlled fashion. In addition to it, the inherent pharmacological properties and excellent biological properties of CMCS like biocompatibility, biodegradability, non-toxicity, increased water solubility and unique mucoadhesivity also facilitate site specific drug delivery. Fig. 16 illustrates the route followed by different CMCS based

818

D

802

793 794

T

800 801

on the adsorption amount of these plasma proteins [199]. Drug loaded biodegradable polymer based nanofibers intended to deliver drugs at the targeted site in a sustained fashion avoiding burst release have received attention by the researchers in the past decade. As far as CMCS based nanofibers are concerned, electrospinning technique has been most widely accepted method. It is relatively a simple approach to control the morphology of ultrafine fibers with outstanding advantages of very large surface-to-volume ration and high porosity with a small pore size [200]. The silver nanoparticles/PVA/CMCS nanofibers of uniform diameter of 295 to 343 nm with 4 to 14 nm sized Ag nanoparticles were synthesised via electrospinning technique which proved suitable as antibacterial biomaterial [201].

791 792

[112]

E

790

F

t3:3

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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O

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14

846 847 848 849 850 851 852 853 854 855 856 857 858

U

Fig. 11. (A) Cellular uptake of curcumin-O-CMC Nps by FACS (a) control L929 cells alone (b) and (c) L929 exposed to 1 and 5 mg/ml curcumin-O-CMC Nps (d) control MCF-7 cells alone (e) and (f) exposed to 1 and 5 mg/ml curcumin-O-CMC Nps (B) Apoptosis assay by FACS (a) control L929 cells exposed to O-CMC Nps (b) and (c) L929 exposed to 1 and 5 mg/ml curcumin-OCMC Nps (d) control MCF-7 cells exposed to O-CMC Nps (e) and (f) exposed to 1 and 5 mg/ml curcumin-O-CMC Nps (reproduced with permission from [179]).

formulations during their delivery to the targeted site of action in human body. Sahu et al. investigated the use of hydrophobically modified CMCS nanoparticles for the delivery of anticancer drug PTX. The results showed that the nanoparticles exhibit a significant inhibitory effect on the folate receptor over expressing tumor cells like HeLa cells [166]. Similarly evaluation of FA modified CMCS nanoparticles loaded with another anticancer drug DOX has been also reported [206]. The confocal and flow cytometry study revealed that the nanoparticles could target the cancerous cells more effectively than the normal cells. Recently, Wang et al. prepared novel biodegradable deoxycholic acid (DA)-O, CMCS-FA micelles for the delivery of PTX which showed enhanced level of uptake compared to plain micelles in MCF-7 cells [207]. N-succinyl-O-carboxymethyl chitosan (NSO, CMCS), another

modified derivative of CMCS has been proven to be an excellent dispersant to prepare a well-dispersed suspension of superparamagnetic Fe3O4 nanoparticles due to its amphiphilic polyelectrolyte property. Its good cytocompatibility and functional carboxyl groups showed its potential for targeted dug delivery [208]. Similarly, magnetic nanoparticles complexed with CMCS were prepared through spraying coprecipitation method and their core-shell structure, stability and magnetic properties were also investigated. The studies revealed that the spraying process is a more practical method due to an increased quantity of adsorbed CMCS and a simplified automated preparation procedure for targeted drug delivery [113]. In this context, the preparation of well-dispersed suspension of superparamagnetic Fe3O4 nanoparticles stabilised by chitosan and O-CMCS respectively by Zhu et al. is worth

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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Fig. 12. Schematic diagrams of the fabrication procedure for CMCH-based folate/luminescent/magnetic nanoparticles (reproduced with permission from [126]).

879

8.1. Cancer-specific drug delivery based on CMCS

880

Despite of tremendous developments in the field of medical science, the cure for cancer is still a major challenge. Indiscriminate distribution of most of the anticancer drugs towards disease and healthy cells following systemic administration ultimately leading to high toxicity remains the critical bottleneck of conventional chemotherapeutics. In addition to this, the poor solubility of most of the anticancer drugs in water creates the need to use organic solvents or detergents for clinical applications, resulting in undesirable side effects such as venous irritation and respiratory distress [210]. Therefore, in order to develop a successful anticancer therapy, it is important to design a distinct carrier system that can encapsulate large amount of anticancer drug and deliver it specifically to the cancerous cells. Till date a large number of CMCS based matrixes that include nanoparticles, micelles, microspheres, nanofibers, composites, hydrogels, films and fibers have been designed by different researchers for delivery of different anticancer drugs like DOX, 5-FU, methotrexate, PTX, ADR, curcumin, camptothecin, 6-Mercaptopurine, Vincristine etc. A study of glycol chitosan-carboxymethyl cyclodextrins drug carrier for efficient targeted delivery of three hydrophobic anticancer drugs namely 5-FU, DOX, and vinblastine have been carried out by Tan et al. [211]. Moreover, the development of multifunctional novel folate conjugated CMCS–Fe3O4–CdTe nanoparticles exhibiting high drug loading efficiency, low cytotoxicity and favorable

883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901

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N C O

881 882

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mentioning. The adsorption mechanism of chitosan and O-CMCS onto the surface of Fe3O4 nanoparticles is believed to be the electrostatic and coordination interactions, respectively and was suitable for site specific drug delivery [209]. Novel multifunctional FA-CMCS-ZnS:Mn (FACMCS-Zinc Sulphide: Manganese) nanoparticles developed through simple aqueous route by Mathew et al. [128], have also shown potential for effective targeted drug delivery and imaging of cancer cells.

873 874

cell compatibility for the delivery of another hydrophobic anticancer drug ADR has been reported by Shen et al. [126]. CMCS based delivery system of another model anticancer drug has been experimented by Jin et al. [165], where the group demonstrated the preparation and in vitro evaluation of amphiphilic DA modified CMCS based pH sensitive self aggregated nanoparticles. The results of the experiment showed the greater cellular uptake and enhanced retention of drug loaded nanoparticles in drug-resistant cells thereby confirming its superior efficacy over free DOX. Maya et al. [212] have prepared O-CMC nanoparticles by ionic gelation technique where negatively charged carboxyl groups of O-CMC were cross-linked using CaCl2 and PTX was loaded within the nanoparticles before the cross-linking step, after allowing the drug to interact with O-CMC. In order to facilitate the targeted delivery of PTX, antibody Cetuximab (Cet) was conjugated onto the PTX O-CMC nanoparticles by EDC coupling chemistry. The complete reaction scheme for the preparation of Cet-PTX-O-CMC nanoparticles is shown in Fig. 17 [212]. Zou et al. [213] used octreotide–polyethylene glycol– stearic acid (OCT–Phe–PEG–SA) as a targeting molecule for N-octyl-O, N-carboxymethyl chitosan (OCC) micelles loaded with DOX to prepare novel active tumor targeting carrier. Fig. 18 [213] illustrates the procedure of self assembly and receptor-mediated cellular internalisation of OCC-OCT micelles. When OCT conjugated to stearic acid (SA) via polyethylene glycol (PEG) spacer (OCT–Phe–PEG–A) was used to modify OCC micelles. SA could insert into the inner hydrophobic core of OCC when it self-assembled in the aqueous environment, thereby increasing the soundness of modification of OCC. On the other hand, PEG, covering the surface of micelles, could increase the blood circulation time of micelles whereas OCT increased the targeting efficiency of the micelles to tumor cells. The results of the in vitro and in vivo studies indicated that OCC–OCT micelles might be a promising tumor-targeting carrier for cancer therapy [159]. Table 6 shows different CMCS based matrices for the delivery of various anticancer drugs.

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933

16 t4:1 t4:2

L. Upadhyaya et al. / Journal of Controlled Release xxx (2014) xxx–xxx

Table. 4 Different nanoformulation for delivery of various anti-cancers, anti-inflammatory, anti-microbial drugs, proteins/peptides and vaccines along with their brief outcome.

t4:3

Drug category

Drug used

Brief method and outcome

Refs.

t4:4

Anti-cancer

Adriamycin

Novel CMCS based folate/Fe3O4/CdTe nanoparticles within size range of 170–190 nm possessing intense superparamagnetic effect and photoluminescence property at room temperature exhibiting high drug loading efficiency, low cytotoxicity and favorable cell compatibility were prepared. A novel organic–inorganic hybrid molecule consisting of carboxymethyl-hexanoyl chitosan modified with (3-aminopropyl) triethoxysilane was synthesised which showed self-assembly behavior into nanoparticles with a stable polygonal geometry consisting of ordered silane layers of 6 nm in thickness. This formulation demonstrated excellent cytocompatibility and cellular internalisation capability in ARPE-19 cell line along with well controlled encapsulation and release profiles. Curcumin loaded N,O-CMCS formulation was prepared by simple ionotropic gelation method with size range of 150 ± 30 nm having high encapsulation efficiency of 80% and indicated slow, controlled and sustained drug release. The nanoformulation was specifically toxic to cancer cells and non-toxic to normal cells DOX·HCl loaded nanospheres and microspheres were prepared by precipitation method with high encapsulation efficiency which displayed sustained drug release. DOX loaded methoxy poly(ethylene glycol)-grafted-CMCS nanoparticles were synthesised by ion complex formation with size b300 nm. Drug release was faster at acidic pH than neutral or basic pH and showed promising antitumor activity. Amphiphilic deoxycholic acid modified CMCS based pH-sensitive self-aggregated nanoparticles were prepared within size range of 87 to 174 nm 5-FU encapsulated FA–CMC–ZnS:Mn nanoparticles with size range of 130–150 nm were prepared which were found to be suitable for targeting, controlled drug delivery and cancer cell imaging using Breast cancer cell line MCF-7 and were non-toxic to L929 cells. 80 ± 20 nm sized 5-FU loaded N,O-CMCS nanoparticles were prepared with drug entrapment efficiency of 65% and were toxic to breast cancer cells showing good blood compatibility. O-CMCS-methotrexate nanoparticles were prepared by dialysis method with size range of 187.2–363.5 nm and zeta potentials ranged from −8.19 mV to −3.08 mV. Drug release behavior was sustained in PBS solution of (pH 4.0, 7.2 and 9.0). Six 6-Mercaptopurine-CMCS were prepared and structurally characterised. 6-Mercaptopurine-CMCS in pH 7.4 PBS could self-assemble into nanoparticles with mean diameter of 155.8 ± 6.0 nm by Dynamic Light Scattering and 100 nm by TEM. 6-Mercaptopurine showed release in media containing 2 mM and 10 mM GSH and maximum cumulative release rates were 65.1% and 74.4%, respectively. Target oriented nanoparticles based on O-CMCS modified with stearic acid with FA covalently attached by carbodiimide reaction by sonication method without using surfactants/emulsifiers. The nanoparticles exhibited significant inhibitory effect on Folate Receptor over expressing tumor cells like HeLa cells. Novel multifunctional O-QCMCS/Cholesterol liposomes were constructed with good physical and thermal stability, excellent solubility in water, and high drug encapsulation efficiency (90.1%) and displayed steady release action over 2 weeks. Magnetic N-benzyl-O-CMCS nanoparticles were synthesised by incorporation and in situ methods and indomethacin was incorporated by solvent evaporation method with loading efficiency of 60.8% to 74.8%. The in vitro drug release profile in Simulated Body Fluid (pH 7.4, 37°) displayed an initial fast release, which became slower as time progressed. Novel O-CMCS/β-cyclodextrin nanoparticles of spherical shape and size with 166 nm were prepared and Ibuprofen was loaded with entrapment efficiency of 93.25 ± 2.89%. The release rate was slower from OCMCS/β-cyclodextrin than from chitosan/β-CD in Simulated Gastric Medium (pH 1.2) while converse was true for Simulated Intestinal Fluid (pH 6.8). Ampiphillic matrices of CMCS-graft-phosphatidylethanolamine were prepared by a EDC-mediated coupling reaction. Novel surface engineered highly branched CMCS/polyamidoamine dendrimer nanoparticles were synthesised which did not exhibited significant cytotoxicity in the range of concentration below 1 mg/mL and displayed high internalisation efficiency by both human osteoblast-like cells and rat bone marrow stromal cells. Interesting physicochemical and biological properties were reported for these macromolecular systems. Tetracycline encapsulated O-CMCS nanoparticles were prepared by ionic gelation method which were biocompatible and 200 nm in size. This nanomedicine was 6-fold more effective in killing intracellular S. aureus compared to Tetracycline alone. Spherical 30–70 nm sized GFLX entrapped O-CMCS nanoparticles were developed which displayed a four-fold lower MIC value against Gram negative bacteria compared to GFLX solution and a similar MIC value against Gram-positive bacteria as compared to GFLX solution. N,O-CMCS modified pristine nanodiamond particles were developed which were biocompatible and showed no cytotoxicity to cells. Out of a series of chitosan derivatives synthesised, 2-iminothiolane modified 2-N sulfated 6-Ocarboxymethylchitosan and chitosan complex was found suitable for preparing nanoparticles by polyelectrolyte self-assembly method which could successfully protect bFGF from inactivation over a 120 h period as determined by L929 fibroblast culture tests. The release of bFGF could be successfully controlled. 40–400 nm sized N-trimethyl chitosan, chitosan and M,N-CMCS nanoparticles with negative surface charge for M,N-CMCS and positive surface charge for chitosan and M,N-CMCS nanoparticles were developed with TT loaded with efficiency N90% m/m. Effective uptake of the Fluorescein isothiocyante-BSA loaded nanoparticles into the cells was demonstrated by cellular uptake studies using J774A.1 cells and enhanced immune response was reported after intranasal application of nanomedicine. Water soluble oleoyl-CMCS was synthesised through covalent modification of chitosan with oleic acid and monochloroacetic acid prepared by self-assembled method. The OCMCS nanoparticles showed high loading efficiency and sustained release of extracellular products. The mucoadhesion and internalisation capability make oleoyl-CMCS nanosystems interesting candidates that could be effective to improve protein drugs adsorption after oral administration.

[126]

Camptothecin

t4:6

Curcumin

t4:7

Doxorubicin

t4:8

Doxorubicin

t4:9

Doxorubicin

t4:10

5-Fluorouracil

t4:11

5-Fluorouracil

t4:12

Methotrexate

t4:13

6-Mercaptopurine

t4:14

Paclitaxel

t4:15

Vincristine

O

R O

P

D

E

T

C

Indomethacin

E

Anti-inflammatory

Ibuprofen

t4:18

Ketoprofen

t4:19

Dexamethasone

O C

Anti-microbial

Tetracycline

N

t4:20

t4:21

t4:23

Gatifloxacin (GFLX)

U

t4:22

[181]

[188]

[118] [124]

[165] [128]

[189] [164]

[119]

[166]

[190]

[191]

[127]

R

t4:17

R

t4:16

F

t4:5

Proteins/Peptides/Vaccines

Bovine Serum Albumin (BSA)

Basic Fibroblast Growth Factor (bFGF)

t4:24

Tetanus Toxoid (TT)

t4:25

Protein drugs

[192] [193]

[194]

[195]

[196] [197]

[198]

[116]

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Fig. 13. Preparation of the PVA/CMCS blank films and drug films (reproduced with permission from [38]).

Organ, or site-specific drug delivery, has several distinct advantages over other means of delivering drugs. For example, direct infusion into the target organ or the vasculature surrounding and supplying blood to the organ ensures that the majority of the drug goes to the site it is intended to act on. This allows for the use of the more toxic drug agents (e.g., chemotherapeutics) in high concentrations, because the exposure of other organs to the compound is limited. Targeting organs or tissues in vivo can greatly reduce the risk of toxic side effects and significantly increase the efficacy of a variety of drugs, including toxic chemotherapeutic agents, pain medications, and gene therapies. The advantages of site-specific employing CMCS vehicles include pH-sensitivity, bioadhesive ability, solubility and absorbability, controllable biodegradability, nontoxicity of the degradation end products, sustained release potential and ease of administration [217]. Many researchers have prepared different CMCS based formulations that exclusively deliver various pharmacological agents at specific organs for their activity. These include different organs of body like intestine, liver, pancreas, colon, eyes, and others which are elaborated below.

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Fig. 14. Release of ornidazole through 30% C blend film at different pH. Results are means 6 standard deviation for n ¼ 3 (reproduced with permission from [129]).

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8.2.2. Liver targeted drug delivery using CMCS Liver targeted delivery of drugs has gained increasing attention for the treatments of a number of chronic hepatic diseases such as hepatitis, hepatocirrhosis, hepatoma and hepatic carcinoma in the recent years. Considerable effort has been made to exploit CMCS as liver-specific drug carrier. This is because nanoparticles prepared from such amphiphilic derivative via self-assembly have been recognised as a promising

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8.2.1. Colon-specific drug delivery using CMCS Colon-specific delivery of drugs has gained much attention in recent years for the treatment of various diseases such as Crohn's disease, ulcerative colitis, and irritable bowel syndrome [218]. The relatively low proteolytic activities of protein/peptide drugs in the colon and even for other nonpeptide drugs such as cardiovascular and antiasthmatic agents has prompted several researchers to focus on colon targeted drug delivery. The absorption and degradation pathways in the upper gastrointestinal tract are the major hindrances in delivering drugs to the colon. To overcome these obstacles, several strategies of colonspecific drug delivery have been attempted till date by various scientists, that include use of prodrugs which become active at the colon, drug-eluting system responding to the pH, and microflora-activatable drug delivery systems have gained increasing attention. These strategies basically emphasise on preventing loss of the drug at the stomach and the small intestine, thereby facilitating quantitative drug delivery to the colon. CMCS based systems have been widely studied for colon targeted drug delivery as colonic microflora can degrade its glycosidic linkage thus facilitating the release of drugs entrapped specifically in colon. Tavakol et al. [219] investigated the release of sulfasalazine drug from the alginate-N,O-CMCS gel beads prepared by ionic gelation method. The in vitro studies revealed that the chitosan coated alginate-N,OCMCS hydrogel may be used as potential polymeric carrier for colonspecific delivery of sulfasalazine. Tu et al. [220] studied the sigmoidal swelling kinetics of a series of CMCS-g-poly (acrylic acid) hydrogels which were pretreated under acidic buffer media. The swelling kinetics of 5-aminosalicylic acid at different pH showed its potential for colonspecific drug delivery. Recently, Vaghani et al. [100] prepared and characterised pH sensitive hydrogel composed of CMCS cross linked with GA. The group evaluated in vitro as a promising carrier for the administration of colon targeted drug delivery of OD.

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8.2. Organ-specific drug delivery based on CMCS

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Fig. 15. Electrostatic interaction of CMCS (a) and trimethyl chitosan (b) biopolymer matrices with encapsulated polyoxometalates (POMs) (reproduced with permission from [125]).

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Table. 5 Different CMCS based composites synthesised for delivery of different drugs.

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8.2.3. Ocular drug delivery using CMCS The field of ocular drug delivery is one of the most interesting and challenging endeavors facing the researchers and scientist community. From drug point of view, it is very difficult to study the eye as an isolated organ. This is due to the presence of highly sensitive ocular tissues like

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hydrophobic MMA and hydrophilic O-CMC, which spontaneously selfassembled into coreshell O-CMC nanoparticle in aqueous solution. The adjacent hydroxyls of glycyrrhizin (GL) were turned into aldehyde groups through periodate oxidation in order to obtain O-CMC-GL nanoparticle. The preparation procedure of O-CMC nanoparticle, GL modified CMC-GL, and PTXL loaded CMC-GL nanoparticle (PTXL/CMC-GL) nanoparticles were illustrated in Fig. 19 [216] In addition, in vitro and in vivo studies of PTX loaded GL-modified O-CMCS nanoparticles were also carried out by for hepatocellular carcinoma targeted drug delivery application. The results established these nanoformulation as promising drug carrier for hepatic cancer.

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drug carrier, since their hydrophobic domain can serve as a depot for sparingly soluble drugs [221]. Zheng et al. [222] synthesised glycyrrhizic acid encapsulated novel thiolated lactosaminated (TLAC)/CMCS nanoparticles through ionic gelification method and characterised these nanoparticles in vitro studies. The in vivo studies of pharmacokinetic parameters were evaluated in rabbits and tissue distribution in mice. The results showed that the TLAC-CMCS may be used as a promising drug carrier for hepatic targeting and controlled release. Similarly, preparation, characterisation and tissue distribution studies of lactosaminated CMCS nanoparticles have been reported by Zheng and coworkers. The experiment demonstrated that the in vitro release of glycyrrhizic acid from the nanoparticles exhibited a biphasic pattern, initial burst release and consequently sustained release. Also, these nanoparticles modify the tissue distribution profile of the glycyrrhizic acid solution, the kidney excretion rate is reduced and drug accumulation in the liver is increased [108]. Recently, Shi et al. [216] prepared O-CMC-methyl methacrylate (MMA) copolymers through the graft copolymerizion of

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Composite

Drug used

Brief method & output

Refs.

t5:4

Folic acid conjugated CMCS-Mn doped ZnS nanocomposite

5-Fluorouracil (5-FU)

[128]

t5:5

O-CMCS/β-CD nanocomposite

Ibuprofen (IB)

t5:6

CMCS/TMCS nanocomposite

t5:7

Nano-hybrid CMCS-hexanoyl chitosan modified with (3-aminopropyl) triethoxysilane Folate conjugated CMCS/Fe3O4/CdTe nanocomposites

Bioactive Polyoxometalates (POMs) Camptothecin (CPT)

Novel multi-functional FA–CMCS–ZnS:Mn nanocomposites prepared by simple aqueous route showed high drug encapsulation of 5-FU (92.08%) with controlled release and were found nontoxic to mouse fibroblast L929 cells and toxic to MCF-7 cell line. 166 nm sized IB loaded O-CMCS/β cyclodextrin nanocomposites by simple ionic cross-linking method showed high drug encapsulation efficiency of 93.25 ± 2.89%. The release rate was slower from O-CMCS/β CD than chitosan/β CD in simulated gastric medium while converse was true for simulated intestinal medium. 50–90 nm sized nanocomposites were prepared by direct cross-linking approach. POM–CMCS composites display negative zeta potentials and larger particle sizes than the positively charged POM– Trimethyl Chitosan composites Highly ordered appx. 6 nm thick silane layer formations upon self-assembly of the hybrid molecule leads to sustained release of CPT. The hybrid molecule showed excellent cytocompatibility and efficient cellular internalisation with tp ARPE-19 cell line. 170–190 nm sized novel folate conjugated CMCS/Fe3O4/CdTe NCs were prepared by layer-by-layer assembly technique. Initial CMCS concentration, medium pH and reaction time strongly influenced coating amount and binding mode of CMCS. The multifunctional nanocomposites exhibited high drug loading efficiency, low cytotoxicity and favorable cell Compatibility.

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Adriamycin (ADR)

[127]

[125]

[181]

[126]

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biocompatibility, biodegradability and ability to prolong ophthalmic drug retention time [226]. In fact the ability of CMCS to prolong the precorneal drug retention, by virtue of its viscosity-increasing affect, of its ability to bind ofloxacin and, probably, of its mucoadhesive properties in comparison to chitosan has been experimentally demonstrated by Colo et al. [226]. An in vitro study of gatifloxacin (GFLX) from novel O-CMCS formulation showed that the release was slower than that from GFLX solution and the MIC of OCMCS formulation against Gramnegative bacteria is fourfold lower than the system without OCMCS. The GFLX is a fourth-generation fluoroguinolone and in vitro studies on isolates from bacterial infections of the eye have shown an

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the uveal tract and retina. In addition to this, the presence of tissue barriers to drug penetration which include the lipophilic corneal epithelium, the hydrophilic corneal and scleral stroma, the conjunctival lymphatics, choroidal vasculature, and the blood-ocular barriers makes ocular drug delivery even more challenging [223]. The choice of chitosan for ocular drug delivery has been justified due to its outstanding mucoadhesive and penetration enhancing properties, as well as by its good biocompatibility with the ocular structures [224]. Application of chitosan based nanostructures in delivery of ocular therapeutics has been well reviewed by Fuente et al. [225]. CMCS has attracted much attention in ophthalmic drug delivery due to its inherent low toxicity,

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Fig. 16. Illustrates the route followed by different CMCS based formulations during their delivery to the targeted site of action in human body.

Fig. 17. Schematic illustration depicting preparation of PTXL-O-CMC nanoparticles and bioconjugation of Cet on PTXL-O-CMC Nps through EDC activation chemistry. EDC activated the carboxyl functionality and subsequently linked to Cet through covalent linkage (reproduced with permission from [212]).

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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Fig. 18. Schematic illustration of the self-assembly and receptor-meditated cellular internalisation of OCC–OCT micelles (reproduced with permission from [213]). Table 6 Different CMCS based matrices for the delivery of various anticancer drugs.

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Anticancer drug CMCS based matrix structure

Matrix composition

Remarks

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Adriamycin

Self aggregated nanoparticles

LA-modified CMCS

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Camptothecin

Aggregates

O-CMCS

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Curcumin

Nanoparticles

O-CMCS

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Doxorubicin

Nanospheres and microspheres

CaCO3–CMCS

t6:8

Self-assemblied nanoparticles

Folic acid (FA) modified CMCS

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Self assembled hollow nanocapsule Nanoparticles

Carboxymethyl-hexanoyl chitosan

Self-aggregated nanoparticles exhibited an increased Loading Capacity and Loading Efficiency, decreased sustained release with an increasing ratio of the hydrophobic LA to hydrophilic CMCS Not only the aggregates but also the unimers of OCMCS can help to enhance the solubility of CPT. In vitro cancer antiproliferative activity test further confirms the slow release of CPT from OCMCS-drug system. Spherical 150 ± 30 nm sized curcumin loaded O-CMCS nanoparticles were prepared with entrapment efficiency of 87%. The nanoparticles were toxic to cancer cells and non-toxic to normal cells. The water soluble DOX·HCl could be effectively loaded in the hybrid microparticles and nanospheres with a high encapsulation efficiency, and the drug release could be effectively sustained, indicating the hybrid microspheres and nanospheres were suitable for delivery of water-soluble drugs 267.8 nm sized nanoparticles were prepared by sonication method. The cellular uptake of Folate modified CMCS nanoparticles was found to be higher than that of nanoparticles based on LA modified CMCS. The model anticancer drug DOX was entrapped with an efficiency of 46.8%, and a corresponding drug release from the nanocapsules for a time period exceeded 7 days can be achieved in vitro.

5-Fluorouracil

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Methotrexate

Nanoparticles

U

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Self assembled nanoparticles

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Nanoparticles

Nanoparticles Nanoparticles

Vincristine

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Methoxy poly(ethylene glycol)-grafted-CMCS Acylated CMCS

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Folate conjugated CMCSMn doped zinc sulphide FA conjugated CMCS

Refs. [123]

[167]

[179] [118]

[166]

[158]

The nanoparticles showed increased cytotoxicity compared to DOX alone.

[124]

The nanoaggregates exhibited an excellent colloidal and structural stability in aqueous medium.

[35]

130–150 nm sized novel nanoparticles loaded with 5-FU exhibited non-toxicity to L929 cells. The nanoparticles could be used for controlled drug delivery and imaging of cancer cells. The encapsulation efficiency and loading capacity of Methotrexate in the FA-O-CMCS nanoparticles were higher, and the particle size of the FA-O-CMCS nanoparticles was also smaller than those in the FACS nanoparticles. Methotrexate conjugated Spherical shaped nanoparticles within size range of 187.2–363.5 nm were prepared by dialysis method. O-CMCS In vitro drug release study by the dynamic dialysis method showed that Methotrexate exhibited significant sustained-release behaviors in PBS buffer solutions (pH 4.0, 7.2 and 9.0), indicating that these nanoparticles had good in vitro stability and the potential to be used as a novel drug carrier system 6-Mercaptopurine-CMCS The 6-Mercaptopurine release from 6-MP-CMC showed dependence on glutathione concentration. In aqueous solution 6-MP-CMC could self-assemble into the nanoparticles through the intra- and intermolecular hydrophobic interactions between 6-MP groups Glycyrrhizin (GL)-modified 100–205 nm sized PTX loaded O-CMCS nanoparticles were prepared with encapsulation efficiency of O-CMCS 83.7% and performed a biphasic release. FA conjugated CMCS modi- The PTX loaded nanoparticles exhibited many desirable properties like pH-sensitive dissolution, low fied with stearic acid cytotoxicity, and high amount drug encapsulation and significant inhibitory effect on the FR over expressing tumor cells like HeLa cells O-Q-CMCS-Cholesterol Vincristine was encapsulated in polymeric liposomes with high entrapment efficiency (90.1%). The formulation was stable in aqueous solution and exhibited slow, steady release action over 2 weeks under physiologic pH (7.4).

[128] [214]

[164]

[215]

[216] [166]

[190]

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encouraging response to it [195]. Currently, Yang et al. investigated both in vitro and in vivo, the ability of 5-FU or bevacizumab loaded N,O-CMCS hydrogels to modulate wound healing after glaucoma filtration surgery. On one hand the in vitro study showed that the nearly 100% of 5-FU was released from the drug-loaded hydrogels within 8 h, but less than 20% bevacizumab was released after 53 h. On the other hand, the in vivo study carried out in rabbits showed that the CMCS hydrogels were nontoxic to the cornea and were gradually biodegraded in the eyes [144]. Recently, to investigate the availability of induced pluripotent stem cells iPSCs as bioengineered substitutes in corneal repair Chien et al. [227] developed a thermo-gelling injectable amphiphatic carboxymethylhexanoyl chitosan (CMHC) nanoscale hydrogel and found that such gel increased the viability and CD44 þ proportion of iPSCs, and maintained their stem-cell like gene expression, in the presence of culture media. The study demonstrated that human keratocyte-reprogrammed iPSCs, when combined with CMHC hydrogel, can be used as a rapid delivery system to efficiently enhance corneal wound healing.

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Fig. 19. Synthetic route of O-CMC-methyl methacrylate (MMA) copolymers and glycyrrhizin (GL) and schematic representation depicting the formation of O-CMC nanoparticles, O-CMCGL nanoparticles, and PTXL loaded O-CMC-GL nanoparticle (PTXL/CMC-GL) (reproduced with permission from [216]).

8.2.4. Others Apart from these, there are a number of other organs for which CMCS based drug delivery systems have been designed by different scientists in the recent times. This include synthesis and in vitro study of microencapsulated beads composed of alginate-N,O-CMCS for the delivery of model protein BSA to different regions of the intestinal tract. The results of the study demonstrated excellent pH sensitivity and proved to be suitable polymeric carrier for site specific delivery of bioactive protein in the intestine. Also the main advantage was that the bioactivity of the protein drug was preserved due to the preparation of drug loaded beads in the aqueous medium at neutral environment [96]. Another similar work for the in vitro and in vivo evaluation of pH sensitive CMCS based hydrogels for intestinal delivery of drug theophylline has

also been reported recently by [148]. While the in vitro results showed that formulation I containing CMC and carbopol in 1:1 ratio showed sustained release, better prolonged action from the prepared hydrogel formulation when compared to (standard) marketed sustained release formulation was reported from the in vivo study. Currently, synthesis, characterisation and in vitro evaluation of anticancer drug 5-FU loaded CMCS nanoparticles have been reported by Anitha et al. [188] The toxicity of the drug loaded CMCS nanoparticles was showed by MTT, apoptosis and caspase 3 assays thereby confirming the potential of 5-FU loaded N,O-CMC nanoparticles in breast cancer chemotherapy in which the side effects of conventional chemo treatment could be reduced. Recently, preparation of metformin loaded O-CMCS nanoparticles prepared by ionic gelation method for delivery to pancreatic cancer cells has showed pH sensitive release of the drug in vitro. While the cytotoxicity study showed the preferential toxicity of the drug loaded nanoparticles on pancreatic cancer cells (MiaPaCa-2) compared to normal cells (L929), the nanoparticles exhibited nonspecific internalisation by normal and pancreatic cancer cells [109].

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9. Tissue engineering: origin and strategies

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Tissue engineering, by definition, is a highly interdisciplinary field that combines the principles and methods of life sciences and engineering to utilise structural and functional relationships in normal and pathological tissue to develop biological substitutes to restore, maintain, or improve biofunction [228]. The term “tissue engineering” was formally coined in 1987 [229] and since then, it has emerged as a scientific field distinct from medical field by providing numerous promising techniques with practical clinical applications. The popular theory of the medical field that the human body possesses an inherent capacity to heal itself has been the fundamental principal that has been exploited

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CMCS is biocompatible, biodegradable, and more bioactive than chitosan with enhanced osteogenesis property and it can be easily formulated in a variety of forms like hydrogels, scaffolds, composites, i-gels, films and membranes which have wide range of potential applications in tissue engineering. The techniques that are suitable for preparation of different CMCS based hydrogels for tissue regeneration purpose have already been discussed in Section 8. As in hydrogels, the cross links can be incorporated either by chemical cross linking method or by radiation cross linking in the scaffolds also as per the requirement of the host tissue and the tissue engineering biomaterial being fabricated. Nowadays, enzymatic cross linking has also gained attention due to its own benefits. Selecting the scaffolding approach for tissue engineering is tissue and application specific. The conventional scaffold

Composition of matrix

Technique/method

Comment

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Gelatin/CMCS/β-tricalcium phosphate composite scaffold

Radiation crosslinking and lyophilizing

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Hydroxyapatite coated CMCS scaffolds

Freeze drying technique

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HAP/CMCS composite scaffold

Coprecipitation method

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Electrospinning

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n-HAP/CMCS biocomposite scaffold

Freeze drying technique

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N-isopropylacrylamide and CMCS hydrogels Gelatin & CMCS hybrid hydrogels

Chemical cross linking & seed emulsion polymerisation Radiation induced cross linking

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CMCS/n-HAP composite

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n-HAP/CMCS composite

Particle filtration and lyophilisation followed by genipin crosslinking

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CMCS/gelatin/n-HAP i-gel

Enzymatic crosslinking

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CMCS film

Covalently crosslinked

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CMCS-graft-D-glucuronic acid membranes

Grafting D-GA onto CMCS in the presence of 1-ethyl-3-(3dimethylaminopropyl) carbodiimide (EDC)

Series of biodegradable scaffolds were prepared where ultrasonic treatment on the polymer solutions affected the β-TCP particles distribution. Excellent biocompatibility and ability of bone regeneration was revealed by in vivo implantation in mandible of beagle dog. Coating of scaffolds with HAP substantially enhanced the viability, attachment, proliferation, and differentiation of the osteoblast and directed stem cell differentiation to osteoblast The scaffolds exhibited 20–500 μm sized pores with regular interconnection with appx. 58.9% of porosity determined from microcomputed tomography analysis. Average scaffolds consisted of 24% HA and 76% CMCS determined from 2D morphometric analysis. The SEM showed that nano/micro particles formed on the surface of the nano-nonwoven CMCS fibrous scaffold. FTIR and XRD confirmed that the nano/micro particles were hydroxyapatite crystalline. HAP particles appeared to have a great effect on the late stages of osteoblast behavior (alkaline phosphatase). The FTIR and XRD results of genipin cross linked n-HAP/CMCS scaffolds revealed that CMCS's hydroxyl, amine and amide groups determined nano homogenous distribution of n-HAP and provided nano topographical features for nanohybrid scaffolds. The scaffolds had pore size of 150 μm sized pores with less toxicity and more facility for adhesion and proliferation of cells. Thermo responsive & core-shell microgels were prepared having phase transition temperature nearer to that of body compared to pure PNIPAM Due to the high water absorption capacity, a similar compressive modulus with soft tissue, controllable biodegradation, and excellent biocompatibility, the hydrogels have potential as skin scaffolds and wound healing materials. The porosity ratio of CMCS/n-HA is about 75% and the compressive strength can exceed 21 MPa with circular pores of diameter ranging from several μm to six hundred μm. The in vivo experiments showed no inflammatory reaction and bone putrescence and toxicity of liver and kidney. The composite scaffold with (VEGF)-transfected bone marrow stromal cells (BMSCs) was studied in a rabbit radial defect model. The scaffold is biocompatible, nontoxic, promotes the infiltration and formation of the microcirculation, and stimulates bone defect repair with degradation rate matching the growing rate of bone. The i-gels prepared susceptible to tyrosinase/p-cresol mediated in situ gelling at physiological temperature that may be used in treating irregular small bone defects with minimal clinical invasion as well as for bone cell delivery Controlling the molecular weight distribution of properly tailored chitosan allows one to regulate the mechanical properties and degradation of chitosan in a sophisticated manner, while maintaining favorable cell interactions. The membranes showed bioactivity which demonstrated its potential for tissue engineering applications.

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Table. 7 Preparation techniques of CMCS based biomaterials for tissue engineering.

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transplantation and tissue reconstruction methods. Over the past 40 years, tissue engineering has shown significant most tissue types, especially those damaged or lost following debilitating health problems such as cancer and degenerative disorders [232].

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in the field of tissue engineering. In fact, the specific tissue or the organ determines the level of ability to self-repair and regenerate from disease, damage or an injury. This capacity is limited by the degree of damage, loss of function and involvement of multiple tissues [230]. The recent developments in tissue engineering like xeno-transplantation of tissues, new prosthetics and localised manipulation of lesion sites at the cellular and molecular level have made significant advancements in reconstructive surgery in comparison to the conventional approaches like tissue auto- and allo-grafting [230,231]. The main objective of tissue engineering is to overcome the lack of tissue donors and the immune repulsion between receptors and donors. In fact, by laying emphasis on tissue and cell-based therapy, tissue engineering and clinical practices strive to achieve same goals. The tissue engineering strategy involves the in vitro seeding and proliferation of relevant cells and/or signaling molecules in an appropriately designed tissue engineering biomaterial like scaffold to form a natural tissue. This tissue is implanted into the defect in the patients. While in some cases, the scaffold or scaffold with cells is directly implanted in vivo where the host body functions as a bioreactor to construct new tissues. Thus, these transplantable constructs enable regeneration of functional tissue in the host providing an alternative to conventional organ

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[40]

[233]

[234]

[235]

[236] [106]

[237]

[238]

[41]

[73]

[239]

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11.1. CMCS scaffolds

Scaffolds are unique tissue engineering biomaterial as they are able to establish three-dimensional environments for propagated cells and specific signalling molecules that can mimic native tissues environments. Tissue engineering scaffolds can be of natural, synthetic or a hybrid of both. CMCS has emerged as a promising scaffolding polymer due to its inherent excellent biocompatibility, ability to promote cell adhesion and increased bioactivity as compared to chitosan. Also in comparison to chitosan that has relatively slow and uncontrollable degradability [246]. CMCS shows accelerated degradation rate which can be regulated through different cross-linking extents by EDC, while retaining excellent mechanical properties. However, EDC cross-linked CMCS porous tubular scaffolds were fabricated for nerve regeneration which showed decreased hydrophilicity and elastic modulus which is desirable for nerve repair [247]. Nanofibrous collagen-coated porous CMCS microcarriers were successfully fabricated by a simple modified phase separation method and thereafter collagen anchoring-assembling. In vitro chondrocyte culture revealed better cell attachment, proliferation, and differentiation on the CMC-MCs immobilised with self-assembled collagen nanofibers. Cells were observed to grow into a tissue-like structure after 7 days of culture. Thus the scaffolds prepared showed potential for application as injectable scaffolds for cell delivery in cartilage tissue engineering [73]. Gelatin/CM-chitosan/β-tricalcium phosphate composite scaffolds were prepared using a green fabrication method, i.e. radiation-induced cross linking. Considering their excellent and adjustable water retention capacity, highly interconnected porous network

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An ideal biomaterial for tissue engineering is expected to meet some important criteria. It must be biocompatible, easily biodegradable in appropriate time window, its degradation products should be non-toxic, and it must support cell adhesion and growth and should exhibit mechanical strength comparable with the host tissue [240]. The applications of chitosan and its derivatives in the field of tissue engineering have been earlier reviewed [241]. CMCS has attracted considerable attention for tissue engineering application due to its inherent increased

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bioactivity as compared to chitosan and its ability to promote osteogenesis [25]. Also the capacity of CMCS to chelate calcium from mineralizing solution containing calcium and phosphate to induce calcium phosphate or hydroxyapatite (HAP) formation has made it suitable biopolymer for tissue engineering [242]. Apart from this, it is well known to exhibit excellent biocompatibility, better biodegradability, nontoxicity, and ability to promote cell adhesion which is desirable in the field of tissue engineering and regenerative medicine. In the past few years, several researchers have utilised CMCS in fabrication of different tissue engineering biomaterials which include scaffolds, hydrogels, composites, nanofibers, nanoparticles, dendrimer, and membranes and for implant functionalisation [243–245] due to easy processibility of CMCS into these constructs.

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fabrication techniques include solvent-casting particulate-leaching method, gas foaming, fibre meshes/fibre bonding, phase separation, melt moulding, emulsion freeze drying, solution casting, and lyophilisation (freeze drying) method. The particle leaching method exhibits advantages of creation of scaffolds with big pores, well‐controlled high interconnected porosity and pore morphology. The benefits of gas foaming technique include lack of solvent, eliminating the risk of remaining residues, and the low processing temperatures preventing degradation of the polymer during processing. Emulsion freeze‐drying is attractive for creation of scaffolds that are relatively thick having large pores. Despite of several positive facets of these traditional methods, the incapability of precisely controlling pore size, pore geometry, spatial distribution of pores and construction of internal channels within the scaffold, presence of residual organic solvent and poor mechanical integrity are some of the most significant problem facing these conventional techniques due to the risks of toxicity and carcinogenicity it poses to cells. Therefore, new techniques like self-assembly systems, solid free-form fabrication and electrospinning technique have attracted the attention of the researchers as these methods can overcome many of the demerits of the conventional scaffolding approaches. Sintering method for scaffold design has also received attention and is usually applied in case of ceramics powders, metals, glasses and certain polymers as well as composites. But most of the composites for tissue repair are prepared by coprecipitation, porogen leaching and freeze drying (lyophilisation) method. In addition to this, injectable-gels, and membranes can be prepared by enzymatic and covalent cross linking and grafting method respectively. CMCS based films are most commonly prepared by blending/casting method that may include covalent cross linking or other linkages. Table 7 shows preparation techniques of CMCS based biomaterials for tissue engineering.

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Fig. 20. SEM images of gelatin/CM-chitosan/β-TCP composite scaffolds with β-TCP fraction of (A) 0%, (B) 5%, (C) 10%, (D) 20%, (E) 30%, and (F) 40%. The ultrasonic time was 20 min (reproduced with permission from [130]).

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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In the past decade, hydrogels have made significant progress in the development of tissue engineering scaffold [248]. A number of synthetic and natural polymers have been exploited in the last few years as hydrogel biomaterials that include alginate [249], chondroitin sulfate [250], hyaluronic acid [251] and collagen [252]. The insufficient mechanical performance and relative harsh gelation conditions for cell encapsulation are the major limitations of hydrogels in tissue engineering application [253]. A double-network complex hydrogel with significantly improved gelation temperature and mechanical properties composed of oxidised gellan gum and CMCS by Ca2+ cross linking and Schiff reaction was prepared. Firstly, polymer chains were cleaved into smaller segments by oxidation reaction, which lead to the decrease of polymer molecular weight and the increase of cross linking aldehyde groups. This allowed for the formation of two entangled networks of different cross linked polymers as described in Fig. 21A [254]. In the second step, the chemical cross linking reaction (Schiff-base formation) between the pendant amino groups of CMCS and the aldehyde group lead to the formation of a complex gel in the oxidised gellan as shown in Fig. 21B [254]. The results showed that the gelation temperature was lowered from 42 °C to below physiological temperature by

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oxidation, and further reduced by complexing with CMCS. Also the complex hydrogel showed an increased compressive modulus of 278 kPa, and an ability to return to the original shape after release of the compressive load. Thus the hydrogels were promising biomaterials for cartilage tissue engineering. A study on the synthesis and characterisation of UV cross-linked hydrogels derived from novel water soluble methacrylated O-CMCS and polyethylene glycol diacrylate. The hydrogel substrates similarly supported attachment and proliferation of Smooth Muscle Cells (SMCs). The results from the study demonstrated these hydrogels to be promising biomaterials for tissue regeneration [146]. A novel microgel class consisting of biocompatible CMCS and temperature-sensitive PNIPAM was designed and synthesised by seeded emulsion polymerisation. The presence of PNIPAM in microgels contributed to the thermoresponsive property to CMCS while CMCS added to the improved biocompatibility to the microgels which made these microgels suitable for tissue regeneration purpose [236]. Yang et al. [106] fabricated CMCS/gelatin hydrogels by green method i.e. radiation cross linking method with excellent and adjustable water retention capacity (10–700 g/g dry gel) and a similar compressive modulus with that of soft tissue (10–200 kPa). These hybrid hydrogels have improved flexibility, antimicrobial and water absorption capacity than gelatin hydrogels and superior handle ability and mechanical properties than CM-chitosan hydrogels. Apart from these, they exhibited excellent and controllable degradability and good cytocompatibility which suggested their potential application in tissue engineering and wound healing.

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In the recent years, composites have drawn attention of researchers towards development of biocompatible and biodegradable composites for tissue regeneration. In this context, preparation of porous biocomposites of nano-hydroxyapatite (n-HAP) and CMCS by porogen leaching method and their characterisation by IR, XRD, SEM and compressive strength has shown potential application for bone tissue engineering. The composites displayed porosity where the pores were interconnected and the compressive strength can exceed 21 MPa

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structure, proper compressive strength and high porosity, the scaffolds met the criteria for bone tissue regeneration. Fig. 20 shows the SEM morphology of scaffolds with different fractions of β-TCP when the ultrasonic time was set to 20 min. From the Fig it is clear that similar pore size (about 350 μm) were observed in the composite scaffold. Although some agglomeration appeared in the walls of scaffolds containing higher fractions of β-TCP which is in agreement with the literature [130]. The bioactivity of a novel CMCS scaffolds with and without incorporating mineral trioxide aggregate (MTA) in a tooth model was characterised. The deposition of HAP was significantly higher (P b 0.05) on MTAcoated CaC (CaMT) scaffold than that on Cross-linked CMCS scaffold (CaC). Therefore, it can be concluded that the bioactivity of the CMCS scaffold can be enhanced by incorporating MTA [242].

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Fig. 21. Schiff-base formation between amino groups of CMCS and aldehyde groups of oxidized gellan gum (A). In gellan chains, cis-dihydroxyl of rhamnose was oxidized to dialdehyde, the addition of Ca2+ introduced ionic bonds between the carboxyl groups of gellan via electrostatic interaction, subsequently aldehyde groups and amino groups of CM-chitosan formed the second network via the Schiff-base reaction. The cross linking mechanism of complex hydrogel (B). Gellan gum chains formed double helix conformations with Ca2+, and then CMCS chains link the aldehyde zones to the formation of a three dimensional network, that created the gel (reproduced with permission from [254]).

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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Apart from popular tissue engineering devices like scaffolds, hydrogels and composites, injectable gels, films and membranes have also been developed by different researchers for tissue repair and regeneration purpose. Development of gelatin and CMCS gels in situ in the presence of tyrosinase and p-cresol where presence of n-HAP does not hamper in situ gelation of the polymers in physiological pH and temperature has been reported by Mishra and coworkers [41]. The results clearly indicate the potential of tyrosinase/p-cresol crosslinked CMCS– gelatin gel as injectable gel matrix for cell based bone tissue engineering. Guangyuan et al. [73] prepared CMCS films and carboxymethylation and bimodal MW distribution were successfully combined to regulate rate of degradation of the films formed. The results displayed that these CMCS films with tunable degradation rates provide a powerful material system for tissue engineering. In this view, the development of CMCS-graft-D-glucuronic acid (CMCS-g-D-GA) membranes prepared by grafting CMCS with D-glucuronic acid by using EDC catalyst in water by Jayakumar and coworkers is worth mentioning. The synthesis method of the CMCS-g-D-GA membranes is shown in Fig. 22 [239]. The results of this investigation indicated that as the membranes were capable of having bioactivity, they were expected to be suitable for tissue engineering purposes.

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12. CMCS applications in different tissues/organs

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As the inherent ability of body to self-repair from disease or injury and to regenerate depends on the specific tissue or organ system, it seems obvious that the choice of tissue engineering device or formulation largely depends on the tissue or organ being repaired, reconstructed and/or regenerated [229]. In context of CMCS, its fabrication depends greatly on the target tissue for which the restorative device is being made which may include different organs like bone [256], nerve, cartilage [73], vascular tissue [243], tooth [242] and even trachea [255].

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In recent years, CMCS based scaffolds, hydrogels and biocomposites have gained importance in orthopedic research because of their potential to minimise surgical invasiveness. When engineering bone tissue, the tissue engineering device must meet a number of requirements like being biocompatible, biodegradable in suitable time window, its degradation products should be non toxic and capable of being easily eliminated by the metabolic pathways, must support cell adhesion and growth and exhibit adequate mechanical stability [257,258]. In addition to this, the biomaterial designed should allow new bone ingrowths (osteoconductive) [259] and angiogenesis to supply the newly formed tissue with nutrients while inducing bone formation (osteoinductive) [260]. In this view, the synthesis, characterisation and in vivo study of an enzymatically cross linked CMCS/gelatin/nHAP injectable in mice reported by Mishra and coworkers have been demonstrated as promising biomaterials that may be used in treating irregular small bone defects with minimal clinical invasion as well as for bone cell delivery. The in vivo injectability study of the i-Gels in murine models (Fig. 23) showed that the injected i-Gels were successfully retrieved from the exact position of euthanised mice. At the site of implantation no apparent sign tof inflammation (redness or edema) was observed which illustrated that the i-Gels were nonimmunogenic in nature. Also the yellowish colour instead of purple colour of the retrieved i-Gels can be attributed to the limitation of ample molecular oxygen inside the human body. The in vivo study also demonstrated that the iGels will have lesser gel strength in vivo as compared to in vitro situation [41]. Oliveira et al. reported high efficiency of DOX-loaded CMCS/

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which should be desirable for bone tissue engineering [237]. Similarly, Shi fabricated N-carboxyethyl chitosan/nanohydroxyapatite N-CECS/nHAP composites for tissue-engineered trachea and investigate its biomechanical and biocompatible properties. The N-CECS/n-HAP composites exhibited satisfactory tensile strength and Young’s modulus values thereby confirming their potential for tissue-engineered trachea [255]. Also, recently, the effect of the n-HAP/CMCS composite with vascular endothelial growth factor (VEGF)-transfected bone marrow stromal cells (BMSCs) in a rabbit radial defect model was studied [238]. This composite was biocompatible, nontoxic, promotes the infiltration and formation of the microcirculation, stimulates bone defect repair and the degradation rate of the composite matched that of growing bone thus demonstrating its potential for bone defect repair.

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Fig. 22. Synthesis of CMCS-graft-D-glucuronic acid (reproduced with permission from [239]).

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Fig. 23. In vivo gel stability study. Representative macroscopic image of post-mortal mouse showing the location and texture of iGel 24 h post-implantation (reproduced with permission from [41]).

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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PAMAM dendrimer nanoparticles on being internalised by different cell types, in vitro, promoting the osteogenic differentiation of rat bone marrow stromal cells in tissue culture polystyrene dishes [261]. Similarly, the low generation poly(amidoamine) (PAMAM) dendrimers with CMCS, CMCS/PAMAM dendrimer nanoparticles were surface engineered and loaded with DOX with the expectation of exhibiting high drug loading efficiency and non cytotoxicity compared to amineterminated PAMAM dendrimers of high generation [262]. Xuefeng Hu carried out a study on an in vitro assessment of titanium functionalised with dopamine followed by CMCS or hyaluronic acid catechol (HAC) conjugated with vascular endothelial growth factor (VEGF). It proved to be promising alternative for enhanced osteointegration and inhibition of bacterial inhibition. Fig. 24 displays the results of mineralisation of cells after two weeks culture on different substrates which was assessed by staining by Alizarin Red. The degree of staining on the TiCMCS substrates (Fig. 24b) and Ti-HAC substrates (Fig. 24d) is not substantially higher than pristine Ti (a). Figure shows an absence of purplish red stains which was control experiment carried out with TiCMCS in cell culture medium without cells. As shown by the dense coverage of calcium deposits on the Ti-CMCS-VEGF (Fig) and Ti-CMCS-HAC (Fig) substrates mineralisation is greatly enhanced which can be attributed to the presence of immobilised VEGF [244]. Also the development of hydroxyapatite scaffolds with macroporous structure and noncytotoxicity which could efficiently support the adhesion, proliferation

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Fig. 24. Optical microscopy images of Alizarin Red stained osteoblasts after culturing for 14 days on (a) Ti, (b) Ti-CMCS, (c) Ti-CMCS-VEGF, (d) Ti-HAC and (e) Ti-HAC-VEGF. Initial seeding was carried out with 3104 cells/cm2. (f) shows the Ti-CMCS substrate which had been placed in cell culture medium for 14 days without cell seeding after Alizarin Red staining. Scale bar ¼ 200 mm (reproduced with permission from [244]).

and osteogenic differentiation of rat bone marrow stromal cells in the presence of 0.01 mg ml−1 DOX-loaded CMCS/PAMAM dendrimer nanoparticles, in vitro has been reported by several research groups [262, 263].

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The choice of biomaterial is very critical for the success of tissue engineering approaches, particularly in cartilage repair [264]. The structural similarity of chitosan with various glycosaminoglycans found in articular cartilage has made it a suitable scaffolding biomaterial in articular cartilage engineering [265,266]. Therefore, CMCS has been now experimented for different cartilage tissue engineering applications. Earlier, N,N-di-CMCS as delivery agent for bone morphogenetic protein in the repair of articular cartilage has already been experimented [267]. Guangyuan et al. [73] successfully fabricated nanofibrous collagencoated porous CMCS microcarriers for cultivating cells and for application in cartilage tissue engineering as injectable scaffolds for cell delivery. Recently, double-network complex hydrogel with significantly improved gelation temperature and mechanical properties have been prepared by mixing oxidised gellan gum with CMCS which was found to be promising material for cartilage tissue engineering [254]. Apart from these research studies, the ability of chitosan and CMCS to protect chondrocytes from apoptosis, significantly suppress the degeneration of

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CMCS-based materials, produced in varying formulations, have been used in a number of wound healing applications. The inherent accelerative wound healing effects of CMCS on second degree burn models performed in rats was demonstrated in vitro and in vivo by Peng et al. [273]. In another experimental study, N,CMCS was used as biomaterial to heal deep second-degree burn wounds. The results demonstrated that the N, CMCS was efficient in accelerating wound healing via activating transforming growth factor-β1/Smad3 signaling pathway [274]. The improved wound healing ability of CMCS of different MW has earlier been experimentally investigated by Chen et al. [20] by using a cell culture which showed positive results. The wound dressings of CMCS developed by Qin and coworkers evaluated for wound healing ability in vitro also displayed promising results [275]. CMCS, not only in its inherent form, but also in many modified forms or in combination with

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Researchers have investigated different biodegradable biomaterials, including collagen, polyglycolic acid, polylactic acid and co-polymers of L-lactide and -caprolactone, for nerve repair [270,271]. A research study on the degradation of covalently cross-linked CMCS in vitro for the first time and its potential application for peripheral nerve regeneration has been carried out by Lu et al. [70]. The results revealed that the faster degradation of EDC-crosslinked CMCS than chitosan and decrease in the hydrophilicity and elastic modulus of CMCS films are beneficial for application of CMCS in nerve repair. The study also suggested that the EDC cross-linked CMCS films enhanced the spread and provided a good proliferation substratum of Neuro-2a cells. Similarly the tunable degradation rates of CMCS have been experimentally demonstrated recently by Guangyuan et al. [73]. He described the ability of Neuro-2a cells to adhere and proliferate when cultured on binary and unary CMCS films was found to be comparable to those on non-modified unary chitosan films which established CMCS as a promising material for neural tissue engineering. Recently, ability of CMCS to stimulate proliferation of Schwann cells in vitro by activating the intracellular signaling cascades of extracellular signal-regulated kinase (ERK1/2) and phosphatidylinositil-3 kinase (PI3K/Akt) has been reported by Bin He and coworkers [272].

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Fig. 25. In vitro Ag release curves of AgNPs/PVA/CM-chitosan nanofibers in PBS (reproduced with permission from [201]).

other biomaterials has demonstrated potential of enhanced wound healing property. In fact, oligo-chitosan, N,O-CMCS and N,CMCS in sheet and paste forms were evaluated in vitro for possible utilisation in wound dressing applications for wound healing [68]. Similarly, N,OCMCS/Collagen matrixes containing chondroitin sulfate or an acellular dermal matrix developed by Chen et al. [84] demonstrated potential as wound dressings for clinical applications. An in vivo experiment to evaluate the wound healing effect of water soluble chitosan/heparin complex on the full thickness skin excision performed on the backs of the rat displayed that the complex is most effective in wound healing [276]. Also, in an in vivo animal experiment using a burn wound model water-soluble O-CMCS derivatives modified with furfuryl glycidyl ether (O-CMCS/FGE) displayed wound healing effects. The results of the study showed that O-CMCS/FGE would be a promising candidate as an anti-adhesion material for biomedical applications [31]. A study on subcutaneous implantation of the ornidazole loaded (PVA)/CMCS films prepared by blending/casting method in the surgical wound did not promote any adverse effect. Over a long period of time, it is expected that these drug film would be absorbed and the wound would be cicatrised by new forming tissues eventually [34]. Angiogenesis of fullthickness burn wounds repaired with collagen-sulfonated CMCS porous scaffold encoding VEGF, DNA plasmids has been reported by Teng et al. [277]. Recently, Ag nanoparticles/(PVA)/CMCS nanofibers prepared by electrospinning technique by Zhao et al. showed potential for wound dressing biomaterial. Fig. 25 shows the in vitro Ag released amount of crosslinks AgNPs/PVA/CMCS nanofibers as a function of time. At the third hour the release of Ag in both the samples was fast and after that became relatively slow. Finally in both the samples after 24 h the concentration of Ag+ reached equilibrium [201]. Apart from enhanced wound healing capacity, CMCS has also been experimentally proven efficacious in preventing as well as reducing post-operative surgical adhesions by several researchers [278–280].

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13. Tissue engineering application is often combined with drug 1480 delivery strategy 1481 In the area of regenerative medicine and reconstructive surgery substantial input has been made from developments in tissue engineering and drug delivery technologies. The regeneration of functional tissue requires an appropriate microenvironment that closely mimics the host site for desired cellular responses which is typically provided by 3-D tissue engineering scaffold that acts as an architectural template [281]. But repair and reconstruction of diseased and/or damaged tissues/organs demands therapy that cannot only provide mechanical and structural integrity to the tissue but also maintains sustained/controlled delivery of therapeutics and/or growth factors in order to enhance the healing and regeneration process. While scaffold provides structural support, diffusivity to enable cellular infiltration and acts as substrate for tissue differentiation and organisation, the drugs/bioactive molecules embedded in it, cues for the surrounding tissues to heal and regenerate. Recent advances in the field of tissue engineering and drug delivery have enabled the design and fabrication of scaffolds that can deliver growth factors/therapeutic agents in a more controlled fashion over a defined period of time. In fact the control over the regenerative and repairing potential of tissue engineering scaffolds has dramatically improved in recent years, mainly by using drug releasing scaffolds or by incorporation of drug delivery devices in the tissue engineering scaffolds [282–284]. While previous approaches of developing drug delivery formulations mainly focused on the encapsulation or embedment of drugs within the bulk phase and targeted delivery, recent strategies of tissue engineering open up the new possibility of constructing scaffolds that can provide the control over the sequestration and delivery of specific bioactive factors to enhance and guide the regeneration process [285, 286]. Fig. 26 shows the more efficient and effective approach of combining tissue engineering applications with drug delivery strategy for

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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CMCS based nanocarriers have become one of the most extensively studied nanometric drug delivery platforms. But these trials are still limited to experimental purposes and are not implicated widely as marketed formulation. Despite of its increased aqueous solubility as compared to native molecule chitosan, its significant hydrophobicity remains the major drawback responsible for its limited use in biomedical field. A drug requires compatible physicochemical properties of the matrix polymer for developing a formulation successfully. CMCS alone or in combination with other polymers, metals, and metal oxides has been

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used either as blends, co-polymers or composites to alter the physicochemical characteristics and degradation behavior. CMCS has been trialled in almost all novel drug delivery systems of current drug delivery approach due to its compatibility with wide range of polymers and its suitability with drugs of different properties. A number of research works have been reported where same drug being encapsulated in different CMCS formulations. Therefore, during the process of formulation development for a particular drug, such information can be used for comparative efficacy improvement studies between two or more formulations. Also, owing to its enhanced bioactivity and its ability to promote osteogenesis, CMCS is being studied at preclinical and clinical level ensuring its potentiality in tissue engineering. CMCS can chelate calcium from mineralizing solution containing calcium and phosphate and induce calcium phosphate or HAP formation thereby making it suitable for bone and cartilage regeneration. But being polymer, the mechanical properties of CMCS are not compatible enough with the host tissues particularly with bone which restricts its usage as such in tissue engineering applications. Thus, efforts to improve the mechanical properties of CMCS based formulations are essential for this type of application. Therefore, CMCS has often been exploited in the form of either composites with ceramics or HAP or in combination with some other polymers with better mechanical strength in order to make it suitable for tissue engineering. CMCS based 3D scaffolds mimic the extracellular matrix and have proved to be highly useful formulations for repair and reconstruction of damaged organs in general and tissues in particular. But despite of its versatility, CMCS based formulations are not commercialised widely in clinical drug delivery and tissue engineering practice. Also, there is a paucity of studies regarding the development of technological strategies to integrate and position drug delivery devices with a submicrometric spatial resolution within the scaffolds. Nevertheless, numerous studies involving study of CMCS as drug delivery carriers and tissue engineering devices are being patented and some are under preclinical or clinical investigation. The main goals are to improve their stability in the biological environment, to mediate the bio distribution of active compounds, enhanced drug loading, targeting, transport, release, and interaction with biological barriers. The cytotoxicity of

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enhanced repairing and regeneration of damaged and/or diseased tissues/organs. Extensive overviews of recent research studies on development and applications of three dimensional scaffolds with potential capabilities for the controlled delivery of therapeutic drugs particularly osteogenic drugs for bone regeneration are reported in literature [287,288]. In fact, this paradigm shift that has taken place to utilise the tissue engineering and drug delivery approaches towards the regeneration of dental, oral and craniofacial structures using matrices and scaffolds capable of controlled drug release has earlier been exhaustively reviewed [289]. In this context, the research work for development of scaffolds with potential of drug delivery for neural [290] and bone [291,292] tissue engineering is worth mentioning. As far as CMCS is considered, not much research work has been done in 3D scaffolding delivery system. But CMCS/gelatin/n-HAP i-gels susceptible to tyrosinase/p-cresol mediated in situ gelling at physiological temperature capable of treating irregular small bone defects have been investigated to exhibit potential of bone cell delivery [41]. Reves et al. [293] prepared microspheres cross linked by two different methods which were incorporated successfully into the composite scaffolds. The X-CMCS beads (obtained by carbodiimide chemistry cross linking) displayed good potential for use in bone tissue engineering applications in which degradation and local drug delivery are desired as compared to Gen-X CMCS (cross linked by genepin) which showed poor degradation and drug release profiles.

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Fig. 26. Shows the more efficient and effective schematic approach of combining tissue engineering applications with drug delivery strategy for enhanced repairing and regeneration of damaged and/or diseased tissues/organs.

Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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The authors would like to thank Ministry of Human Resource Development, Govt. of India for providing fellowship for research. The authors 1616 also want to acknowledge the Director, Motilal Nehru National Institute 1617 of Technology, Allahabad, India for providing other necessary facilities 1618 for research work. 1619

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CMCS based drug delivery and tissue engineering formulations research has reached significant maturity in the last few years. There are numerous compelling evidences for the potential of CMCS as biomaterial for many novel challenging drug delivery and tissue engineering applications. CMCS has been shown to improve the dissolution rate of many otherwise poorly soluble drugs, and thus, can be exploited for bioavailability improvement of drugs. Various therapeutic agents, such as anticancer, anti-inflammatory, antibiotics, antithrombotic, proteins, and amino acids have been effectively incorporated in CMCS-based systems to increase bioavailability and to achieve targeted and/or controlled release. While this concept is still mostly within the academic frame, results from several laboratories studies confirm enhancements in the bioavailability of these macromolecules to a level that might suffice for industrial development. Various CMCS based formulations presented herein this review like hydrogels, microspheres, nanoparticles, films, fibers, composites and scaffolds can be helpful in deciding the context of using CMCS in selectively capturing a therapeutic payload and control release in a target site as well as for tissue engineering purposes. CMCS's innate tissue engineering potential as a biopolymer to generate structures with predictable pore sizes and controllable degradation rates makes it particularly suitable for bone and cartilage regeneration. In concluding remarks, CMCS, the polymer with intact or derived properties makes it suitable to use and prepare all kinds of novel drug delivery and tissue engineering formulations. From the above investigations it may be concluded that CMCS is indeed a versatile biodegradable polymer derivative having tremendous potential in pharmaceutical drug delivery and tissue engineering application in near future.

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nanoparticles or their degradation products remains a major problem, and improvements in biocompatibility obviously are a major concern 1583 of future research in CMCS based drug delivery.

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Please cite this article as: L. Upadhyaya, et al., The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.04.043

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The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications.

Over the last decade carboxymethyl chitosan (CMCS) has emerged as a promising biopolymer for the development of new drug delivery systems and improved...
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