1 Pharmaceutics 2013 Vol: 5(2):. DOI: 10.3390/pharmaceutics5020329

Polysaccharide-Based Micelles for Drug Delivery

Delivery of hydrophobic molecules and proteins has been an issue due to poor bioavailability following administration. Thus, micelle carrier systems are being investigated to improve drug solubility and stability. Due to problems with toxicity and immunogenicity, natural polysaccharides are being explored as substitutes for synthetic polymers in the development of new micelle systems. By grafting hydrophobic moieties to the polysaccharide backbone, self-assembled micelles can be readily formed in aqueous solution. Many polysaccharides also possess inherent bioactivity that can facilitate mucoadhesion, enhanced targeting of specific tissues, and a reduction in the inflammatory response. Furthermore, the hydrophilic nature of some polysaccharides can be exploited to enhance circulatory stability. This review will highlight the advantages of polysaccharide use in the development of drug delivery systems and will provide an overview of the polysaccharide-based micelles that have been developed to date.

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References
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  88. K.M. Park; J.W. Bae; Y.K. Joung; J.W. Shin; K.D. Park Nanoaggregate of thermosensitive chitosan-Pluronic for sustained release of hydrophobic drug Colloids Surf. B Biointerfaces 63, 1-6 (2008) .
  89. D.H. Nguyen; Y.K. Joung; J.H. Choi; H.T. Moon; K.D. Park Targeting ligand-functionalized and redox-sensitive heparin-Pluronic nanogels for intracellular protein delivery Biomed. Mater. 6, 055004 (2011) .
  90. S.J. Huang; S.L. Sun; T.H. Feng; K.H. Sung; W.L. Lui; L.F. Wang Folate-mediated chondroitin sulfate-Pluronic 127 nanogels as a drug carrier Eur. J. Pharm. Sci. 38, 64-73 (2009) .
  91. J.H. Lee; H. Lee; Y.K. Joung; K.H. Jung; J.H. Choi; D.H. Lee; K.D. Park; S.S. Hong The use of low molecular weight heparin-pluronic nanogels to impede liver fibrosis by inhibition the TGF-beta/Smad signaling pathway Biomaterials 32, 1438-1445 (2011) .
  92. C. Manaspon; K. Viravaidya-Pasuwat; N. Pimpha Preparation of folate-conjugated pluronic f127/chitosan core-shell nanoparticles encapsulating doxorubicin for breast cancer treatment J. Nanomater. 2012, 593878:1-593878:11 (2012) .
  93. H.W. Zhang; G.Q. Cai; G.P. Tang; L.Q. Wang; H.L. Jiang Synthesis, self-assembly, and cytotoxicity of well-defined trimethylated chitosan-O-poly(epsilon-caprolactone): Effect of chitosan molecular weight J. Biomed. Mater. Res. B 98B, 290-299 (2011) .
  94. C. Chen; G.Q. Cai; H.W. Zhang; H.L. Jiang; L.Q. Wang Chitosan-poly(epsilon-caprolactone)-poly(ethylene glycol) graft copolymers: Synthesis, self-assembly, and drug release behavior Jo. Biomed. Mater. Res. Part A 96A, 116-124 (2011) .
  95. J.Y. Liu; L.M. Zhang Preparation of a polysaccharide-polyester diblock copolymer and its micellar characteristics Carbohydr. Polym. 69, 196-201 (2007) .
  96. R.W. Shi; H.M. Burt Synthesis and characterization of amphiphilic hydroxypropylcellulose-graft-poly(epsilon-caprolactone) J. Appl. Polym. Sci. 89, 718-727 (2003) .
  97. Y.J. Lin; Y.S. Liu; H.H. Yeh; T.L. Cheng; L.F. Wang Self-assembled poly(epsilon-caprolactone)-g-chondroitin sulfate copolymers as an intracellular doxorubicin delivery carrier against lung cancer cells Int. J. Nanomed. 7, 4169-4183 (2012) .
  98. C.H. Chen; N.V. Cuong; Y.T. Chen; R.C. So; I. Liau; M.F. Hsieh Overcoming multidrug resistance of breast cancer cells by the micellar doxorubicin nanoparticles of mPEG-PCL-graft-cellulose J. Nanosci. Nanotechnol. 11, 53-60 (2011) .
  99. K. Duan; X. Zhang; X. Tang; J. Yu; S. Liu; D. Wang; Y. Li; J. Huang Fabrication of cationic nanomicelle from chitosan-graft-polycaprolactone as the carrier of 7-ethyl-10-hydroxy-camptothecin Colloids Surf. B Biointerfaces 76, 475-482 (2010) .
  100. M.F. Hsieh; N.V. Cuong; C.H. Chen; Y.T. Chen; J.M. Yeh Nano-sized micelles of block copolymers of methoxy poly(ethylene glycol)-poly(epsilon-caprolactone)-graft-2-hydroxyethyl cellulose for doxorubicin delivery J. Nanosci. Nanotechnol. 8, 2362-2368 (2008) .
  101. S.K. Sahu; S. Maiti; T.K. Maiti; S.K. Ghosh; P. Pramanik Hydrophobically modified carboxymethyl chitosan nanoparticles targeted delivery of paclitaxel J. Drug Target. 19, 104-113 (2011) .
  102. X. Huang; X.H. Jiang; F.Q. Hu; Y.Z. Du; Q.F. Zhu; C.S. Jin In vitro antitumour activity of stearic acid-g-chitosan oligosaccharide polymeric micelles loading podophyllotoxin J. Microencapsul. 29, 1-8 (2012) .
  103. S.T. Huang; Y.Z. Du; H. Yuan; X.G. Zhang; J. Miao; F.D. Cui; F.Q. Hu Synthesis and anti-hepatitis B virus activity of acyclovir conjugated stearic acid-g-chitosan oligosaccharide micelle Carbohydr. Polym. 83, 1715-1722 (2011) .
  104. H. Yuan; L.J. Lu; Y.Z. Du; F.Q. Hu Stearic acid-g-chitosan polymeric micelle for oral drug delivery: In vitro transport and in vivo absorption Mol. Pharma. 8, 225-238 (2011) .
  105. Y.Z. Du; L.L. Cai; P. Liu; J. You; H. Yuan; F.Q. Hu Tumor cells-specific targeting delivery achieved by A54 peptide functionalized polymeric micelles Biomaterials 33, 8858-8867 (2012) .
  106. Y.T. Xie; Y.Z. Du; H. Yuan; F.Q. Hu Brain-targeting study of stearic acid-grafted chitosan micelle drug-delivery system Int. J. Nanomed. 7, 3235-3244 (2012) .
  107. Y.Z. Du; L.L. Cai; J. Li; M.D. Zhao; F.Y. Chen; H. Yuan; F.Q. Hu Receptor-mediated gene delivery by folic acid-modified stearic acid-grafted chitosan micelles Int. J. Nanomed. 6, 1559-1568 (2011) .
  108. F.Q. Hu; X.H. Jiang; X. Huang; X.L. Wu; H. Yuan; X.H. Wei; Y.Z. Du Enhanced cellular uptake of chlorine e6 mediated by stearic acid-grafted chitosan oligosaccharide micelles J. Drug Target. 17, 384-391 (2009) .
  109. F.Q. Hu; X.L. Wu; Y.Z. Du; J. You; H. Yuan Cellular uptake and cytotoxicity of shell crosslinked stearic acid-grafted chitosan oligosaccharide micelles encapsulating doxorubicin Eur. J. Pharm. Biopharm. 69, 117-125 (2008) .
  110. F.Q. Hu; W.W. Chen; M.D. Zhao; H. Yuan; Y.Z. Du Effective antitumor gene therapy delivered by polyethylenimine-conjugated stearic acid-g-chitosan oligosaccharide micelles Gene Ther. , (2012) .
  111. F.Q. Hu; L.N. Liu; Y.Z. Du; H. Yuan Synthesis and antitumor activity of doxorubicin conjugated stearic acid-g-chitosan oligosaccharide polymeric micelles Biomaterials 30, 6955-6963 (2009) .
  112. S.W. Jung; Y.I. Jeong; S.H. Kim Characterization of hydrophobized pullulan with various hydrophobicities Int. J. Pharm. 254, 109-121 (2003) .
    • . . . Other pullulan based-micelle systems include pullulan acetate [112], poly(DL-lactide-co-glycolide)-graft pullulan [77], pullulan-g-poly(L-lactide) [71,76], and pullulan hydrophobic drug conjugates, such as pullulan-doxorubicin (DOX) [113] and pullulan-biotin [114] . . .
  113. D.X. Lu; X.T. Wen; J. Liang; Z.W. Gu; X.D. Zhang; Y.J. Fan A pH-sensitive nano drug delivery system derived from pullulan/doxorubicin conjugate J. Biomed. Mater. Res. Part B Appl Biomater. 89B, 177-183 (2009) .
    • . . . Other pullulan based-micelle systems include pullulan acetate [112], poly(DL-lactide-co-glycolide)-graft pullulan [77], pullulan-g-poly(L-lactide) [71,76], and pullulan hydrophobic drug conjugates, such as pullulan-doxorubicin (DOX) [113] and pullulan-biotin [114] . . .
  114. K.H. Park; D. Kang; K. Na Physicochemical characterization and carcinoma cell interaction of self-organized nanogels prepared from polysaccharide/biotin conjugates for development of anticancer drug carrier J. Microbiol. Biotechnol. 16, 1369-1376 (2006) .
    • . . . Other pullulan based-micelle systems include pullulan acetate [112], poly(DL-lactide-co-glycolide)-graft pullulan [77], pullulan-g-poly(L-lactide) [71,76], and pullulan hydrophobic drug conjugates, such as pullulan-doxorubicin (DOX) [113] and pullulan-biotin [114] . . .
  115. S. Kamel; N. Ali; K. Jahangir; S.M. Shah; A.A. El-Gendy Pharmaceutical significance of cellulose: A review Exp. Polym. Lett. 2, 758-778 (2008) .
    • . . . For example, hydroxypropyl cellulose (HPC) was produced by modifying some of the cellulose hydroxyl groups with propylene oxide to improve the cellulose solubility and control drug release [115] . . .
  116. M.F. Francis; M. Piredda; F.M. Winnik Solubilization of poorly water soluble drugs in micelles of hydrophobically modified hydroxypropylcellulose copolymers J. Contr. Release 93, 59-68 (2003) .
    • . . . In vitro studies showed HPC-PEO-C16 micellar system had high affinity to mucus and could enhance the permeability of entrapped therapeutics across intestine epithelial-Caco-2 cells [60,116,117,118,119,120,121,122,123,124,125,126,127] . . .
    • . . . In addition, heparin-based micelles have demonstrated enhanced inhibition of tumor growth and angiogenesis [138,139], while cellulose [116,117,118], chitosan [104,139], and pullulan-based [180] systems promoted drug absorption across the small intestine due to enhanced mucoadhesion. . . .
  117. S. Chayed; F.M. Winnik In vitro evaluation of the mucoadhesive properties of polysaccharide-based nanoparticulate oral drug delivery systems Eur. J. Pharma. Biopharm. 65, 363-370 (2007) .
    • . . . In vitro studies showed HPC-PEO-C16 micellar system had high affinity to mucus and could enhance the permeability of entrapped therapeutics across intestine epithelial-Caco-2 cells [60,116,117,118,119,120,121,122,123,124,125,126,127] . . .
    • . . . In addition, heparin-based micelles have demonstrated enhanced inhibition of tumor growth and angiogenesis [138,139], while cellulose [116,117,118], chitosan [104,139], and pullulan-based [180] systems promoted drug absorption across the small intestine due to enhanced mucoadhesion. . . .
  118. M.F. Francis; M. Cristea; Y.L. Yang; F.M. Winnik Engineering polysaccharide-based polymeric micelles to enhance permeability of cyclosporin a across Caco-2 cells Pharma. Res. 22, 209-219 (2005) .
    • . . . In vitro studies showed HPC-PEO-C16 micellar system had high affinity to mucus and could enhance the permeability of entrapped therapeutics across intestine epithelial-Caco-2 cells [60,116,117,118,119,120,121,122,123,124,125,126,127] . . .
    • . . . Additional in vitro studies demonstrated that dextran-PEO-C16 could significantly improved CyA permeability across Caco-2 cells, although the improvement was lower than that achieved by CyA loaded HPC-PEO-C16 [119] and, unlike HPC-PEO-C16, dextran-PEO-C16 showed no affinity to mucus [118] . . .
    • . . . In addition, heparin-based micelles have demonstrated enhanced inhibition of tumor growth and angiogenesis [138,139], while cellulose [116,117,118], chitosan [104,139], and pullulan-based [180] systems promoted drug absorption across the small intestine due to enhanced mucoadhesion. . . .
  119. Y. Enomoto-Rogers; H. Kamitakahara; A. Yoshinaga; T. Takano Synthesis of diblock copolymers with cellulose derivatives 4. Self-assembled nanoparticles of amphiphilic cellulose derivatives carrying a single pyrene group at the reducing-end Cellulose 18, 1005-1014 (2011) .
    • . . . In vitro studies showed HPC-PEO-C16 micellar system had high affinity to mucus and could enhance the permeability of entrapped therapeutics across intestine epithelial-Caco-2 cells [60,116,117,118,119,120,121,122,123,124,125,126,127] . . .
    • . . . Of interest, micelles prepared from cellulose-C15-pyrene with longer cellulose chains (Mw = 4860 g/mol, number average degree of polymerization (Dn) = 30) were smaller in size (~40.0 nm, monolayer micelle) relative to those prepared from short chain cellulose (Mw = 2106 g/mol, Dn = 13) (~108.8 nm, multilayer micelle) [119]. . . .
    • . . . Additional in vitro studies demonstrated that dextran-PEO-C16 could significantly improved CyA permeability across Caco-2 cells, although the improvement was lower than that achieved by CyA loaded HPC-PEO-C16 [119] and, unlike HPC-PEO-C16, dextran-PEO-C16 showed no affinity to mucus [118] . . .
  120. G.P. Clagett; F.A. Anderson; W. Geerts; J.A. Heit; M. Knudson; J.R. Lieberman; G.J. Merli; H.B. Wheeler Prevention of venous thromboembolism Chest 114, 531S-560S (1998) .
    • . . . In vitro studies showed HPC-PEO-C16 micellar system had high affinity to mucus and could enhance the permeability of entrapped therapeutics across intestine epithelial-Caco-2 cells [60,116,117,118,119,120,121,122,123,124,125,126,127] . . .
    • . . . Dextran is another polysaccharide that has long been used in drug formulation and has shown no toxicity [120] . . .
  121. M.F. Francis; L. Lavoie; F.M. Winnik; J.C. Leroux Solubilization of cyclosporin A in dextran-g-polyethyleneglycolalkyl ether polymeric micelles Eur. J. Pharm. Biopharm. 56, 337-346 (2003) .
    • . . . In vitro studies showed HPC-PEO-C16 micellar system had high affinity to mucus and could enhance the permeability of entrapped therapeutics across intestine epithelial-Caco-2 cells [60,116,117,118,119,120,121,122,123,124,125,126,127] . . .
    • . . . Dextran-PEG-C16 showed no toxicity to Caco-2 cells after 4 h of exposure, although free PEG-C16 did inhibit cell growth [121] . . .
  122. M.F. Francis; M. Cristea; F.M. Winnik Exploiting the vitamin B-12 pathway to enhance oral drug delivery via polymeric micelles Biomacromolecules 6, 2462-2467 (2005) .
    • . . . In vitro studies showed HPC-PEO-C16 micellar system had high affinity to mucus and could enhance the permeability of entrapped therapeutics across intestine epithelial-Caco-2 cells [60,116,117,118,119,120,121,122,123,124,125,126,127] . . .
    • . . . To improve the relative low transport efficiency, vitamin B12 was conjugated to the micelle and the vitamin B12-dextran-PEO-C16 showed increased transportation of CyA across the Caco-2 monolayer and internalization of CyA by Caco-2 cells via the vitamin B12 pathway [122]. . . .
  123. D.E. Discher; F. Ahmed Polymersomes Annu. Rev. Biomed. Eng. 8, 323-341 (2006) .
    • . . . In vitro studies showed HPC-PEO-C16 micellar system had high affinity to mucus and could enhance the permeability of entrapped therapeutics across intestine epithelial-Caco-2 cells [60,116,117,118,119,120,121,122,123,124,125,126,127] . . .
  124. X.B. Yuan; H. Li; X.X. Zhu; H.G. Woo Self-aggregated nanoparticles composed of periodate-oxidized dextran and cholic acid: Preparation, stabilization and in-vitro drug release J. Chem. Technol. Biotechnol. 81, 746-754 (2006) .
    • . . . In vitro studies showed HPC-PEO-C16 micellar system had high affinity to mucus and could enhance the permeability of entrapped therapeutics across intestine epithelial-Caco-2 cells [60,116,117,118,119,120,121,122,123,124,125,126,127] . . .
    • . . . Improved systems were developed by Yuan et al. [124] and Xu et al. [125] based on periodate-oxidized dextran which possessed free aldehyde and hydroxyl group that were used to form hydrogen bonds to increase system stability . . .
  125. Q.G. Xu; X.B. Yuan; J. Chang Self-aggregates of cholic acid hydrazide-dextran conjugates as drug carriers J. Appl. Polym. Sci. 95, 487-493 (2005) .
    • . . . In vitro studies showed HPC-PEO-C16 micellar system had high affinity to mucus and could enhance the permeability of entrapped therapeutics across intestine epithelial-Caco-2 cells [60,116,117,118,119,120,121,122,123,124,125,126,127] . . .
    • . . . Improved systems were developed by Yuan et al. [124] and Xu et al. [125] based on periodate-oxidized dextran which possessed free aldehyde and hydroxyl group that were used to form hydrogen bonds to increase system stability . . .
  126. C. Houga; J. Giermanska; S. Lecommandoux; R. Borsali; D. Taton; Y. Gnanou; J.F. Le Meins Micelles and polymersomes obtained by self-assembly of dextran and polystyrene based block copolymers Biomacromolecules 10, 32-40 (2009) .
    • . . . In vitro studies showed HPC-PEO-C16 micellar system had high affinity to mucus and could enhance the permeability of entrapped therapeutics across intestine epithelial-Caco-2 cells [60,116,117,118,119,120,121,122,123,124,125,126,127] . . .
    • . . . Additional dextran-based micelles have been synthesized by grafting of polycaprolactone [95], poly (L-lactide) [55], polystyrene [126], lauryl group [127], and methyl methacrylate-ethylene glycol dimethacrylate [128] to the dextran backbone. . . .
  127. S. Daoud-Mahammed; P. Couvreur; K. Bouchemal; M. Cheron; G. Lebas; C. Amiel; R. Gref Cyclodextrin and polysaccharide-based nanogels: Entrapment of two hydrophobic molecules, benzophenone and tamoxifen Biomacromolecules 10, 547-554 (2009) .
    • . . . In vitro studies showed HPC-PEO-C16 micellar system had high affinity to mucus and could enhance the permeability of entrapped therapeutics across intestine epithelial-Caco-2 cells [60,116,117,118,119,120,121,122,123,124,125,126,127] . . .
    • . . . Additional dextran-based micelles have been synthesized by grafting of polycaprolactone [95], poly (L-lactide) [55], polystyrene [126], lauryl group [127], and methyl methacrylate-ethylene glycol dimethacrylate [128] to the dextran backbone. . . .
  128. D.J. Krasznai; T.F.L. McKenna; M.F. Cunningham; P. Champagne; N.M.B. Smeets Polysaccharide-stabilized core cross-linked polymer micelle analogues Polym. Chem. 3, 992-1001 (2012) .
    • . . . Therefore, a high CMC, as obtained with dextran-cholic acid, is suggestive of low thermodynamic stability [128] . . .
  129. Q. Tian; X.H. Wang; W. Wang; C.N. Zhang; P. Wang; Z. Yuan Self-assembly and liver targeting of sulfated chitosan nanoparticles functionalized with glycyrrhetinic acid Nanomed. Nanotechnol. Biol. Med. 8, 870-879 (2012) .
    • . . . Most of these core-shell systems were developed by modifying chitosan with hydrophobic moieties that include stearic acid [106,107,108,109,110], (deoxy)cholic acid [58,66,67,68], glycyrrhetinic acid [58,129], polycaprolactone [93,94], etc . . .
  130. R. Mo; X. Jin; N. Li; C.Y. Ju; M.J. Sun; C. Zhang; Q.N. Ping The mechanism of enhancement on oral absorption of paclitaxel by N-octyl-O-sulfate chitosan micelles Biomaterials 32, 4609-4620 (2011) .
    • . . . Various anti-tumor therapeutics such as paclitaxel (PTX) [94,101,130,131], doxorubicin [58,65,66,92,132,133], and camptothecin [134], have been used as model drugs and encapsulated by chitosan-based micelles . . .
  131. H. Lian; J. Sun; Y.P. Yu; Y.H. Liu; W. Cao; Y.J. Wang; Y.H. Sun; S.L. Wang; Z.G. He Supramolecular micellar nanoaggregates based on a novel chitosan/vitamin E succinate copolymer for paclitaxel selective delivery Int. J. Nanomed. 6, 3323-3334 (2011) .
    • . . . Various anti-tumor therapeutics such as paclitaxel (PTX) [94,101,130,131], doxorubicin [58,65,66,92,132,133], and camptothecin [134], have been used as model drugs and encapsulated by chitosan-based micelles . . .
    • . . . Small molecules include glycyrrhetinic acid, a liver targeting ligand [58,139], vitamin E succinate-specific toxicity to tumor cells [131], and folic acid with a high affinity to the folate receptor overexpressed on tumor cells [64,101,146,177,178,179] . . .
  132. Y.Z. Du; L. Wang; H. Yuan; F.Q. Hu Linoleic acid-grafted chitosan oligosaccharide micelles for intracellular drug delivery and reverse drug resistance of tumor cells Int. J. Biol. Macromol. 48, 215-222 (2011) .
    • . . . Various anti-tumor therapeutics such as paclitaxel (PTX) [94,101,130,131], doxorubicin [58,65,66,92,132,133], and camptothecin [134], have been used as model drugs and encapsulated by chitosan-based micelles . . .
    • . . . Evaluated by a Caco-2 cell monolayer, chitosan-based micelles were demonstrated to inhibit the activity of P-glycoprotein 1 (P-gp) ATPase, which, consequently, can inhibit drug efflux and enhance drug permeation [105,132] . . .
    • . . . In vivo studies showed that N-octyl-O-sulfate chitosan can improve the oral bioavailability of PTX by 6 folds compared to the current commercially improved formulation-Taxol (Bristle-Myers Squibb, New York, NY, USA) [132] . . .
  133. T. Srinophakun; J. Boonmee Preliminary study of conformation and drug release mechanism of doxorubicin-conjugated glycol chitosan, via cis-aconityl linkage, by molecular modeling Int. J. Mol. Sci. 12, 1672-1683 (2011) .
    • . . . Various anti-tumor therapeutics such as paclitaxel (PTX) [94,101,130,131], doxorubicin [58,65,66,92,132,133], and camptothecin [134], have been used as model drugs and encapsulated by chitosan-based micelles . . .
  134. Z.G. Li; X.Y. Li; Z.X. Cao; Y.Z. Xu; H.J. Lin; Y.L. Zhao; Y.Q. Wei; Z.Y. Qian Camptothecin nanocolloids based on N,N,N-trimethyl chitosan: Efficient suppression of growth of multiple myeloma in a murine model Oncol. Rep. 27, 1035-1040 (2012) .
    • . . . Various anti-tumor therapeutics such as paclitaxel (PTX) [94,101,130,131], doxorubicin [58,65,66,92,132,133], and camptothecin [134], have been used as model drugs and encapsulated by chitosan-based micelles . . .
  135. G.B. Jiang; Z.T. Lin; X.J. Xu; H. Zhang; K. Song Stable nanomicelles based on chitosan derivative: In vitro antiplatelet aggregation and adhesion properties Carbohydr. Polym. 88, 232-238 (2012) .
    • . . . The chitosan-based micelles were characterized by low CMCs, suggestive of high stability [135] and resistance to the harsh environment of the GI tract . . .
  136. K. Sonaje; K.J. Lin; M.T. Tseng; S.P. Wey; F.Y. Su; E.Y. Chuang; C.W. Hsu; C.T. Chen; H.W. Sung Effects of chitosan-nanoparticle-mediated tight junction opening on the oral absorption of endotoxins Biomaterials 32, 8712-8721 (2011) .
    • . . . Additionally, chitosan-based micelles were demonstrated to be a relatively safe carrier for oral formulation [136] . . .
  137. Z.T. Lin; K. Song; J.P. Bin; Y.L. Liao; G.B. Jiang Characterization of polymer micelles with hemocompatibility based on N-succinyl-chitosan grafting with long chain hydrophobic groups and loading aspirin J. Mater. Chem. 21, 19153-19165 (2011) .
    • . . . Chitosan-based micelle systems have also been investigated for applications in antivirus [103], anti-thrombogenicity [137], and antiplatelet aggregation [135]. . . .
  138. T.M.H. Niers; C.P.W. Klerk; M. DiNisio; C.J.F. van Noorden; H.R. Buller; P.H. Reitsma; D.J. Richel Mechanisms of heparin induced anti-cancer activity in experimental cancer models Crit. Rev. Oncol. Hematol. 61, 195-207 (2007) .
    • . . . Heparin is a polysaccharide that has a variety of biological functions, such as anticoagulant activity, inhibition of angiogenesis and anti-tumor development [138,139] . . .
    • . . . In addition, heparin-based micelles have demonstrated enhanced inhibition of tumor growth and angiogenesis [138,139], while cellulose [116,117,118], chitosan [104,139], and pullulan-based [180] systems promoted drug absorption across the small intestine due to enhanced mucoadhesion. . . .
  139. S.S. Karti; E. Ovali; O. Ozgur; M. Yilmaz; M. Sonmez; S. Ratip; F. Ozdemir Induction of apoptosis and inhibition of growth of human hepatoma HepG2 cells by heparin HepatoGastroenterology 50, 1864-1866 (2003) .
    • . . . Heparin is a polysaccharide that has a variety of biological functions, such as anticoagulant activity, inhibition of angiogenesis and anti-tumor development [138,139] . . .
    • . . . Small molecules include glycyrrhetinic acid, a liver targeting ligand [58,139], vitamin E succinate-specific toxicity to tumor cells [131], and folic acid with a high affinity to the folate receptor overexpressed on tumor cells [64,101,146,177,178,179] . . .
  140. Y. Wang; D.C. Xin; K.J. Liu; M.Q. Zhu; J.N. Xiang Heparin-paclitaxel conjugates as drug delivery system: Synthesis, self-assembly property, drug release, and antitumor activity Bioconjug. Chem. 20, 2214-2221 (2009) .
    • . . . Other micelle systems include heparin-PTX [140,141] and heparin-poly(β-benzyl-l-aspartate) [142]. . . .
  141. I.K. Park; Y.J. Kim; T.H. Tran; K.M. Huh; Y.K. Lee Water-soluble heparin-PTX conjugates for cancer targeting Polymer 51, 3387-3393 (2010) .
    • . . . Other micelle systems include heparin-PTX [140,141] and heparin-poly(β-benzyl-l-aspartate) [142]. . . .
  142. L. Li; H.T. Moon; J.Y. Park; Y.J. Heo; Y. Choi; T.H. Tran; Y.K. Lee; S.Y. Kim; K.M. Huh Heparin-based self-assembled nanoparticles for photodynamic therapy Macromol. Res. 19, 487-494 (2011) .
    • . . . Other micelle systems include heparin-PTX [140,141] and heparin-poly(β-benzyl-l-aspartate) [142]. . . .
  143. H.J. Cho; I.S. Yoon; H.Y. Yoon; H. Koo; Y.J. Jin; S.H. Ko; J.S. Shim; K. Kim; I.C. Kwon; D.D. Kim Polyethylene glycol-conjugated hyaluronic acid-ceramide self-assembled nanoparticles for targeted delivery of doxorubicin Biomaterials 33, 1190-1200 (2012) .
    • . . . Most recent HA-based micelle systems have focused on cancer treatment with DOX [83,143,144,145], PTX [63,146,147], siRNA [148], and curcumin [149] . . .
    • . . . HA-based micelles showed significantly higher cellular uptake by a CD44 overexpressed cancer cell line compared to a CD44 negative cell line, NIH3T3 [143] . . .
    • . . . For example, studies have shown that PEG protected octyl-succinyl-chitosan from plasma protein absorption [157] and that PEG modification could prolong HA-ceramide circulation [143] . . .
    • . . . Therefore, HA has been highly investigated as an active targeting agent to tumor tissue or liver with many micelle systems [82,143,144] . . .
  144. J.L. Wu; C.G. Liu; X.L. Wang; Z.H. Huang Preparation and characterization of nanoparticles based on histidine-hyaluronic acid conjugates as doxorubicin carriers J. Mater. Sci. Mater. Med. 23, 1921-1929 (2012) .
    • . . . Most recent HA-based micelle systems have focused on cancer treatment with DOX [83,143,144,145], PTX [63,146,147], siRNA [148], and curcumin [149] . . .
    • . . . Therefore, HA has been highly investigated as an active targeting agent to tumor tissue or liver with many micelle systems [82,143,144] . . .
  145. Y.J. Jin; U. Termsarasab; S.H. Ko; J.S. Shim; S. Chong; S.J. Chung; C.K. Shim; H.J. Cho; D.D. Kim Hyaluronic acid derivative-based self-assembled nanoparticles for the treatment of melanoma Pharma. Res. 29, 3443-3454 (2012) .
    • . . . Most recent HA-based micelle systems have focused on cancer treatment with DOX [83,143,144,145], PTX [63,146,147], siRNA [148], and curcumin [149] . . .
  146. Y.H. Liu; J. Sun; W. Cao; J.H. Yang; H. Lian; X. Li; Y.H. Sun; Y.J. Wang; S.L. Wang; Z.G. He Dual targeting folate-conjugated hyaluronic acid polymeric micelles for paclitaxel delivery Int. J. Pharm. 421, 160-169 (2011) .
    • . . . Most recent HA-based micelle systems have focused on cancer treatment with DOX [83,143,144,145], PTX [63,146,147], siRNA [148], and curcumin [149] . . .
    • . . . To further improve targeting, folic acid, another active targeting agent was conjugated to HA and higher cellular uptake was observed with folic acid-HA-octadecyl group compare to HA-octadecyl group [146] . . .
    • . . . Selective release at the tumor site is accomplished by incorporating various moieties with hydrophobic and electronic interactions that change with pH [66,146,157,170,171]. . . .
    • . . . Small molecules include glycyrrhetinic acid, a liver targeting ligand [58,139], vitamin E succinate-specific toxicity to tumor cells [131], and folic acid with a high affinity to the folate receptor overexpressed on tumor cells [64,101,146,177,178,179] . . .
  147. G. Saravanakumar; K.Y. Choi; H.Y. Yoon; K. Kim; J.H. Park; I.C. Kwon; K. Park Hydrotropic hyaluronic acid conjugates: Synthesis, characterization, and implications as a carrier of paclitaxel Int. J. Pharm. 394, 154-161 (2010) .
    • . . . Most recent HA-based micelle systems have focused on cancer treatment with DOX [83,143,144,145], PTX [63,146,147], siRNA [148], and curcumin [149] . . .
  148. Y. Shen; B.H. Wang; Y. Lu; A. Ouahab; Q. Li; J.S. Tu A novel tumor-targeted delivery system with hydrophobized hyaluronic acid-spermine conjugates (HHSCs) for efficient receptor-mediated siRNA delivery Int. J. Pharm. 414, 233-243 (2011) .
    • . . . Most recent HA-based micelle systems have focused on cancer treatment with DOX [83,143,144,145], PTX [63,146,147], siRNA [148], and curcumin [149] . . .
  149. S. Manju; K. Sreenivasan Conjugation of curcumin onto hyaluronic acid enhances its aqueous solubility and stability J. Colloid Interface Sci. 359, 318-325 (2011) .
    • . . . Most recent HA-based micelle systems have focused on cancer treatment with DOX [83,143,144,145], PTX [63,146,147], siRNA [148], and curcumin [149] . . .
  150. K.Y. Choi; K.H. Min; H.Y. Yoon; K. Kim; J.H. Park; I.C. Kwon; K. Choi; S.Y. Jeong PEGylation of hyaluronic acid nanoparticles improves tumor targetability in vivo Biomaterials 32, 1880-1889 (2011) .
    • . . . Intravital tumor imaging also confirmed PEG-HA-5 beta-cholanic acid had rapid extravasation into tumor tissue [150]. . . .
    • . . . Moreover, PEG could inhibit liver uptake of HA-conjugated micelles, thereby increasing the systemic circulation [150]. . . .
  151. R.A. Bader; A.L. Silvers; N. Zhang Polysialic acid-based micelles for encapsulation of hydrophobic drugs Biomacromolecules 12, 314-320 (2011) .
    • . . . Using CyA as a model drug, a high loading capacity was achieved with micelles prepared from polycaprolactone (PCL) modified PSA [151] . . .
    • . . . Recently, Bader et al. synthesized PSA-based micelle systems for future applications in drug delivery [151]. . . .
  152. N. Li; X.R. Li; Y.X. Zhou; W.J. Li; Y. Zhao; S.J. Ma; J.W. Li; Y.J. Gao; Y. Liu; X.L. Wang The use of polyion complex micelles to enhance the oral delivery of salmon calcitonin and transport mechanism across the intestinal epithelial barrier Biomaterials 33, 8881-8892 (2012) .
    • . . . Alginic acid-PEG showed very significant enhancement of hypocalcemia efficacy in rats after intraduodenal administration and can improve the oral absorption of salmon calcitionin via alginic acid-PEG facilitated transcytosis across Caco-2 cells [152] . . .
  153. W. Ha; H. Wu; X.L. Wang; S.L. Peng; L.S. Ding; S. Zhang; B.J. Li Self-aggregates of cholesterol-modified carboxymethyl konjac glucomannan conjugate: Preparation, characterization, and preliminary assessment as a carrier of etoposide Carbohydr. Polym. 86, 513-519 (2011) .
    • . . . Mannan based-micelle systems with high stability were developed by grafting cholesterol [153] or hexadecanethiol (C16) [154,155] to mannan . . .
  154. S.A. Ferreira; P. Pereira; P. Sampaio; P.J.G. Coutinho; F.M. Gama Supramolecular assembled nanogel made of mannan J. Colloid Interface Sci. 361, 97-108 (2011) .
    • . . . Mannan based-micelle systems with high stability were developed by grafting cholesterol [153] or hexadecanethiol (C16) [154,155] to mannan . . .
  155. S.A. Ferreira; P.J.G. Coutinho; F.M. Gama Self-assembled nanogel made of mannan: Synthesis and characterization Langmuir 26, 11413-11420 (2010) .
    • . . . Mannan based-micelle systems with high stability were developed by grafting cholesterol [153] or hexadecanethiol (C16) [154,155] to mannan . . .
  156. S. De Medeiros Modolon; I. Otsuka; S. Fort; E. Minatti; R. Borsali; S. Halila Sweet block copolymer nanoparticles: Preparation and self-assembly of fully oligosaccharide-based amphiphile Biomacromolecules 13, 1129-1135 (2012) .
    • . . . In addition, Modolon et al. have led an investigation of maltoheptaosyl-based micelles composed of hydrophilic maltoheptaosyl and hydrophobic peracetylated maltoheptaosyl [156] . . .
  157. J.X. Niu; Z.G. Su; Y.Y. Xiao; A.W. Huang; H.Y. Li; X. Bao; S. Li; Y.A. Chen; M.J. Sun; Q.N. Ping Octreotide-modified and pH-triggering polymeric micelles loaded with doxorubicin for tumor targeting delivery Eur. J. Pharm. Sci. 45, 216-226 (2012) .
    • . . . For example, studies have shown that PEG protected octyl-succinyl-chitosan from plasma protein absorption [157] and that PEG modification could prolong HA-ceramide circulation [143] . . .
    • . . . Selective release at the tumor site is accomplished by incorporating various moieties with hydrophobic and electronic interactions that change with pH [66,146,157,170,171]. . . .
    • . . . Peptides include octreotide targeting for the somatostatin receptors on tumor cells [65,157], the A54 hepatocarcinoma binding peptide [105], and Arg-Gly-Asp (RGD) containing peptide for αvβ3 and αvβ5 integrins [89,176] . . .
  158. P. Caliceti; F.M. Veronese Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates Adv. Drug Deliv. Rev. 55, 1261-1277 (2003) .
    • . . . Despite the demonstrable improvements relative to unmodified systems, there are potential drawbacks of PEG usage, such as the non-biodegradable PEG backbone, continuous accumulation in the body, and possible induction of an immune response [158,159,160] . . .
  159. G. Gregoriadis; S. Jain; I. Papaioannou; P. Laing Improving the therapeutic efficacy of peptides and proteins: A role for polysialic acids Int. J. Pharm. 300, 125-130 (2005) .
    • . . . Despite the demonstrable improvements relative to unmodified systems, there are potential drawbacks of PEG usage, such as the non-biodegradable PEG backbone, continuous accumulation in the body, and possible induction of an immune response [158,159,160] . . .
  160. K. Knop; R. Hoogenboom; D. Fischer; U.S. Schubert Poly(ethylene glycol) in drug delivery: Pros and cons as well as potential alternatives Angew. Chem. Int. Ed. 49, 6288-6308 (2010) .
    • . . . Despite the demonstrable improvements relative to unmodified systems, there are potential drawbacks of PEG usage, such as the non-biodegradable PEG backbone, continuous accumulation in the body, and possible induction of an immune response [158,159,160] . . .
  161. R.L. Hong; C.J. Huang; Y.L. Tseng; V.F. Pang; S.T. Chen; J.J. Liu; F.H. Chang Direct comparison of liposomal doxorubicin with or without polyethylene glycol coating in C-26 tumor-bearing mice: Is surface coating with polyethylene glycol beneficial? Clin. Cancer Res. 5, 3645-3652 (1999) .
    • . . . In addition, the PEG coating may interfere with cellular uptake of drugs because PEG has been reported to reduce drug-cell interaction and to hinder the drug release from carrier systems [161,162,163] . . .
  162. J.W. Holland; C. Hui; P.R. Cullis; T.D. Madden Poly(ethylene glycol)—Lipid conjugates regulate the calcium-induced fusion of liposomes composed of phosphatidylethanolamine and phosphatidylserine Biochemistry 35, 2618-2624 (1996) .
    • . . . In addition, the PEG coating may interfere with cellular uptake of drugs because PEG has been reported to reduce drug-cell interaction and to hinder the drug release from carrier systems [161,162,163] . . .
  163. P. Erbacher; T. Bettinger; P. Belguise-Valladier; S. Zou; J.L. Coll; J.P. Behr; J.S. Remy Transfection and physical properties of various saccharide, poly(ethylene glycol), and antibody-derivatized polyethylenimines (PEI) J. Gene Med. 1, 210-222 (1999) .
    • . . . In addition, the PEG coating may interfere with cellular uptake of drugs because PEG has been reported to reduce drug-cell interaction and to hinder the drug release from carrier systems [161,162,163] . . .
  164. S. Jain; D.H. Hreczuk-Hirst; B. McCormack; M. Mital; A. Epenetos; P. Laing; G. Gregoriadis Polysialylated insulin: Synthesis, characterization and biological activity in vivo Biochim. Biophys. Acta 1622, 42-49 (2003) .
    • . . . Gregoriadis et al. have investigated a series of PSA-protein conjugate and shown prolonged circulation of insulin [164], asparaginase [165,166], and catalase [167,168] . . .
  165. A.I. Fernandes; G. Gregoriadis Polysialylated asparaginase: Preparation, activity and pharmacokinetics Biochim. Biophys. Acta 1341, 26-34 (1997) .
    • . . . Gregoriadis et al. have investigated a series of PSA-protein conjugate and shown prolonged circulation of insulin [164], asparaginase [165,166], and catalase [167,168] . . .
  166. A.I. Fernandes; G. Gregoriadis The effect of polysialylation on the immunogenicity and antigenicity of asparaginase: Implication in its pharmacokinetics Int. J. Pharm. 217, 215-224 (2001) .
    • . . . Gregoriadis et al. have investigated a series of PSA-protein conjugate and shown prolonged circulation of insulin [164], asparaginase [165,166], and catalase [167,168] . . .
  167. A.G. Fernandes G FC41 catalase-polysialic acid conjugates Eur. J. Pharma. Sci. 2, 111 (1994) .
    • . . . Gregoriadis et al. have investigated a series of PSA-protein conjugate and shown prolonged circulation of insulin [164], asparaginase [165,166], and catalase [167,168] . . .
  168. A.I. Fernandes; G. Gregoriadis Synthesis, characterization and properties of sialylated catalase Biochim. Biophys. Acta 1293, 90-96 (1996) .
    • . . . Gregoriadis et al. have investigated a series of PSA-protein conjugate and shown prolonged circulation of insulin [164], asparaginase [165,166], and catalase [167,168] . . .
  169. J.K. Kim; Y.W. Won; K.S. Lim; Y.H. Kim Low-molecular-weight methylcellulose-based thermo-reversible gel/pluronic micelle combination system for local and sustained docetaxel delivery Pharma. Res. 29, 525-534 (2012) .
    • . . . The solution phase is expected to facilitate injection, while the gel phase was demonstrated to sustain drug release for approximately 3 weeks [169] . . .
  170. X. Wang; C.J. Chen; D. Huo; H.Q. Qian; Y. Ding; Y. Hu; X.Q. Jiang Synthesis of beta-cyclodextrin modified chitosan-poly(acrylic acid) nanoparticles and use as drug carriers Carbohydr. Polym. 90, 361-369 (2012) .
    • . . . Selective release at the tumor site is accomplished by incorporating various moieties with hydrophobic and electronic interactions that change with pH [66,146,157,170,171]. . . .
  171. K. Na; K.H. Lee; Y.H. Bae pH-Sensitivity and pH-dependent interior structural change of self-assembled hydrogel nanoparticles of pullulan acetate/oligo-sulfonamide conjugate J. Contr. Release 97, 513-525 (2004) .
    • . . . Selective release at the tumor site is accomplished by incorporating various moieties with hydrophobic and electronic interactions that change with pH [66,146,157,170,171]. . . .
  172. X.Y. Gong; Y.H. Yin; Z.J. Huang; B. Lu; P.H. Xu; H. Zheng; F.L. Xiong; H.X. Xu; X. Xiong; X.B. Gu Preparation, characterization and in vitro release study of a glutathione-dependent polymeric prodrug cis-3-(9H-purin-6-ylthio)-acrylic acid-graft-carboxymethyl chitosan Int. J. Pharm. 436, 240-247 (2012) .
    • . . . As an example, a negligible amount of prodrug was released from carboxymethylchitosan-based micelles without GSH and at low concentrations of GSH; however, 75% of the conjugated drug was released with the presence of GSH at 20 mM [172,173] . . .
  173. H. Zheng; Y. Rao; Y.H. Yin; X.O. Xiong; P.H. Xu; B. Lu Preparation, characterization, and in vitro drug release behavior of 6-mercaptopurine-carboxymethyl chitosan Carbohydr. Polym. 83, 1952-1958 (2011) .
    • . . . As an example, a negligible amount of prodrug was released from carboxymethylchitosan-based micelles without GSH and at low concentrations of GSH; however, 75% of the conjugated drug was released with the presence of GSH at 20 mM [172,173] . . .
  174. T. Hirakura; Y. Nomura; Y. Aoyama; K. Akiyoshi Photoresponsive nanogels formed by the self-assembly of spiropyrane-bearing pullulan that act as artificial molecular chaperones Biomacromolecules 5, 1804-1809 (2004) .
    • . . . The amphiphilicity of the spiropyrane core was modulated through irradiation with visible light, which consequently impacted the interaction and release of associated proteins [174] . . .
  175. S. Patnaik; A.K. Sharma; B.S. Garg; R.P. Gandhi; K.C. Gupta Photoregulation of drug release in azo-dextran nanogels Int. J. Pharm. 342, 184-193 (2007) .
    • . . . Similarly, release of model compounds from micelles formed from azobenzene-dextran was controlled through exposure to UV-Vis light [175]. . . .
  176. L.L. Cai; P. Liu; X. Li; X. Huang; Y.Q. Ye; F.Y. Chen; H. Yuan; F.Q. Hu; Y.Z. Du RGD peptide-mediated chitosan-based polymeric micelles targeting delivery for integrin-overexpressing tumor cells Int. J. Nanomed. 6, 3499-3508 (2011) .
    • . . . Peptides include octreotide targeting for the somatostatin receptors on tumor cells [65,157], the A54 hepatocarcinoma binding peptide [105], and Arg-Gly-Asp (RGD) containing peptide for αvβ3 and αvβ5 integrins [89,176] . . .
  177. Y.L. Tan; C.G. Liu Preparation and characterization of self-assemblied nanoparticles based on folic acid modified carboxymethyl chitosan J. Mater. Sci. Mater. Med. 22, 1213-1220 (2011) .
    • . . . Small molecules include glycyrrhetinic acid, a liver targeting ligand [58,139], vitamin E succinate-specific toxicity to tumor cells [131], and folic acid with a high affinity to the folate receptor overexpressed on tumor cells [64,101,146,177,178,179] . . .
  178. H.Y. Zhu; F. Liu; J. Guo; J.P. Xue; Z.Y. Qian; Y.Q. Gu Folate-modified chitosan micelles with enhanced tumor targeting evaluated by near infrared imaging system Carbohydr. Polym. 86, 1118-1129 (2011) .
    • . . . Small molecules include glycyrrhetinic acid, a liver targeting ligand [58,139], vitamin E succinate-specific toxicity to tumor cells [131], and folic acid with a high affinity to the folate receptor overexpressed on tumor cells [64,101,146,177,178,179] . . .
  179. M. Nayebsadrian; J. Varshosaz; F. Hassanzadeh; H. Sadeghi; M. Banitalebi; M. Rostami Screening the most effective variables on physical properties of folate-targeted dextran/retinoic acid micelles by taguchi design J. Nanomater. 2012, 860691:1-860691:7 (2012) .
    • . . . Small molecules include glycyrrhetinic acid, a liver targeting ligand [58,139], vitamin E succinate-specific toxicity to tumor cells [131], and folic acid with a high affinity to the folate receptor overexpressed on tumor cells [64,101,146,177,178,179] . . .
  180. M. Dionisio; C. Cordeiro; C. Remunan-Lopez; B. Seijo; A.M. Rosa da Costa; A. Grenha Pullulan-based nanoparticles as carriers for transmucosal protein delivery Eur. J. Pharm. Sci. , (2013) .
    • . . . In addition, heparin-based micelles have demonstrated enhanced inhibition of tumor growth and angiogenesis [138,139], while cellulose [116,117,118], chitosan [104,139], and pullulan-based [180] systems promoted drug absorption across the small intestine due to enhanced mucoadhesion. . . .
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