title: Carboxymethyl-chitosan-tethered lipid vesicles: hybrid nanoblanket for oral delivery of paclitaxel.
abstract: We describe the development and evaluation of a hybrid lipopolymeric system comprising carboxymethyl chitosan (CMC), covalently tethered to phosphatidylethanolamine units on the surface of lipid nanovesicles, for oral delivery of paclitaxel. The bioploymer is intended to act as a blanket, thereby shielding the drug from harsh gastrointestinal conditions, whereas the lipid nanovesicle ensures high encapsulation efficiency of paclitaxel and its passive targeting to tumor. CMC-tethered nanovesicles (LN-C-PTX) in the size range of 200-300 nm improved the gastrointestinal resistance and mucoadhesion properties as compared with unmodified lipid nanovesicles (LN-PTX). Conjugation of CMC did not compromise the cytotoxic potential of paclitaxel yet facilitated the interaction and uptake of the nanovesicles by murine melanoma (B16F10) cells through an ATP-dependent process. CMC-conjugated nanovesicles, upon oral administration in rats, improved the plasma concentration profile of paclitaxel, with 1.5 fold increase in its bioavailability and 5.5 folds increase in elimination half life in comparison with Taxol. We also found that CMC in addition to providing a gastric resistant coating also imparted stealth character to the nanovesicles, thereby reducing their reticuloendothelial system (RES)-mediated uptake by liver and spleen and bypassing the need for PEGylation. In vivo efficacy in subcutaneous model of B16F10 showed significantly improved tumor growth inhibition and survival with CMC-tethered nanovesicles as compared with unmodified nanovesicles, both administered orally. LN-C-PTX exhibited therapeutic efficacy comparable to Taxol and Abraxane and also showed reduced toxicity and improved survival. Overall, these results suggest the therapeutic potential of CMC tethered nanovesicles as a platform for oral administration of paclitaxel and also unravel the ability of CMC to impart stealth character to the nanoparticles, thereby preventing their RES clearance.
authors.affiliation: WRCBB, Department of Biosciences and Bioengineeering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
authors.forename: Nitin
authors.initials: N
authors.lastname: Joshi
authors.forename: Rama
authors.initials: R
authors.lastname: Saha
authors.forename: Thanigaivel
authors.initials: T
authors.lastname: Shanmugam
authors.forename: Biji
authors.initials: B
authors.lastname: Balakrishnan
authors.forename: Prachi
authors.initials: P
authors.lastname: More
authors.forename: Rinti
authors.initials: R
authors.lastname: Banerjee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D048271:Chitosan / Q000031:analogs & derivatives* / Q000737:chemistry; D004337:Drug Carriers; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use; D017239:Paclitaxel / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D010714:Phosphatidylethanolamines / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D022161:Transport Vesicles
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008055:Lipids; D010714:Phosphatidylethanolamines; C514968:carboxymethyl-chitosan; C483858:phosphatidylethanolamine; D048271:Chitosan; D017239:Paclitaxel