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.

In Vivo Evaluation of Paclitaxel-Loaded Lipid Nanocapsules After Intravenous and Oral Administration on Resistant Tumor

“…Doses ranging from 0.5 to 10 mg/kg were used for intravenous route [18][19][20][21][22] and ranging from 2 to 100 mg/kg for oral route [18,[23][24][25] but oral doses were not below 10 mg/kg in most studies [26][27][28][29][30][31]. The calculated (mg/kg) dose by extrapolation for rat is around sixfold higher than for adult human because the surface area to weight ratio depends on species [32].…”

Cysteine-Functionalized Nanostructured Lipid Carriers for Oral Delivery of Docetaxel: A Permeability and Pharmacokinetic Study

“…4 Many researchers have attempted to coat the nanoparticles with chitosan or its derivatives to increase mucoadhesion. [10][11][12] Positively-charged chitosan can adhere to negatively charged sialic and sulfonic acids in the mucus layer via electrostatic interaction. 13 Yet another approach involves thiolated polymers have been developed to improve the mucoadhesive properties of nanoparticles, and these are often termed "thiomers".…”

Synergistic locoregional chemoradiotherapy using a composite liposome-in-gel system as an injectable drug depot

“…41 PTX was not detected in plasma and other organs of the animal, showing that the formulation effectively localizes the drug at the tumor site only ( Figure 5). Previous studies with intravenous injection of Taxol in a subcutaneous murine melanoma model have shown significant PTX distribution in the plasma and other organs (such as liver and lung) at 2 h, 17,42 while that from LG-PTX showed drug levels only in the tumor. Other references have shown that only a fraction of the intravenous Taxol dose (5%, ~10 µg/g) is accumulated in subcutaneous tumors, 43,44 while a substantial fraction of drug is accumulated in the tumor when LG-PTX is used (33%, ~343 µg/g).…”

“…In such a scenario, the strategy of utilizing nanotechnology in the field of oncology presents huge opportunities to overcome these limitations and improve the therapeutic ratio for effective regional delivery of radiosensitizers. 16 A number of nano-sized carriers [17][18][19] and synthetic poly(ethylene glycol) (PEG)-based gels have been studied as drug carriers [20][21][22][23][24] but have inherent limitations.…”