Conjugated Chitosan as a Novel Platform for Oral Delivery of Paclitaxel

Abstract

A new platform for oral delivery of paclitaxel (PTX) was developed through chemical conjugation of PTX to a low molecular weight chitosan (LMWC). The LMWC-PTX conjugate contained approximately 12 wt % PTX and showed greatly enhanced water solubility (>1 mg/mL) as compared to native PTX. The conjugate showed comparable IC 50 values to that of the parent PTX against human cancer cell lines. The pharmacokinetic data revealed approximately 42% of bioavailability after oral administration of 5 mg PTX/kg of the conjugate. When the conjugate (10 mg/kg based on PTX content) was administered orally to mice bearing xenograft or allograft tumors, the conjugate-treated group showed significant inhibition of tumor growth, which was comparable to that seen with PTX of the clinically available injected form, formulated in cremophor EL/ethanol (iv) but with much lower toxicity. Tracking I (125)-labeled conjugate showed that LMWC-PTX was likely to be absorbed mainly from the ileum and reach the blood as the intact conjugate.

Poly-cyclodextrin and poly-paclitaxel nano-assembly for anticancer therapy

“…Polymeric delivery systems can also enhance the aqueous solubility and modify the pharmacokinetics and biodistribution of lipophilic drugs [5][6][7][8][9][10][11][12] . However, not all polymeric nanocarriers work efficiently.…”

“…For example, some polymeric micelles formed via self-assembly of amphiphilic block copolymers are unstable when diluted below their critical micelle concentration within the circulatory system; this can result in a burst release of drugs that may cause significant toxicity to healthy cells. Although polymer-drug conjugates minimize such an initial burst of drug and may also enhance the solubility of hydrophobic drugs, they still may be less effective than a free drug when taken up into cells due to imperfect degradable characteristics of polymer-drug conjugates [8][9][10][11] . To maximize the efficacy of drugs, the conjugated drugs should undergo intracellular enzyme-mediated release in their free forms after entering the cells.…”

Modification of Carbon Nanotubes as an Effective Solution for Cancer Therapy

“…3 The preparation of SWCNT with targeting properties involves several steps: coating SCNTs with paclitaxel, attaching Fluorescein isothiocyanate probe to the SWCNT-PTX, and finally targeting molecules (FA) attachment [50]. propyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) [144,145]. It is suggested that the drug was successfully loaded onto the SWCNTs, which may be mainly broken up by covalent stacking and hydrophobic interactions.…”

Chitosan Mediated Targeted Drug Delivery System: A Review

“…LMWC-PTX was absorbed in the small intestine after oral administration and remained in its intact conjugate form until it reached the bloodstream. An advantage of LMWC-PTX for oral delivery of PTX is that LMWC-PTX has the ability to bypass the Pgpmediated barrier (ef.ux pump) in the gastrointestinal tract and CYP450-dependent metabolism in the intestine and liver [68]. Nsuccinyl-chitosan derivatives were conjugated with mitomycin C (MMC) using carbodiimide chemistry [69].…”