Low molecular weight chitosan-based conjugate: A new platform for oral delivery of paclitaxel

A new platform for oral delivery of paclitaxel (PTX) was developed using a chemical conjugate system between PTX and low molecular weight chitosan (LMWC) having a narrow range of molecular weight (Mw). Three different Mws of chitosan (3k, 6k, and 9k) were used to prepare the conjugates. LMWC-PTX conjugates were synthesized by two step reactions: i) modification of PTX with succinic acid and ii) coupling reaction between an activated ester form of PTX and amine groups of chitosan. The conjugates contained 27-42% of PTX in weight and showed greatly enhanced water solubility (> 1 mg/mL) compared to native PTX (> 0.01 mg/mL). In vitro cytotoxicity of the conjugates on murine lung carcinoma cells was evaluated by MTT assay, resulting in sight loss of cytotoxicity less than a fifth compared to that of PTX. When the conjugates (60 mg/kg based on PTX content) were administered to murine carcinoma bearing mice, the conjugate-treated groups showed significant inhibition of tumor growth, resulting in up to 31% in tumor mass relative to control (saline treatment). No distinct difference in the effect of chitosan Mw on antitumor activity was observed for the three conjugates. On the other hand, there was only slight loss (less than 5%) in final body weight after removal of tumor mass, suggesting that the conjugates may not cause severe systemic toxicity.