Synthesis and characterization of 3,6-O,O'- dimyristoyl chitosan micelles for oral delivery of paclitaxel.

The aim of the present study was to investigate the potential application of 3,6-O,O'- dimyristoyl chitosan DMCh, an amphiphilic derivative of chitosan, for improving the oral bioavailability of paclitaxel (PTX), a water insoluble anticancer drug. The O-acylation of chitosan with myristoyl chloride was carried out by employing high (≈13.3) or low (2.0) molar excess of chitosan to result in samples DMCh07 and DMCh12, respectively. The successful O-acylation of chitosan was confirmed by FTIR and H NMR spectroscopy, the latter allowing also the determination of average degree of substitution (DS). The critical aggregation concentration (CAC) of samples DMCh07 (DS≈6.8%) and DMCh12 (DS≈12.0%) were 8.9×10mg/mL and 13.2×10mg/mL, respectively. It was observed by TEM that the DMCh micelles showed spherical shape while DLS measurements allowed the determination of their average size (287nm-490nm) and zeta potential (+32mV to +44mV). Such DMCh micelles were able to encapsulate paclitaxel with high drug encapsulation efficiency (EE), as confirmed by HPLC analyses. Studies on the cytotoxicity of DMCh07 micelles toward Caco-2 and HT29-MTX cells showed that, regardless the PTX loaded, DMCh07 micelles slightly decreased cellular viability at low micelles concentration (≤1μg/mL) while at high concentration (>10μg/mL) PTX-loaded DMCh07 micelles were less toxic toward Caco-2 cells when compared to free PTX. The PTX permeation across Caco-2 monoculture and Caco-2/HT29-MTX co-culture model confirmed the potential of DMCh micelles in improving the intestinal absorption of PTX. These results suggest that DMCh micelles may be a promising carrier to encapsulate PTX aiming cancer therapy.