Solubilizing and sustained-releasing abilities and safety preliminary evaluation for paclitaxel based on N-octyl-O,N-carboxymethyl chitosan polymeric micelles

A series of novel self-assembled polymeric micelles based on carboxymethyl chitosan bearing long chain alkyl chains (N-octyl-O,N-carboxymethyl chitosan, OCC) was synthesized. PTX loaded OCC polymeric micelles (PTX-OCC) were prepared by dialysis method. The effects of the degree of substitutions (DS) of octyl groups on the solubilizing abilities of OCC for paclitaxel were studied. The PTX-OCC were characterized using drug loading content, drug encapsulation efficiency, dynamic light scattering, zeta potential and transmission electron microscopy (TEM). Take PTX injection (PTX-INJ) as control, the safety of PTX-OCC including hemolysis, hypersensitiveness in guinea pigs and acute toxicity in mice were also evaluated. OCC showed excellent loading capacities for paclitaxel with the DS of octyl groups in the range of 37.9%-58.6%. Drug loading contents were up to 24.9%-34.4% with drug encapsulation efficiency 56.3%-89.3%, which both increased with the increasing of DS of octyl groups. The mean size of PTX-OCC was 186.4-201.1 nm which decreased with the increasing of DS of octyl groups. The zeta potential was -47.5 to -50.9 mV, which had no obvious relation with the DS of octyl groups. The TEM images showed a spherical shape. No burst release phenomena were observed and drug cumulative release was in the range of 60%-95% in 15 days. PTX-OCC with higher DS of octyl groups showed stronger sustained releasing ability. In terms of the induction of membrane damage and hypersensitiveness, PTX-OCC was superior to PTX-INJ. The LD₅₀ and its 95% confidence interval of PTX-OCC were 134.4 (125.0-144.6) mg·kg^-1, which was 2.7 fold of PTX-INJ. The present PTX-OCC could be potentially useful as safety carriers for intravenous delivery.