N-辛基-O,N-羧甲基壳聚糖聚合物胶束对紫杉醇的增溶、缓释及其安全性初步评价

本文合成了一系列两亲性壳聚糖衍生物N-辛基-O,N-羧甲基壳聚糖(OCC)，以透析法制备紫杉醇(PTX)-OCC载药聚合物胶束，并考察疏水烷基取代度对包封率、载药量、粒径和zeta电位的影响，通过透射电镜(TEM)观察其形态结构，并以市售制剂为对照；通过体外溶血实验、豚鼠急性过敏实验及小鼠尾静脉注射急性毒性实验初步评价其安全性。结果表明，OCC对PTX有良好的增溶效果，在疏水基取代度为37.9%～58.6%时，载药量为24.9%～34.4%，包封率为56.3%～89.3%，且随着疏水辛基取代度的增加，载药量和包封率皆显著提高。疏水烷基链进一步提高则可能破坏胶束亲水疏水平衡而导致载药能力降低；载药胶束粒径为186.4～201.1 nm，随疏水烷基取代度的增加而减小， zeta电位为-47.5～-50.9 mV，疏水烷基取代度对其无显著影响，TEM照片显示该聚合物胶束为规则球形结构，粒径分布均匀。OCC对紫杉醇具有优良的缓释效果，未见突释，15 d累计药物释放量在60%～95%，缓释能力随疏水基取代度的增加而增强。溶血实验、 豚鼠急性过敏实验和小鼠尾静脉注射急性毒性实验结果表明，PTX-OCC溶血性和急性过敏反应低于市售制剂， PTX-OCC小鼠尾静脉注射的LD₅₀及95%可信限为134.4(125.0～144.6) mg·kg^-1，为市售制剂LD₅₀的2.7倍。初步认为PTX-OCC是安全可靠的静脉注射用纳米制剂。

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.