乙二醇壳聚糖-胆固醇接枝物载多柔比星自聚集纳米粒的制备及其大鼠体内药动学研究

Preparation of Doxorubicin Loaded Self-Aggregated Nanoparticles Based on Cholesterol-Modified Glycol Chitosan Conjugate and Its Pharmacokinetics in Rats

目的制备乙二醇壳聚糖-胆固醇接枝物(CHGC)载多柔比星(DOX)自聚集纳米粒,并考察其在大鼠体内的药动学行为。方法采用透析法制备乙二醇壳聚糖-胆固醇接枝物载多柔比星纳米粒(DCN);应用动态光散射粒度仪和原子力显微镜测定载药纳米粒的Zeta电位、粒径与形态,考察DCN的稳定性;以pH(5.5,6.5,7.4)磷酸盐缓冲溶液(PBS)作为释放介质,考察DCN的体外释放行为;采用HPLC测定多柔比星在大鼠血浆中的药物浓度。结果随着投药量的增加,DCN的载药量、Ze-ta电位和粒径增大;粒子形态呈球形;体外释放实验结果表明,释放介质的pH值越低,药物释放越快,且释放速率随着纳米粒载药量的增大而降低;大鼠体内药动学实验结果表明,DCN-10组的AUC(0-∞)是游离DOX组的5.84倍(P<0.01);DCN-10组的MRT0-∞是DOX组的21.90倍(P<0.01)。结论CHGC作为高分子药物载体材料,载多柔比星纳米粒的体外释放行为具有缓释和pH依赖特征;DCN能够在血液中长时间滞留,明显提高DOX的生物利用度,结果表明,以CHGC纳米粒作为抗肿瘤药物载体具有较好的应用前景。

OBJECTIVE To prepare doxorubicin（DOX） loaded self-aggregated nanoparticles based on cholesterol-modified glycol chitosan conjugate（CHGC）and study its pharmacokinetics in rats. METHODS DOX was physically entrapped into the CHGC nanoparticles by a dialysis method. The characteristics of DOX-loaded CHGC （DCN） nanoparticles were analyzed using dynamic lightscattering（DLS） and atomic force microscope （AFM）. The stabihty of DCN nanoparticles was investigated at 37 ℃in phosphate buffered （PBS） at pH 7.4. The release of DOX from the DCN nanoparticles was studied in vitro by a dialysis method in PBS （ pH 5. 5, 6. 5 and 7.4 ）. The concentration of DOX in rats plasma was determined by high-performance liquid chromatography （HPLC）. RESULTS The DCN nanoparticles were almost spherical in shape. Their size and Zeta potential were increased with the increase of DOX-loading content. The in vitro release behavior of DOX from the DCN nanoparticles was pH-dependent. DOX release from the low drug-loading nanoparticles was also much faster than drug release from higher drug-loading nanoparticales. In rat pharmacokinetic study, the AUC（0-∞）of DCN -10 was 5.84 times as the value of DOX（P 〈 0. 01 ）. Moreover, MRT0-∞ of DCN-10 was increased by 20. 90 times than that of DOX（P 〈 0.01 ）. CONCLUSION CHGC nanoparticles could be used as a drug carrier. The drug release from the DCN nanoparticles was in sustained and pH-dependent manner. Moreover, DCN delayed release compared with free DOX. These results showed that DCN could improve the bioavailability of DOX significantly. Therefore, CHGC has a good prospect of application in drug delivery system for cancer therapy.