阿霉素纳米脂质体的制备及安全性评价(英文)

Preparation of doxorubicin-hydrochloride nanoliposomes and its safety evaluation

目的制备阿霉素纳米脂质体,并研究其急性毒性和慢性毒性。方法通过乙醇注入法结合pH梯度法,制备阿霉素纳米脂质体,并通过粒径仪测定其物理化学性质。阿霉素纳米脂质体的长期毒性和慢性毒性则通过昆明小鼠实验进行评价。结果通过该方法制备的阿霉素纳米脂质体粒径为140～170 nm,包封率高达99.85%。急性毒性实验表明,阿霉素纳米脂质体的LD50为31.69 mg/kg,病理结果提示,阿霉素纳米脂质体在0 mg/kg和6 mg/kg的剂量下未对小鼠各脏器产生明显的毒性;12 mg/kg及以上剂量,对小鼠心、肺及肝组织都有一定的毒性,且与剂量大小相关;18 mg/kg及更低的剂量下,未见其对小鼠肾脾组织有明显毒性。慢性毒性实验中,与空白对照组比较,6 mg/kg和9 mg/kg剂量组小鼠体质量、RBC压积、平均RBC体积、PLT计数和嗜酸性粒细胞百分数及尿素氮含量(BUN)有显著影响(P<0.05)。结论该方法制备的阿霉素纳米脂质体质量稳定,且对动物的毒性具有剂量依赖性。

[ Objective ] To evaluate the characteristics, acute and chronic toxicity of doxorubicin-hydrochlofide nanoliposomes （DHNP） which were prepared by our methods and prescription. [ Methods ] The DHNP were made by a new type of ethanol injection-pH gradient method, and their characteristics were determined by Zetasizer. The acute and chronic toxicity were conducted in Kuming mice with administration of different dose of DHNP. [ Results ] The results showed that the DHNP prepared by our method had the uniform distribution size which ranged in 140- 170 nm, the entrapment rate reached as high as 99.85%, and they were relatively stable in low temperature. The LDS0 of the DHNP was 31.69 mg/kg. In the chronic toxicity study, there were significantly influences （P 〈0.05） on body weight, hematocrit, the mean red blood cel! volume, platelets counts and percentage of eosinophil in the 6 rag/ kg and 9 mg/kg groups compared with the control group, while other parameters had no significantly difference. In the tissue analysis, pathological change was found in the lung of the treated group, and its pathological degree in- creased as the dose increased, while there were no pathological changes detected in other tissues. [ Conclusions] The DHNP prepared by ethanol injection-pH gradient method possess the advantage of uniform distribution size, high encapsulation efficiency, high drug loading rate and low toxicity compared to free doxorubicin.