氨甲喋呤多相脂质体的制备及其动物抑瘤活性和临床前药理学实验研究

采用融熔法制备了氨甲喋吟(MTX)多相脂质体,并进行了抑瘤活性、小鼠急性毒性、家兔亚急性毒性和安全性实验。结果表明多相脂质体剂型显著提高了 MTX 对小鼠 EC 和 L615瘤株的抑瘤活性。急性毒性实验结果表明 MTX 多相脂质体和 MTX 水溶液的 ivLD_(50)值无显著性差异。亚急性毒性实验表明 MTX 多相脂质体大剂量给药时可出现肝细胞变性坏死。安全性实验未见异常反应。

PREPARATION OF POLYPHASE LIPOSOME OF METHOTREXATE AND STUDIES ON IT'S ANTITUMOR EFFECTS AND IT'S PRECLINICAL PHARMACOLOGY

An improved Fusion method was introduced to prepare polyphase liposome of methotrexate(PL-MTX),and its antitumor effects on experimental EC and L615 mouse tumor were reported.The antitumor effects of PL-MTX were com- pared with those of methotrexate aqueous solution(F-MTX),mixture of blank polyphase liposome and methotrexate(PL+MTX),and blank polyphase liposome (PL)respectively.Toxicity and preclinical safety tests of PL-MTX were also carried out. After ip.ad.of accumulative doses of 2,3,4,5mg/kg,PL-MTX increased EC and L615 mice mean survival time by an average of 67.7%and71.2%,F- MTX,14.9% and 36.8%,PL+MTX,29.4% and 43.9%,respectively.While with PL,no antitumor effects were observed.Significant differences between antitumor effects of PL-MTX,F-MTX and PL+MTX were observed (P< 0.05). After a single dose of iv.ad.into normal mice,LD50 value of PL-MTX was 24.1±6.2mg/kg,F-MTX,26.6±8.5mg/kg.No abnormal response was observed in preclinical safty tests of PL-MTX e.g.stimulation test,blood test, or allergic test.Hepatic toxicity was observed in rabbit subacute toxicity test when PL-MTX was injected into rabbit at a dose of 3.Smg/kg for 30 days.