Preclinical pharmacology, toxicology and efficacy of sphingomyelin/cholesterol liposomal vincristine for therapeutic treatment of cancer
Preclinical pharmacology, toxicology and efficacy of sphingomyelin/cholesterol liposomal vincristine for therapeutic treatment of cancer
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DOI：
10.1007/s002800050846
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发表时间：
1998-11-01
影响因子：
3
通讯作者：
Bally, MB
中科院分区：
文献类型：
--
作者：
Webb, MS;Logan, P;Bally, MB
目的：对小鼠鞘磷脂/胆固醇（SM/chol）脂质体长春新碱和未包封长春新碱进行临床前综合评价，以建立药物生物分布与药物毒性/疗效之间的药效学关系。方法：在药物/脂质比为0.05或0.10 （wt/wt）的情况下，对未包封的长春新碱和脂质体长春新碱在静脉给药后的毒性、抗肿瘤活性和药代动力学进行了评估。结果：给药2 mg/kg长春新碱脂质体小鼠血液和血浆中长春新碱的浓度比给药相同剂量的未包封的小鼠高至少2个数量级。注射长春新碱脂质体后1天，腋窝淋巴结、心脏、腹股沟淋巴结、肾脏、肝脏中药物含量至少比未包封的长春新碱高10倍。皮肤，小肠和脾脏。SM/chol脂质体包封导致血浆和组织暴露于长春新碱的增加与药物毒性增加无关。在小鼠P388腹水肿瘤细胞接种后1天，以2、3、4 mg/kg剂量单次静脉注射未包封药物治疗小鼠P388腹水肿瘤，可使小鼠寿命延长33 ~ 38%。相比之下，在SM/chol脂质体长春新碱制剂剂量为2、3和4 mg/kg的所有组中，长期存活率均达到50%或更高。在4 mg/kg剂量下，分别以0.05和0.1药脂比制备的SM/chol脂质体长春新碱，10只动物中有8只和9只存活了60天。结论：总体而言，与未包封的药物相比，脂质体包封后长春新碱血药浓度的增加和延长与抗肿瘤活性的显著增加相关，但药代动力学参数与毒性之间没有相关性。
Purpose: To establish the pharmacodynamic relationships between drug biodistribution and drug toxicity/efficacy, a comprehensive preclinical evaluation of sphingomyelin/cholesterol (SM/chol) liposomal vincristine and unencapsulated vincristine in mice was undertaken. Methods: Pharmaceutically acceptable formulations of unencapsulated vincristine and liposomal vincristine at drug/lipid ratios of 0.05 or 0.10 (wt/wt) were evaluated for toxicity, antitumor activity and pharmacokinetics following intravenous administration. Results: Mice given liposomal vincristine at 2 mg/kg vincristine had concentrations of vincristine in blood and plasma at least two orders of magnitude greater then those achieved after an identical dose of unencapsulated drug. One day after administration of the liposomal vincristine, there were at least tenfold greater drug quantities, relative to unencapsulated vincristine, in the axillary lymph nodes, heart, inguinal lymph nodes, kidney, liver? skin, small intestines and spleen. Increased plasma and tissue exposure to vincristine as a result of encapsulation in SM/chol liposomes was not associated with increased drug toxicities. Treatment of the murine P388 ascitic tumor with a single intravenous dose of unencapsulated drug at 2, 3 and 4 mg/kg, initiated 1 day after tumor cell inoculation, resulted in a 33 to 38% increase in lifespan. In contrast, long-term survival rates of 50% or more were achieved in all groups treated with the SM/chol liposomal vincristine formulations at doses of 2, 3 and 4 mg/kg. At the 4 mg/kg dose, eight of ten and nine of ten animals survived past day 60 when treated with SM/chol liposomal vincristine prepared at the 0.05 and 0.1 drug/lipid ratios, respectively. Conclusions: Overall, increased and prolonged plasma concentrations of vincristine achieved by liposomal encapsulation were correlated with dramatically increased antitumor activity in comparison with the unencapsulated drug, but no correlations could be established between pharmacokinetic parameters and toxicity.