Webb M S, Harasym T O, Masin D, Bally M B, Mayer L D
Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, Canada.
Br J Cancer. 1995 Oct;72(4):896-904. doi: 10.1038/bjc.1995.430.
This study reports on the development of a liposomal formulation of vincristine with significantly enhanced stability and biological properties. The in vitro and in vivo pharmacokinetic, tumour delivery and efficacy properties of liposomal vincristine formulations based on sphingomyelin (SM) and cholesterol were compared with liposomes composed of distearoylphosphatidylcholine (DSPC) and cholesterol. SM/cholesterol liposomes had significantly greater in vitro stability than did similar DSPC/cholesterol liposomes. SM/cholesterol liposomes also had significantly improved biological properties compared with DSPC/cholesterol. Specifically, SM/cholesterol liposomes administered intravenously retained 25% of the entrapped vincristine after 72 h in the circulation, compared with 5% retention in DSPC/cholesterol liposomes. The improved retention properties of SM/cholesterol liposomes resulted in plasma vincristine levels 7-fold higher than in DSPC/cholesterol liposomes. The improved circulation lifetime of vincristine in SM/cholesterol liposomes correlated with increased vincristine accumulation in peritoneal ascitic murine P388 tumours and in subcutaneous solid A431 human xenograft tumours. Increased vincristine delivery to tumours was also accompanied by increased anti-tumour efficacy. Treatment with SM/cholesterol liposomal formulations of vincristine resulted in greater than 50% cures in mice bearing ascitic P388 tumours, an activity that could not be achieved with the DSPC/cholesterol formulation. Similarly, treatment of mice with severe combined immunodeficiency (SCID) bearing solid human A431 xenograft tumours with SM/cholesterol vincristine formulations delayed the time required for 100% increase in tumour mass to > 40 days, compared with 5 days, 7 days and 14 days for mice receiving no treatment or treatment with free vincristine or DSPC/cholesterol formulations of vincristine respectively.
本研究报告了一种长春新碱脂质体制剂的研发情况，该制剂具有显著增强的稳定性和生物学特性。将基于鞘磷脂（SM）和胆固醇的长春新碱脂质体制剂的体外和体内药代动力学、肿瘤递送及疗效特性，与由二硬脂酰磷脂酰胆碱（DSPC）和胆固醇组成的脂质体进行了比较。SM/胆固醇脂质体在体外的稳定性明显高于类似的DSPC/胆固醇脂质体。与DSPC/胆固醇脂质体相比，SM/胆固醇脂质体的生物学特性也有显著改善。具体而言，静脉注射的SM/胆固醇脂质体在循环72小时后，仍保留25%包封的长春新碱，而DSPC/胆固醇脂质体的保留率为5%。SM/胆固醇脂质体保留特性的改善，使血浆长春新碱水平比DSPC/胆固醇脂质体高7倍。长春新碱在SM/胆固醇脂质体中循环寿命的延长，与长春新碱在腹膜腹水小鼠P388肿瘤和皮下实体A431人异种移植肿瘤中的蓄积增加相关。长春新碱向肿瘤的递送增加，也伴随着抗肿瘤疗效的提高。用长春新碱的SM/胆固醇脂质体制剂治疗，使携带腹水P388肿瘤的小鼠治愈率超过50%，而DSPC/胆固醇制剂无法达到这一活性。同样，用SM/胆固醇长春新碱制剂治疗患有严重联合免疫缺陷（SCID）且携带实体人A431异种移植肿瘤的小鼠，使肿瘤质量增加100%所需的时间延迟至>40天，而未治疗或接受游离长春新碱或长春新碱的DSPC/胆固醇制剂治疗的小鼠分别为5天、7天和14天。
