Mayer L D, Masin D, Nayar R, Boman N L, Bally M B
British Columbia Cancer Agency, Division of Medical Oncology, Vancouver, Canada.
Br J Cancer. 1995 Mar;71(3):482-8. doi: 10.1038/bjc.1995.98.
Vincristine pharmacokinetic, tumour uptake and therapeutic characteristics were investigated here in order to elucidate the processes underlying the enhanced efficacy observed for vincristine entrapped in small (120 nm) distearoylphosphatidylcholine/cholesterol liposomes. Plasma vincristine levels after intravenous (i.v.) injection are elevated more than 100-fold in the liposomal formulation compared with free drug in tumour-bearing as well as non-tumour-bearing mice over 24 h. Biodistribution studies demonstrate that the extent and duration of tumour exposure to vincristine is dramatically improved when the drug is administered i.v. in liposomal form. Specifically, 72 h trapezoidal area under the curve values for liposomal vincristine in the murine L1210 ascitic and B16/BL6 solid tumours are 12.9- to 4.1-fold larger, respectively, than observed for free drug. Similar to previous results with the L1210 model, increased drug delivery to the B16 tumour results in significant inhibition of tumour growth, whereas no anti-tumour activity is observed with free vincristine. Comparisons of drug and liposomal lipid accumulation in tumour and muscle tissue indicate that the enhanced efficacy of liposomal vincristine is related predominantly to drug delivered by liposomes to the tumour site rather than drug released from liposomes in the circulation. Consequently, improvements in liposomal vincristine formulations must focus on factors that increase uptake of liposomes into tumour sites as well as enhance liposomal drug retention in the circulation.
本文研究了长春新碱的药代动力学、肿瘤摄取及治疗特性，以阐明包裹于小尺寸（120nm）二硬脂酰磷脂酰胆碱/胆固醇脂质体中的长春新碱疗效增强的潜在机制。与游离药物相比，在荷瘤及非荷瘤小鼠中，静脉注射脂质体制剂后24小时内血浆长春新碱水平升高超过100倍。生物分布研究表明，当以脂质体形式静脉给药时，肿瘤接触长春新碱的程度和持续时间显著改善。具体而言，脂质体长春新碱在小鼠L1210腹水瘤和B16/BL6实体瘤中的72小时曲线下梯形面积值分别比游离药物大12.9至4.1倍。与之前L1210模型的结果相似，向B16肿瘤增加药物递送可显著抑制肿瘤生长，而游离长春新碱未观察到抗肿瘤活性。肿瘤和肌肉组织中药物及脂质体脂质积累的比较表明，脂质体长春新碱疗效增强主要与脂质体递送至肿瘤部位的药物有关，而非循环中脂质体释放的药物。因此，脂质体长春新碱制剂的改进必须关注增加脂质体摄取到肿瘤部位以及增强脂质体药物在循环中的保留的因素。
