Comparative pharmacokinetics, tissue distribution, and therapeutic effectiveness of cisplatin encapsulated in long-circulating, pegylated liposomes (SPI-077) in tumor-bearing mice
Comparative pharmacokinetics, tissue distribution, and therapeutic effectiveness of cisplatin encapsulated in long-circulating, pegylated liposomes (SPI-077) in tumor-bearing mice
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DOI：
10.1007/s002800050855
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发表时间：
1999-01-01
影响因子：
3
通讯作者：
Amantea, MA
中科院分区：
文献类型：
--
作者：
Newman, MS;Colbern, GT;Amantea, MA
目的：在两种小鼠（C26 结肠癌和 Lewis 肺）肿瘤模型中比较长循环聚乙二醇化 (Stealth(R)) 脂质体 (SPI-077) 封装的顺铂与非脂质体顺铂的药代动力学 (PK)、生物分布和治疗效果。方法：III 治疗效果研究，携带鼠 C26 或 Lewis 肺肿瘤的小鼠以多种治疗方案和累积剂量接受多次静脉注射 SPI-077 或顺铂。在 PK 和生物分布研究中，小鼠在接种 10(6) C26 肿瘤细胞后 14 天接受单次静脉推注 3 mg/kg SPI-077 或顺铂。通过石墨炉（无焰）原子吸收分光光度法 (GF-AAS) 分析血浆和组织的总铂 (Pt) 含量。结果：功效研究表明，与相同累积剂量的顺铂相比，SPI-077 具有优越的抗肿瘤活性。当将较低剂量的 SPI-077 与最大耐受剂量的顺铂在 Lewis 肺肿瘤中进行比较时，仅用顺铂剂量的一半即可观察到等效的 SPI-077 抗肿瘤活性。 SPI-077 较高累积剂量的耐受性良好，并且具有增强的抗肿瘤作用。 SPI-077 PK 通过具有非线性（可饱和）消除的一室模型来描述，而顺铂 PK 通过具有线性消除的两室模型来描述。与顺铂相比，SPI-077 的分布容积高出 55 倍，血浆峰浓度高出 3 倍，血浆 AUC 高出 60 倍。此外，与顺铂相比，接受 SPI-077 治疗的动物递送至肾脏（主要毒性靶器官）的 Pt 减少了 4 倍，但肿瘤 AUC 却比顺铂高 28 倍。结论：根据我们的研究结果，将顺铂封装在长循环聚乙二醇化脂质体中克服了其他脂质体顺铂制剂所经历的局限性。 SPI-077具有延长的循环时间和增加的肿瘤Pt分布，在小鼠结肠癌和肺癌模型中其抗肿瘤效果较顺铂显着提高。
Purpose: The pharmacokinetics (PK), biodistribution and therapeutic efficacy of cisplatin encapsulated in long-circulating pegylated (Stealth(R)) liposomes (SPI-077) were compared with those of nonliposomal cisplatin in two murine (C26 colon carcinoma and Lewis lung) tumor models. Methods: III therapeutic effectiveness studies, mice bearing murine C26 or Lewis lung tumors received multiple intravenous doses of SPI-077 or cisplatin in a variety of treatment schedules and cumulative doses. In the PK and biodistribution study, mice received a single intravenous bolus injection of 3 mg/kg of either SPI-077 or cisplatin 14 days after inoculation with 10(6) C26 tumor cells. Plasma and tissues were analyzed for total platinum (Pt) content by graphite furnace (flameless) atomic absorption spectro-photometery (GF-AAS). Results: Efficacy studies showed that SPI-077 had superior antitumor activity compared to the same cumulative dose of cisplatin. When lower doses of SPI-077 were compared to cisplatin at its maximally tolerated dose in Lewis lung tumors, equivalent SPI-077 antitumor activity was seen at only half the cisplatin dose. Higher cumulative doses of SPI-077 were well tolerated and had increased antitumor effect. SPI-077 PK were characterized by a one-compartment model with nonlinear (saturable) elimination, whereas cisplatin PK were described by a two-compartment model with linear elimination. SPI-077 had a 55-fold higher volume of distribution, 3-fold higher peak plasma levels, and a 60-fold larger plasma AUC compared with cisplatin. In addition, SPI-077-treated animals displayed a 4-fold reduction in Pt delivered to the kidneys (primary target organ of toxicity) relative to cisplatin, but a 28-fold higher tumor AUC than cisplatin. Conclusions: Based on the results of our studies, encapsulation of cisplatin in long-circulating pegylated liposomes has overcome limitations experienced with other liposomal cisplatin formulations. SPI-077 has a prolonged circulation time and increased tumor Pt disposition, and its antitumor effect is significantly improved compared to cisplatin in murine colon and lung cancer models.