Polymer-bound camptothecin: initial biodistribution and antitumour activity studies
Polymer-bound camptothecin: initial biodistribution and antitumour activity studies
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DOI：
10.1016/s0168-3659(99)00243-6
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发表时间：
2000-03-01
影响因子：
10.8
通讯作者：
Suarato, A
中科院分区：
文献类型：
--
作者：
Caiolfa, VR;Zamai, M;Suarato, A
喜树碱 (CPT) 是一种有效的抗肿瘤药物，主要通过抑制细胞周期 S 期的拓扑异构酶 I 发挥作用。尽管其抗肿瘤活性令人印象深刻，但临床开发因不可预测的毒性事件而停止。合成了两种可溶性 N-(2-羟丙基)甲基丙烯酰胺 (HPMA) 共聚物，其中含有 CPT（5 wt.% 和 10 wt.%）。 CPT 通过 Gly-Phe-Leu-Gly- 间隔基在其 α-羟基处与聚合物共价连接。在体外，喜树碱结合物在血浆中与在中性 pH 缓冲液中（0.2-0.4% 游离喜树碱/小时）一样对水解具有相当的抵抗力，而弹性蛋白酶和半胱氨酸蛋白酶能够释放活性药物。静脉注射喜树碱结合物后小鼠的血浆水平证实了血浆中的适度水解。血浆水平比在经典载体中施用最高耐受剂量的 CPT 时观察到的水平低 5 倍。静脉注射[H-3]CPT-缀合物和游离[H-3]CPT后，在携带HT29人结肠癌的小鼠中进行生物分布。仅在 [H-3]CPT 缀合物治疗后，肿瘤中的放射性吸收才明显。对携带 HT29 的小鼠重复静脉注射喜树碱 (CPT) 缀合物，可抑制 90% 以上的肿瘤，部分肿瘤完全消退，并且没有中毒性死亡。第一个聚(HPMA)-喜树碱缀合物对HT29人结肠癌异种移植物的药理学特性的改善可能归因于它们在肿瘤内的长时间保留和活性药物的持续释放。 (C) 2000 Elsevier Science B.V. 保留所有权利。
Camptothecin (CPT) is a potent, antitumour drug acting mainly through inhibition of topoisomerase I during the S-phase of the cell cycle. Despite its impressive antitumour activity, clinical development was halted for unpredictable toxic events. Two soluble N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers were synthesised to contain CPT (5 wt.% and 10 wt.%). CPT was covalently linked at its alpha-hydroxyl group to the polymers through a Gly-Phe-Leu-Gly- spacer. In-vitro, CPT-conjugates were fairly resistant to hydrolysis in plasma as in buffer at neutral pH (0.2-0.4% Free CPT/h), while elastase and cysteine-proteases were able to release the active drug. Plasma levels in mice after intravenous administration of CPT-conjugates confirmed the modest hydrolysis in plasma. Plasma levels were similar to 5-fold lower than those observed at the highest tolerated dose of CPT administered in classical vehicles. Biodistribution in HT29 human colon carcinoma bearing mice was carried out after i.v, injection of [H-3]CPT-conjugate and free [H-3]CPT. Radioactivity uptake in tumour was evident only after [H-3]CPT-conjugate treatment. Repeated intravenous administration of CPT-conjugates to HT29-bearing mice gave more than 90% tumour inhibition, some complete tumour regressions and no toxic deaths. The improved pharmacological profile on HT29 human colon carcinoma xenografts of the first poly(HPMA)-CPT conjugates might be ascribed to their prolonged intra-tumour retention and sustained release of the active drug. (C) 2000 Elsevier Science B.V. All rights reserved.