Synthesis of a macromolecular camptothecin conjugate with dual phase drug release.
Synthesis of a macromolecular camptothecin conjugate with dual phase drug release.
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DOI：
10.1021/mp0499306
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发表时间：
2004-08
影响因子：
4.9
通讯作者：
A. Yurkovetskiy;A. Hiller;S. Syed;M. Yin;X. Lu;A. Fischman;M. Papisov
中科院分区：
文献类型：
--
作者：
A. Yurkovetskiy;A. Hiller;S. Syed;M. Yin;X. Lu;A. Fischman;M. Papisov
以分子量为60 kDa的可生物降解的亲水性"隐形"聚缩醛-聚（1-羟甲基乙烯基羟甲基缩甲醛）为原料，制备了一种具有双相水解释药机制的喜树碱水溶性大分子偶联物。琥珀酰氨基-甘氨酸酯用作前药释放基团。CPT含量为7.5%w/w的模型制剂是水溶性的。亲脂性喜树碱前药喜树碱-（O20）-琥珀酰亚胺甘氨酸盐在啮齿动物血浆中从偶联物中释放，t（1/2）= 2.2 +/-0.1 h。通过CPT测量的啮齿动物模型中的血液清除率为释放受限，t（1/2）= 2.1 +/-0.2 h，而结合物半衰期为14.2 +/-1.7 h。在异种移植肿瘤模型中，在低于等毒性剂量下，缀合物表现出比CPT更高的抗肿瘤功效。这种改善的治疗窗口与改良的药物药代动力学和稳定的亲脂性前药形式的喜树碱释放一致。通过接头结构修饰调节前药释放和水解速率将为进一步改善药代动力学和药效学开辟道路。
A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t(1/2) = 2.2 +/- 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t(1/2) = 2.1 +/- 0.2 h, while the conjugate half-life was 14.2 +/- 1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics.