School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK.
Adv Drug Deliv Rev. 2009 Nov 12;61(13):1131-48. doi: 10.1016/j.addr.2009.05.007. Epub 2009 Aug 20.
The concept of polymer-drug conjugates was proposed more than 30 years ago, and an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugate of doxorubicin covalently bound to the polymer backbone by a Gly-Phe-Leu-Gly peptidyl linker (FCE28068) became the first synthetic polymer-based anticancer conjugate to enter clinical trial in 1994. This conjugate arose from rational design attempting to capitalise on passive tumour targeting by the enhanced permeability and retention effect and, at the cellular level, lysosomotropic drug delivery to improve therapeutic index. Early clinical results were promising, confirming activity in chemotherapy refractory patients and the safety of HPMA as a new polymer platform. Subsequent Phase I/II trials have investigated an HPMA copolymer-based conjugate containing a doxorubicin and additionally galactose as a targeting moiety to promote liver targeting (FCE28069), and also HPMA copolymer conjugates of paclitaxel (PNU 166945), camptothecin (PNU 166148) and two platinates (AP5280 and AP5346- ProLindac). The preclinical and clinical observations made in these, and clinical studies with other polymer conjugates, should shape the development of next generation anticancer polymer therapeutics.
聚合物-药物偶联物的概念早在 30 多年前就被提出了，阿霉素通过甘氨酰-苯丙氨酰-亮氨酰-甘氨酸肽连接子共价结合到聚合物主链上的 N-(2-羟丙基)甲基丙烯酰胺（HPMA）共聚物偶联物（FCE28068）于 1994 年成为第一个进入临床试验的基于合成聚合物的抗癌偶联物。该偶联物源于合理设计，试图利用增强的通透性和保留效应进行被动肿瘤靶向，并在细胞水平上通过溶酶体靶向药物递送来提高治疗指数。早期的临床结果令人鼓舞，证实了在化疗耐药患者中的活性以及 HPMA 作为新型聚合物平台的安全性。随后的 I/II 期试验研究了一种含有阿霉素和半乳糖作为靶向部分以促进肝脏靶向的 HPMA 共聚物缀合物（FCE28069），以及紫杉醇（PNU 166945）、喜树碱（PNU 166148）和两种铂配合物（AP5280 和 AP5346-ProLindac）的 HPMA 共聚物缀合物。这些药物的临床前和临床观察结果，以及其他聚合物缀合物的临床研究，应该为下一代抗癌聚合物治疗药物的开发提供参考。
