It is almost four decades since N-(2-hydroxypropyl)methacrylamide (HPMA)-based copolymers arose as drug carriers. Although fundamentals have been established and significant advantages have been proved, the commercialization of this platform technology was hampered due to modest outcome of clinical trial initiated with PK1, the symbol of first generation polymer-drug conjugates. In this review, we illustrate the exciting progress and approaches offered by more effective 2nd generation HPMA-based polymer-drug conjugates in cancer treatment. For example, a new synthetic strategy endorses inert HPMA polymer with biodegradability, which permitted to prepare high molecular weight HPMA-drug conjugates with simple linear architecture while maintaining good biocompatibility. As expected, extended long-circulating pharmacokinetics and enhanced antitumor activities were achieved in several preclinical investigations. In addition, greater inhibition of tumor growth in combination regimes exhibits the remarkable capability and flexibility of HPMA-based macromolecular therapeutics. The review also discusses the main challenges and strategies for further translation development of 2nd generation HPMA-based polymer-drug conjugates.

自N以来已经快40年了出现了基于-（2-羟丙基）甲基丙烯酰胺（HPMA）的共聚物作为药物载体。尽管已经建立了基础并已证明了显着的优势，但是由于以PK1（第一代聚合物-药物缀合物的象征）启动的临床试验的适度结果，该平台技术的商业化受到了阻碍。在这篇综述中，我们说明了更有效的第二代基于HPMA的聚合物-药物偶联物在癌症治疗中提供的令人兴奋的进展和方法。例如，一种新的合成策略认可了具有生物可降解性的惰性HPMA聚合物，该聚合物可以制备具有简单线性结构的高分子量HPMA-药物偶联物，同时保持良好的生物相容性。不出所料 在一些临床前研究中获得了延长的长循环药代动力学和增强的抗肿瘤活性。另外，在组合方案中对肿瘤生长的更大抑制表现出基于HPMA的大分子疗法的显着能力和灵活性。该评论还讨论了第二代基于HPMA的聚合物-药物缀合物进一步翻译开发的主要挑战和策略。