van den Elsen Tieze, Neumann Kevin
Institute for Molecules and Materials, Radboud University, The Netherlands.
J Mater Chem B. 2025 Jul 30;13(30):8953-8974. doi: 10.1039/d5tb01111f.
Targeted drug delivery strategies have emerged as promising solutions to overcome traditional challenges such as poor bioavailability and side effects associated with conventional drug delivery methods. Among these strategies, the use of prodrugs offers a viable approach by leveraging enzymatic or controlled chemical transformations to enhance drug efficacy and specificity. The advent of bioorthogonal chemistry has revolutionized prodrug activation, providing a multitude of activation strategies beyond conventional methods. This review explores the integration of bioorthogonal chemistry, particularly transition metal catalysis, into prodrug activation strategies, with a focus on the use of macromolecular scaffolds as platforms to enable and localize these chemistries in biological environments. Specifically, this review focuses on the growing field of bond-forming synthesis mediated by transition metal catalysts, often enabled by the use of macromolecular platforms. By forming carbon-carbon or carbon-heteroatom bonds intra- or intermolecularly, this approach offers advantages over traditional uncaging strategies through the absence of the pharmacoactive motif in the prodrug. We emphasize the central role of macromolecular platforms in integrating bioorthogonal chemistries into multimodal systems that enable targeting strategies and stimuli-responsive behavior, both crucial for achieving site-specific activation and minimizing off-target effects. We conclude that the future of this field lies with the development of retrosynthetic prodrug design, and the use and development of multimodular macromolecular platforms to host and enable new bioorthogonal transition metal catalysis.
靶向给药策略已成为克服传统挑战（如生物利用度低以及与传统给药方法相关的副作用）的有前景的解决方案。在这些策略中，前药的使用通过利用酶促或可控化学转化来提高药物疗效和特异性，提供了一种可行的方法。生物正交化学的出现彻底改变了前药活化方式，提供了许多超越传统方法的活化策略。本综述探讨了生物正交化学，特别是过渡金属催化，在前药活化策略中的整合，重点是使用大分子支架作为平台，以便在生物环境中实现并定位这些化学反应。具体而言，本综述关注由过渡金属催化剂介导的成键合成这一不断发展的领域，这通常借助大分子平台得以实现。通过分子内或分子间形成碳 - 碳或碳 - 杂原子键，这种方法相对于传统的解笼策略具有优势，因为前药中不存在药理活性基序。我们强调大分子平台在将生物正交化学整合到多模式系统中的核心作用，这些系统能够实现靶向策略和刺激响应行为，这两者对于实现位点特异性活化和最小化脱靶效应都至关重要。我们得出结论，该领域的未来在于逆合成前药设计的发展，以及使用和开发多模块大分子平台来承载并实现新的生物正交过渡金属催化。
