From simple delivery to multimodal systems: the critical role of macromolecular platforms in bioorthogonal drug synthesis

Abstract

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 in vivo 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 in situ 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.