Issue 15, 2022

Stimulus-responsive self-assembled prodrugs in cancer therapy

Abstract

Small-molecule prodrugs have become the main toolbox to improve the unfavorable physicochemical properties of potential therapeutic compounds in contemporary anti-cancer drug development. Many approved small-molecule prodrugs, however, still face key challenges in their pharmacokinetic (PK) and pharmacodynamic (PD) properties, thus severely restricting their further clinical applications. Self-assembled prodrugs thus emerged as they could take advantage of key benefits in both prodrug design and nanomedicine, so as to maximize drug loading, reduce premature leakage, and improve PK/PD parameters and targeting ability. Notably, temporally and spatially controlled release of drugs at cancerous sites could be achieved by encoding various activable linkers that are sensitive to chemical or biological stimuli in the tumor microenvironment (TME). In this review, we have comprehensively summarized the recent progress made in the development of single/multiple-stimulus-responsive self-assembled prodrugs for mono- and combinatorial therapy. A special focus was placed on various prodrug conjugation strategies (polymer–drug conjugates, drug–drug conjugates, etc.) that facilitated the engineering of self-assembled prodrugs, and various linker chemistries that enabled selective controlled release of active drugs at tumor sites. Furthermore, some polymeric nano-prodrugs that entered clinical trials have also been elaborated here. Finally, we have discussed the bottlenecks in the field of prodrug nanoassembly and offered potential solutions to overcome them. We believe that this review will provide a comprehensive reference for the rational design of effective prodrug nanoassemblies that have clinic translation potential.

Graphical abstract: Stimulus-responsive self-assembled prodrugs in cancer therapy

Article information

Article type
Review Article
Submitted
16 Feb 2022
Accepted
17 Mar 2022
First published
18 Mar 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2022,13, 4239-4269

Stimulus-responsive self-assembled prodrugs in cancer therapy

X. Dong, R. K. Brahma, C. Fang and S. Q. Yao, Chem. Sci., 2022, 13, 4239 DOI: 10.1039/D2SC01003H

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