Abstract
Proteolysis targeting chimeras (PROTACs) have emerged as revolutionary anticancer therapeutics that degrade disease-causing proteins. However, the anticancer performance of PROTACs is often impaired by their insufficient bioavailability, unsatisfactory tumor specificity and ability to induce acquired drug resistance. Herein, we propose a polymer-conjugated PROTAC prodrug platform for the tumor-targeted delivery of the most prevalent von Hippel–Lindau (VHL)- and cereblon (CRBN)-based PROTACs, as well as for the precise codelivery of a degrader and conventional small-molecule drugs. The self-assembling PROTAC prodrug nanoparticles (NPs) can specifically target and be activated inside tumor cells to release the free PROTAC for precise protein degradation. The PROTAC prodrug NPs caused more efficient regression of MDA-MB-231 breast tumors in a mouse model by degrading bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinase 9 (CDK9) with decreased systemic toxicity. In addition, we demonstrated that the PROTAC prodrug NPs can serve as a versatile platform for the codelivery of a PROTAC and chemotherapeutics for enhanced anticancer efficiency and combination benefits. This study paves the way for utilizing tumor-targeted protein degradation for precise anticancer therapy and the effective combination treatment of complex diseases.
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Acknowledgements
# These authors contributed equally to this study. Financial supports from the National Natural Science Foundation of China (22074043, U22A20328, 22177120), Science and Technology Commission of Shanghai Municipality (20430711800 and 23ZR1475000), the Sino German Workshop grant (W-0005, LMU/Fudan U) were appreciated. The Mass Spectrometry System and the cell sorter BD Influx of the National Facility for Protein Science in Shanghai (NFPS), Shanghai Advanced Research Institute, CAS are gratefully acknowledged. All animal procedures were carried out under the guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of Shanghai Institute of Materia Medica, CAS.
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ZFZ, LY, HJN, JG: Investigation, Methodology, Formal analysis, and Preparation of the original draft; SML, YL: Investigation; FZ, EW: Writing-review & editing; XHC, ZAX, HJY: Investigation, Methodology, Writing-review & editing, Funding acquisition, Supervision, and Project administration. All authors have approved the final version of the manuscript.
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Zou, Zf., Yang, L., Nie, Hj. et al. Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01266-z
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DOI: https://doi.org/10.1038/s41401-024-01266-z