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Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy

Acta Pharmacologica Sinica (2024)Cite this article

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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Fig. 1: Schematic illustration of the reduction-activatable PROTAC prodrug NPs for tumor-targeted delivery and anticancer therapy.
Fig. 2: Synthesis and characterization of reduction-activatable BRD4 PROTAC prodrug and construction of prodrug NPs.
Fig. 3: CRGDK-functionalized RPG7 NPs significantly increased uptake of MDA-MB-231 cells and remarkably increased tumor distribution of ARV-771 in MDA-MB-231 tumor-bearing mouse in vivo.
Fig. 4: Antitumor efficiency of RPG7 PROTAC prodrug NPs in the MDA-MB-231 TNBC tumor-bearing BALB/c nude mice.
Fig. 5: Synthesis and characterization of the reduction-activatable CDK9 PROTAC prodrug.
Fig. 6: Antitumor efficiency of RPGD43 PROTAC prodrug NPs in the MDA-MB-231 TNBC tumor-bearing BALB/c nude mice.
Fig. 7: Antitumor efficiency of DOX-loaded PROTAC prodrug NPs in MDA-MB-231 TNBC tumor bearing mice model.

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References

  1. Sun X, Gao H, Yang Y, He M, Wu Y, Song Y, et al. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019;4:64.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Toure M, Crews CM. Small-molecule PROTACS: new approaches to protein degradation. Angew Chem Int Ed Engl. 2016;55:1966–73.

    Article  CAS  PubMed  Google Scholar 

  3. Liu J, Ma J, Liu Y, Xia J, Li Y, Wang ZP, et al. PROTACs: a novel strategy for cancer therapy. Semin Cancer Biol. 2020;67:171–9.

    Article  CAS  PubMed  Google Scholar 

  4. Lai AC, Crews CM. Induced protein degradation: an emerging drug discovery paradigm. Nat Rev Drug Discov. 2017;16:101–14.

    Article  CAS  PubMed  Google Scholar 

  5. Li X, Song Y. Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy. J Hematol Oncol. 2020;13:50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Burslem GM, Crews CM. Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell. 2020;181:102–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Luh LM, Scheib U, Juenemann K, Wortmann L, Brands M, Cromm PM. Prey for the proteasome: targeted protein degradation-a medicinal chemist’s perspective. Angew Chem Int Ed Engl. 2020;59:15448–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Popovic D, Vucic D, Dikic I. Ubiquitination in disease pathogenesis and treatment. Nat Med. 2014;20:1242–53.

    Article  CAS  PubMed  Google Scholar 

  9. Chamberlain PP, Hamann LG. Development of targeted protein degradation therapeutics. Nat Chem Biol. 2019;15:937–44.

    Article  CAS  PubMed  Google Scholar 

  10. Dale B, Cheng M, Park KS, Kaniskan HU, Xiong Y, Jin J. Advancing targeted protein degradation for cancer therapy. Nat Rev Cancer. 2021;21:638–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Noblejas-Lopez MDM, Nieto-Jimenez C, Burgos M, Gomez-Juarez M, Montero JC, Esparis-Ogando A, et al. Activity of BET-proteolysis targeting chimeric (PROTAC) compounds in triple negative breast cancer. J Exp Clin Cancer Res. 2019;38:383.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K, et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem Biol. 2015;22:755–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Minko T. Nanoformulation of BRD4-degrading PROTAC: improving druggability to target the ‘Undruggable’ MYC in pancreatic cancer. Trends Pharmacol Sci. 2020;41:684–6.

    Article  CAS  PubMed  Google Scholar 

  14. Schapira M, Calabrese MF, Bullock AN, Crews CM. Targeted protein degradation: expanding the toolbox. Nat Rev Drug Discov. 2019;18:949–63.

    Article  CAS  PubMed  Google Scholar 

  15. Ocana A, Pandiella A. Proteolysis targeting chimeras (PROTACs) in cancer therapy. J Exp Clin Cancer Res. 2020;39:189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Moreau K, Coen M, Zhang AX, Pachl F, Castaldi MP, Dahl G, et al. Proteolysis-targeting chimeras in drug development: a safety perspective. Br J Pharmacol. 2020;177:1709–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen Y, Tandon I, Heelan W, Wang Y, Tang W, Hu Q. Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation. Chem Soc Rev. 2022;51:5330–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yokoo H, Naito M, Demizu Y. Investigating the cell permeability of proteolysis-targeting chimeras (PROTACs). Expert Opin Drug Discov. 2023;18:357–61.

    Article  PubMed  Google Scholar 

  19. Li J, Chen X, Lu A, Liang C. Targeted protein degradation in cancers: orthodox PROTACs and beyond. Innovation. 2023;4:100413.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Gao J, Yang L, Lei S, Zhou F, Nie H, Peng B, et al. Stimuli-activatable PROTACs for precise protein degradation and cancer therapy. Sci Bull. 2023;68:1069–85.

    Article  CAS  Google Scholar 

  21. Liu J, Chen H, Ma L, He Z, Wang D, Liu Y, et al. Light-induced control of protein destruction by opto-PROTAC. Sci Adv. 2020;6:eaay5154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Reynders M, Matsuura BS, Berouti M, Simoneschi D, Marzio A, Pagano M, et al. PHOTACs enable optical control of protein degradation. Sci Adv. 2020;6:eaay5064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu J, Chen H, Liu Y, Shen Y, Meng F, Kaniskan HU, et al. Cancer selective target degradation by folate-caged PROTACs. J Am Chem Soc. 2021;143:7380–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dragovich PS, Pillow TH, Blake RA, Sadowsky JD, Adaligil E, Adhikari P, et al. Antibody-mediated delivery of chimeric BRD4 degraders. part 1: exploration of antibody linker, payload loading, and payload molecular properties. J Med Chem. 2021;64:2534–75.

    Article  CAS  PubMed  Google Scholar 

  25. Maneiro MA, Forte N, Shchepinova MM, Kounde CS, Chudasama V, Baker JR, et al. Antibody-PROTAC conjugates enable HER2-dependent targeted protein degradation of BRD4. ACS Chem Biol. 2020;15:1306–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. He S, Gao F, Ma J, Ma H, Dong G, Sheng C. Aptamer-PROTAC conjugates (APCs) for tumor-specific targeting in breast cancer. Angew Chem Int Ed Engl. 2021;60:23299–305.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang C, Zeng Z, Cui D, He S, Jiang Y, Li J, et al. Semiconducting polymer nano-PROTACs for activatable photo-immunometabolic cancer therapy. Nat Commun. 2021;12:2934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhang C, He S, Zeng Z, Cheng P, Pu K. Smart nano-PROTACs reprogram tumor microenvironment for activatable photo-metabolic cancer immunotherapy. Angew Chem Int Ed Engl. 2022;61:e202114957.

    Article  CAS  PubMed  Google Scholar 

  29. Gao J, Hou B, Zhu Q, Yang L, Jiang X, Zou Z, et al. Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy. Nat Commun. 2022;13:4318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yang C, Yang Y, Li Y, Ni Q, Li J. Radiotherapy-triggered proteolysis targeting chimera prodrug activation in tumors. J Am Chem Soc. 2023;145:385–91.

    Article  CAS  PubMed  Google Scholar 

  31. Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31–46.

    Article  CAS  PubMed  Google Scholar 

  32. Narayan RS, Molenaar P, Teng J, Cornelissen FMG, Roelofs I, Menezes R, et al. A cancer drug atlas enables synergistic targeting of independent drug vulnerabilities. Nat Commun. 2020;11:2935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jin H, Wang L, Bernards R. Rational combinations of targeted cancer therapies: background, advances and challenges. Nat Rev Drug Discov. 2023;22:213–34.

    Article  CAS  PubMed  Google Scholar 

  34. Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature. 2019;575:299–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, et al. A selective BCL-X(L) PROTAC degrader achieves safe and potent antitumor activity. Nat Med. 2019;25:1938–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Flanagan JJ, Qian Y, Gough SM, Andreoli M, Bookbinder M, Cadelina G, et al. Abstract P5-04-18: ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer. Cancer Res. 2021;81:44.

    Article  Google Scholar 

  37. Cao C, Yang J, Chen Y, Zhou P, Wang Y, Du W, et al. Discovery of SK-575 as a highly potent and efficacious proteolysis-targeting chimera degrader of PARP1 for treating cancers. J Med Chem. 2020;63:11012–33.

    Article  CAS  PubMed  Google Scholar 

  38. Jiang B, Gao Y, Che J, Lu W, Kaltheuner IH, Dries R, et al. Discovery and resistance mechanism of a selective CDK12 degrader. Nat Chem Biol. 2021;17:675–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Vannam R, Sayilgan J, Ojeda S, Karakyriakou B, Hu E, Kreuzer J, et al. Targeted degradation of the enhancer lysine acetyltransferases CBP and p300. Cell Chem Biol. 2021;28:503–14.e12.

    Article  CAS  PubMed  Google Scholar 

  40. Thummuri D, Khan S, Underwood PW, Zhang P, Wiegand J, Zhang X, et al. Overcoming gemcitabine resistance in pancreatic cancer using the BCL-XL-specific degrader DT2216. Mol Cancer Ther. 2022;21:184–92.

    Article  CAS  PubMed  Google Scholar 

  41. He Y, Ju Y, Hu Y, Wang B, Che S, Jian Y, et al. Brd4 proteolysis-targeting chimera nanoparticles sensitized colorectal cancer chemotherapy. J Control Release. 2023;354:155–66.

    Article  CAS  PubMed  Google Scholar 

  42. Li X, Zhang Z, Gao F, Ma Y, Wei D, Lu Z, et al. c-Myc-targeting PROTAC based on a TNA-DNA bivalent binder for combination therapy of triple-negative breast cancer. J Am Chem Soc. 2023;145:9334–42.

    Article  CAS  PubMed  Google Scholar 

  43. Sun B, Luo C, Yu H, Zhang X, Chen Q, Yang W, et al. Disulfide bond-driven oxidation- and reduction-responsive prodrug nanoassemblies for cancer therapy. Nano Lett. 2018;18:3643–50.

    Article  CAS  PubMed  Google Scholar 

  44. Zhang J, Zhang X, Li Z, Wang Q, Shi Y, Jiang X, et al. The miR-124-3p/neuropilin-1 axis contributes to the proliferation and metastasis of triple-negative breast cancer cells and co-activates the TGF-beta pathway. Front Oncol. 2021;11:654672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Feng B, Zhou F, Xu Z, Wang T, Wang D, Liu J, et al. Versatile prodrug nanoparticles for acid-triggered precise imaging and organelle-specific combination cancer therapy. Adv Funct Mater. 2016;26:7431–42.

    Article  CAS  Google Scholar 

  46. Hou B, Zhou L, Wang H, Saeed M, Wang D, Xu Z, et al. Engineering stimuli-activatable boolean logic prodrug nanoparticles for combination cancer immunotherapy. Adv Mater. 2020;32:e1907210.

    Article  PubMed  Google Scholar 

  47. Zhou F, Gao J, Tang Y, Zou Z, Jiao S, Zhou Z, et al. Engineering chameleon prodrug nanovesicles to increase antigen presentation and inhibit PD-L1 expression for circumventing immune resistance of cancer. Adv Mater. 2021;33:e2102668.

    Article  PubMed  Google Scholar 

  48. Zhu Q, Sun F, Li T, Zhou M, Ye J, Ji A, et al. Engineering oxaliplatin prodrug nanoparticles for second near-infrared fluorescence imaging-guided immunotherapy of colorectal cancer. Small. 2021;17:e2007882.

    Article  PubMed  Google Scholar 

  49. Cao C, He M, Wang L, He Y, Rao Y. Chemistries of bifunctional PROTAC degraders. Chem Soc Rev. 2022;51:7066–114.

    Article  CAS  PubMed  Google Scholar 

  50. Wei D, Wang H, Zeng Q, Wang W, Hao B, Feng X, et al. Discovery of potent and selective CDK9 degraders for targeting transcription regulation in triple-negative breast cancer. J Med Chem. 2021;64:14822–14847.

    Article  CAS  PubMed  Google Scholar 

  51. Xie Z, Hou S, Yang X, Duan Y, Han J, Wang Q, et al. Lessons learned from past cyclin-dependent kinase drug discovery efforts. J Med Chem. 2022;65:6356–89.

    Article  CAS  PubMed  Google Scholar 

  52. Zhou F, Feng B, Wang T, Wang D, Cui Z, Wang S, et al. Theranostic prodrug vesicles for reactive oxygen species-triggered ultrafast drug release and local-regional therapy of metastatic triple-negative breast cancer. Adv Funct Mater. 2017;27:1703674.

    Article  Google Scholar 

  53. Ferrari P, Scatena C, Ghilli M, Bargagna I, Lorenzini G, Nicolini A. Molecular mechanisms, biomarkers and emerging therapies for chemotherapy resistant TNBC. Int J Mol Sci. 2022;23:1665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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Author notes

  1. These authors contributed equally: Zhi-feng Zou, Lei Yang, Hui-jun Nie.

Authors and Affiliations

  1. School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China

    Zhi-feng Zou & Zhi-ai Xu

  2. State Key Laboratory of Chemistry Biology & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Zhi-feng Zou, Lei Yang, Jing Gao, Yi Lai & Hai-jun Yu

  3. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Lei Yang, Hui-jun Nie, Shu-min Lei, Hai-jun Yu & Xiao-hua Chen

  4. Department of Chemistry, Fudan University, Shanghai, 20043, China

    Fan Zhang

  5. Department of Pharmacy, Ludwig-Maximilians-Universität, 81377, München, Germany

    Ernst Wagner

  6. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China

    Xiao-hua Chen

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Contributions

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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Correspondence to Jing Gao, Hai-jun Yu, Xiao-hua Chen or Zhi-ai Xu.

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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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