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<p>Castration-resistant prostate cancer demonstrates intrinsic or acquired resistance to second-generation androgen-targeted therapies, posing a challenge in clinical treatment. In this study, on the basis of in vivo self-assembly nanotechnology, we designed a PSMA-targeted nano-PROTAC with a proximity degradation effect. Nano-PROTAC not only precisely degrades the AR receptor but also cleverly degrades the HSP90 that is closely bound to the AR receptor, utilizing the spatial distance self-adaptive characteristics of its nanostructure. In the 22Rv1 cell model, Nano-PROTAC degraded 80% of the AR protein and 65% of the HSP90 protein. More importantly, nano-PROTAC could degrade 74% of the AR splice variant AR-V7 protein, showing the potential ability to overcome drug resistance. We further constructed an enzalutamide-resistant xenograft tumor mouse model to evaluate the therapeutic effect of the Nano-PROTAC. Compared with the combination treatment group of AR and HSP90 inhibitors (enzalutamide and pimitespib), the nano-PROTAC treatment group presented a high tumor growth inhibition value of up to 78% and a median survival extension of 15 days. Nano-PROTACs that simultaneously degrade AR and HSP90 can overcome the resistance of prostate cancer to PSMA- and AR-positive castration-resistant prostate cancer, except for neuroendocrine prostate cancer, which provides a new therapeutic strategy for the treatment of prostate cancer.</p>

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In vivo self-assembled nano-PROTAC for the dual degradation of AR and HSP90 to overcome castration-resistant prostate cancer resistance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月15日

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  • Fei-Ya Yang,
  • Ni-Yuan Zhang,
  • Yang Yang,
  • Dong Chen,
  • Li-Yuan Wu,
  • Wen-Kuan Wang,
  • Hao-Xi Wang,
  • Zhuan Wen,
  • Ming-Ze Cai,
  • Hao-Ze Li,
  • Haojie Huang,
  • Hong-Wei An,
  • Hao Wang,
  • Nian-Zeng Xing

摘要

Castration-resistant prostate cancer demonstrates intrinsic or acquired resistance to second-generation androgen-targeted therapies, posing a challenge in clinical treatment. In this study, on the basis of in vivo self-assembly nanotechnology, we designed a PSMA-targeted nano-PROTAC with a proximity degradation effect. Nano-PROTAC not only precisely degrades the AR receptor but also cleverly degrades the HSP90 that is closely bound to the AR receptor, utilizing the spatial distance self-adaptive characteristics of its nanostructure. In the 22Rv1 cell model, Nano-PROTAC degraded 80% of the AR protein and 65% of the HSP90 protein. More importantly, nano-PROTAC could degrade 74% of the AR splice variant AR-V7 protein, showing the potential ability to overcome drug resistance. We further constructed an enzalutamide-resistant xenograft tumor mouse model to evaluate the therapeutic effect of the Nano-PROTAC. Compared with the combination treatment group of AR and HSP90 inhibitors (enzalutamide and pimitespib), the nano-PROTAC treatment group presented a high tumor growth inhibition value of up to 78% and a median survival extension of 15 days. Nano-PROTACs that simultaneously degrade AR and HSP90 can overcome the resistance of prostate cancer to PSMA- and AR-positive castration-resistant prostate cancer, except for neuroendocrine prostate cancer, which provides a new therapeutic strategy for the treatment of prostate cancer.