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PSMA-Targeted Nanoparticles with PI3K/mTOR Dual Inhibitor Downregulate P-Glycoprotein and Inactivate Myeloid-Derived

Lu Yin1,2, Feiya Yang1,2, Wenkuan Wang1,2

  • 1Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P. R. China.

Advanced Materials (Deerfield Beach, Fla.)
|April 21, 2025
PubMed

Insights

New nanoparticles targeting prostate cancer (PC) can overcome drug resistance and improve chemotherapy and immunotherapy. This approach inhibits the PI3K/mTOR pathway, enhancing treatment efficacy for advanced prostate cancer.

Area of Science:

  • Oncology
  • Nanomedicine
  • Drug Delivery

Background:

  • Acquired drug resistance and immunosuppressive tumor microenvironment limit advanced prostate cancer treatment.
  • Targeting the PI3K/mTOR pathway shows promise for enhancing chemotherapy and immunotherapy sensitivity.

Purpose of the Study:

  • To develop glutathione (GSH)-sensitive nanoparticles (PSMA-NP/BEZ) targeting prostate-specific membrane antigen (PSMA) for advanced prostate cancer.
  • To evaluate the efficacy of PSMA-NP/BEZ in combination with paclitaxel and immunotherapy.

Main Methods:

  • PSMA-NP/BEZ nanoparticles loaded with PI3K/mTOR dual inhibitor prodrug BEZ235 were synthesized.
  • BEZ235 release was triggered by elevated GSH levels in prostate cancer tissues.
  • The combination therapy's effects on drug efflux, immune microenvironment, and therapeutic efficacy were assessed.

Main Results:

  • PSMA-NP/BEZ inhibited the PI3K/AKT/mTOR pathway, affecting cell proliferation, DNA repair, and protein synthesis.
  • Combination with paclitaxel reduced P-glycoprotein expression, enhancing chemosensitivity.
  • PSMA-NP/BEZ modulated myeloid-derived suppressor cells and improved the immune microenvironment, boosting immunotherapy.

Conclusions:

  • PSMA-NP/BEZ nanoparticles represent a promising strategy to overcome resistance in advanced prostate cancer.
  • This approach enhances both chemotherapy and immunotherapy efficacy, potentially leading to long-term immune memory.
Keywords:
PI3K/mTOR inhibitorP‐glycoproteindrug resistancemyeloid‐derived suppressor cellsnanoparticlesprostate‐specific membrane antigen

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