Novel Nanococktail of a Dual PI3K/mTOR Inhibitor and Cabazitaxel for Castration-Resistant Prostate Cancer

Yee Huang, Xiangdong Xue, Xiaocen Li, Bei Jia, Chong Xian Pan, Yuanpei Li, Tzu Yin Lin

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Prognosis for castration-resistant prostate cancer (CRPC) is poor, and no effective therapeutic regimen is yet known. The PI3K/Akt/mTOR pathway plays a predominant role and may be a promising molecular target for CRPC. However, the toxicity of the dual PI3K inhibitors in clinical trials limits their clinical efficacy for CRPC. To solve this problem, a highly integrated precision nanomedicine strategy is employed to molecularly and physically target CRPC through enhanced targeted drug delivery efficiency and reduced unwanted side-effects. Gedatolisib (Ge), a potent inhibitor of PI3K/mTOR, is formulated into disulfide cross-linked micelle platform (NanoGe), which exhibits excellent water solubility, small size, excellent stability with redox stimulus-responsive disintegration, and preferential uptake at tumor sites. NanoGe improves the anti-neoplastic effect of free Ge by 53 times in PC-3M cells and 13 times in C4-2B cells, through its enhanced uptake via caveolae- and clathrin-mediated endocytic pathways and the subsequent inhibition of the PI3K/mTOR pathway, resulting in Bax/Bcl-2-dependent apoptosis. In vivo, NanoGe shows superior efficacy than free Ge, and synergizes with nanoformulated cabazitaxel (NanoCa) as a nanococktail format to achieve a cure rate of 83%. Taken together, the results of this study demonstrate the potency of NanoGe in combination with NanoCa against CRPC.

Original languageEnglish (US)
Article number2000075
JournalAdvanced Therapeutics
Volume3
Issue number10
DOIs
StatePublished - Oct 1 2020

Keywords

  • disulfide cross-linked micelles
  • gedatolisib
  • PI3K pathways
  • synergistic antitumor effects

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, medical
  • Pharmacology (medical)
  • Genetics(clinical)
  • Pharmaceutical Science
  • Pharmacology

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