4.6 Article

Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone Conjugate

Journal

MOLECULES
Volume 27, Issue 24, Pages -

Publisher

MDPI
DOI: 10.3390/molecules27248795

Keywords

prostate cancer; abiraterone; drug delivery; prostate-specific membrane antigen

Funding

  1. Russian Science Foundation
  2. Ministry of Education and Science of the Russian Federation [22-15-00098, 03.G25.31.0219]
  3. [22-19-00824]

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In this study, a novel small-molecule PSMA-targeted conjugate PSMA-Abi was synthesized, which showed a preferential effect on prostate tumor cells with minimal side effects.
Prostate cancer is the second most common type of cancer among men. The main method of its treatment is androgen deprivation therapy, which has a wide range of side effects. One of the solutions to this challenge is the targeted delivery of drugs to prostate cancer cells. In this study, we performed the synthesis of a novel small-molecule PSMA-targeted conjugate based on abiraterone. Cytotoxicity, the induction of intracellular reactive oxygen species, and P450-cytochrome species inhibition were investigated for this conjugate PSMA-abiraterone. The conjugate demonstrated a preferential effect on prostate tumor cells, remaining inactive at up to 100 mu M in human fibroblast cells. In addition, it revealed preferential efficacy, specifically on PSMA-expressing lines with a 65% tumor growth inhibition level on 22Rv1 (PSMA+) xenografts after 14-fold oral administration of PSMA-Abi at a single dose of 500 mg/kg (7.0 g/kg total dose) was observed. This compound showed significantly reduced acute toxicity with comparable efficacy compared to AbiAc.

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