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Updated: Aug 16, 2025
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Published on: March 6, 2018
Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone
Aleksei E Machulkin1, Ekaterina A Nimenko1, Nikolay U Zyk1
1Chemistry Department, Lomonosov Moscow State University, Leninskie Gory, Building 1/3, GSP-1, 119991 Moscow, Russia.
Abstract:
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 µM 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.
Insights
A novel PSMA-targeted abiraterone conjugate (PSMA-Abi) shows preferential efficacy against prostate cancer cells with reduced toxicity compared to standard treatment. This targeted approach offers a promising alternative for androgen deprivation therapy side effects.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Prostate cancer is a leading cancer in men, often treated with androgen deprivation therapy (ADT).
- ADT causes significant side effects, necessitating improved treatment strategies.
- Targeted drug delivery to prostate cancer cells offers a potential solution to enhance efficacy and minimize toxicity.
Purpose of the Study:
- To synthesize and evaluate a novel small-molecule PSMA-targeted conjugate based on abiraterone.
- To assess the cytotoxicity, reactive oxygen species induction, and P450-cytochrome inhibition of the PSMA-abiraterone conjugate.
- To determine the in vivo efficacy and toxicity profile of the conjugate in prostate cancer models.
Main Methods:
- Synthesis of a novel PSMA-targeted abiraterone conjugate (PSMA-Abi).
- In vitro assessment of cytotoxicity on prostate cancer and fibroblast cell lines.
- Evaluation of intracellular reactive oxygen species and P450-cytochrome inhibition.
- In vivo efficacy study using PSMA-expressing 22Rv1 xenografts in mice with oral administration of PSMA-Abi.
Main Results:
- The PSMA-abiraterone conjugate demonstrated preferential cytotoxicity towards prostate tumor cells, with no activity in human fibroblasts up to 100 µM.
- Significant tumor growth inhibition (65%) was observed in PSMA-positive 22Rv1 xenografts after repeated oral administration of PSMA-Abi.
- The novel conjugate exhibited comparable efficacy to AbiAc but with significantly reduced acute toxicity.
Conclusions:
- PSMA-targeted abiraterone conjugate (PSMA-Abi) is a promising therapeutic agent for prostate cancer.
- Targeted delivery enhances efficacy and reduces systemic toxicity compared to conventional abiraterone acetate (AbiAc).
- This conjugate represents a potential advancement in managing prostate cancer by overcoming ADT-related side effects.
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