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

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...

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Detalles Bibliográficos
Autores principales: Machulkin, Aleksei E., Nimenko, Ekaterina A., Zyk, Nikolay U., Uspenskaia, Anastasiia A., Smirnova, Galina B., Khan, Irina I., Pokrovsky, Vadim S., Vaneev, Alexander N., Timoshenko, Roman V., Mamed-Nabizade, Vugara V., Zavertkina, Maria V., Erofeev, Alexander, Gorelkin, Petr, Majouga, Alexander G., Zyk, Nikolay V., Khazanova, Elena S., Beloglazkina, Elena K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9783881/
https://www.ncbi.nlm.nih.gov/pubmed/36557929
http://dx.doi.org/10.3390/molecules27248795
Descripción
Sumario: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.