Synthesis and Preclinical Evaluation of Small-Molecule Prostate-Specific Membrane Antigen-Targeted Abiraterone Conjugate.
Aleksei E MachulkinEkaterina A NimenkoNikolay U ZykAnastasiia A UspenskaiaGalina B SmirnovaIrina I KhanVadim S PokrovskyAlexander N VaneevRoman V TimoshenkoVugara V Mamed-NabizadeMaria V ZavertkinaAlexander ErofeevPeter V GorelkinAlexander G MajougaNikolay V ZykElena S KhazanovaElena K BeloglazkinaPublished in: Molecules (Basel, Switzerland) (2022)
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 .
Keyphrases
- pet ct
- prostate cancer
- small molecule
- pet imaging
- cancer therapy
- reactive oxygen species
- radical prostatectomy
- drug delivery
- positron emission tomography
- protein protein
- endothelial cells
- mycobacterium tuberculosis
- induced apoptosis
- liver failure
- benign prostatic hyperplasia
- stem cells
- oxidative stress
- papillary thyroid
- drug induced
- middle aged
- intensive care unit
- mass spectrometry
- squamous cell
- cell proliferation
- high resolution
- respiratory failure
- replacement therapy
- cell therapy
- hepatitis b virus
- cell death
- extracorporeal membrane oxygenation
- induced pluripotent stem cells
- acute respiratory distress syndrome
- lymph node metastasis