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

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.

Synthesis and Preclinical Evaluation of Urea-Based Prostate-Specific Membrane Antigen-Targeted Conjugates Labeled with 177Lu

“…The previously known structural motifs of PSMA ligands, which demonstrated a high potential for interaction with PSMA in previous publications, were chosen as the basis for the structural motifs of the synthesized six conjugates with DOTA 13A – 13F in this work. , These ligand conjugates are already well-established for the delivery of fluorescent dyes as well as the therapeutic agents abiraterone, docetaxel, and monomethylauristatin E and as a platform for bimodal conjugates …”

Synthesis of Prostate-Specific Membrane Antigen-Targeted Bimodal Conjugates of Cytotoxic Agents and Antiandrogens and Their Comparative Assessment with Monoconjugates

“…In vitro studies of compounds with MMAE have evaluated the cytotoxicity of both bimodal 13a-d and 15 conjugates and 12a-d precursor compounds. The chosen reference compounds were the previously described monoconjugates with MMAE and Abiraterone (I and II) [33,34], their equimolar mixture (Combo) and the MMAE. The structures of the reference compounds are shown in Figure 5.…”

Optimizing Abiraterone Delivery through Intratumoral In Situ Implant: A Prospective Pharmaceutical Development Approach

“…It is also interesting to study the synthesis of a low molecular weight abiraterone conjugate targeting the prostatespecific antigen membrane. The conjugate showed a preferential effect on prostate tumor cells, reducing prostate-specific membrane antigen expression and acute toxicity with comparable efficacy to abiraterone acetate (35). Nanocrystals, or nanosuspensions, are semi-crystalline structures with an API and surrounding stabilizers (36).…”