Design, Synthesis, and In Vitro Evaluation of a PSMA-Targeted Doxorubicin Conjugate

Area of Science:

• Oncology
• Medicinal Chemistry
• Computational Chemistry

Background:

• Prostate cancer treatment, especially metastatic castration-resistant prostate cancer (mCRPC), relies on targeting prostate-specific membrane antigen (PSMA).
• Small molecule-drug conjugates (SMDCs) combining PSMA ligands with chemotherapy are promising targeted therapeutics.

Purpose of the Study:

• To design and evaluate novel PSMA-targeting small molecule-drug conjugates (SMDCs) for prostate cancer therapy.
• To synthesize and characterize a new PSMA-Dox conjugate for selective cancer cell targeting and cytotoxicity.

Main Methods:

• In silico analysis of 39 designed ligands using molecular docking and dynamics simulations.
• Synthesis of the lead compound conjugated with doxorubicin via an acid-labile imine linkage.
• In vitro evaluation of the PSMA-Dox conjugate in PSMA-positive and -negative prostate cancer cell lines, including cell cycle analysis.

Main Results:

• Identification of optimal ligand structures through computational screening.
• Successful synthesis of a novel PSMA-Dox conjugate.
• Demonstrated selective binding and cytotoxicity of the conjugate towards PSMA-positive cancer cells (LNCaP, C4-2) compared to PSMA-negative cells (PC3).
• Confirmation of apoptosis induction in PSMA-positive cells via cell cycle analysis.

Conclusions:

• A novel SMDC targeting PSMA has been successfully designed, synthesized, and validated.
• The PSMA-Dox conjugate exhibits promising selective anticancer efficacy against PSMA-positive prostate cancer cells.
• This study provides a foundation for developing advanced SMDCs with improved targeting and therapeutic potential for prostate cancer.