Advances in non-radioactive PSMA-targeted small molecule-drug conjugates in the treatment of prostate cancer

[Display omitted] •PSMA is a promising biological target for advanced PCa drug delivery.•Non-radioactive PSMA-targeted SMDCs show promising properties in both in vitro and in vivo evaluations, leading to better anti-tumor effects.•Structure-activity relationship and pharmacokinetics of Non-radioactive PSMA-targeted SMDCs was discussed. Most patients with advanced prostate cancer (PCa) will develop metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy, at this time the tumor enters the end stage, and the clinical treatment is very complicated, which requires rationalization of drugs to prolong the life of patients while improving their quality of life. Prostate-specific membrane antigen (PSMA) is a promising biological target for drug delivery in mCRPC due to its high level of specific expression in PCa cell membranes and low expression in normal tissues. Non-radioactive PSMA-targeted small molecule-drug conjugates (SMDCs) are gradually becoming a heat of discovery due to their good affinity and specificity; simple synthesis steps and transport management methods. Non-radioactive PSMA-targeted SMDCs under investigation can be divided into two categories: SMDCs and dual-ligand coupled drugs, among which SMDCs are the most widespread form of this type of conjugate. SMDCs have three key components: cytotoxic load, linker, and small molecule targeting ligands. SMDCs are internalized into the cell after binding to PSMA on the cell membrane and stored in endosomes and lysosomes, where they are usually enzymatically cleaved to allow precise release of cytotoxic molecules and uniform diffusion into the tumor tissue. More than a dozen non-radioactive PSMA-targeted SMDCs have been developed, many of which have shown favorable properties in both in vitro and in vivo evaluations, demonstrating more favorable results than unmodified cytotoxic drugs. Therefore, non-radioactive PSMA-targeted SMDCs have great therapeutic potential for mCRPC as a form of targeted therapy.