PSMA-Oriented Target Delivery of Novel Anticancer Prodrugs: Design, Synthesis, and Biological Evaluations of Oligopeptide-Camptothecin Conjugates.

Clinical applications of camptothecin () have been heavily hindered due to its non-targeted toxicity, active lactone ring instability, and poor water solubility. Targeted drug delivery systems may offer the possibility to overcome the above issues as reported. In this research, a series of prostate-specific membrane antigen (PSMA)-activated prodrugs were designed and synthesized by coupling water-soluble pentapeptide, a PSMA hydrolyzing substrate, to through an appropriate linker. The cytotoxicity of prodrugs was masked temporarily until they were hydrolyzed by the PSMA present within the tumor sites, which restored cytotoxicity. The in vitro selective cytotoxic activities of the prodrugs were evaluated against PSMA-expressing human prostate cancer cells LNCaP-FGC and non-PSMA-expressing cancer cells HepG2, Hela, MCF-7, DU145, PC-3 and normal cells MDCK, LO2 by standard methylthiazol tetrazolium (MTT) assay. Most of the newly synthesized prodrugs showed excellent selective toxicity to PSMA-producing prostate cancer cells LNCaP-FGC with improved water solubility. From among the library, showed the best cytotoxic selectivity between the PSMA-expressing and the non-PSMA-expressing cancer cells. For example, the cytotoxicity of (IC = 1.00 ± 0.20 µM) against LNCaP-FGC (PSMA⁺) was 40-fold, 40-fold, 21-fold, 5-fold and 40-fold, respectively, higher than that against the non-PSMA-expressing cells HepG2 (IC > 40.00 µM), Hela (IC > 40.00 µM), MCF-7 (IC = 21.68 ± 4.96 µM), DU145 (IC = 5.40 ± 1.22 µM), PC-3 (IC = 42.96 ± 3.69 µM) cells. Moreover, exhibited low cytotoxicity (IC > 40 μM) towards MDCK and LO2 cells. The cellular uptake experiment demonstrated the superior PSMA-targeting ability of the , which was significantly accumulated in LNCaP-FGC (PSMA⁺), while it was minimized in HepG2 (PSMA) cells. Further cell apoptosis analyses indicated that it showed a dramatically higher apoptosis-inducing activity in LNCaP-FGC (PSMA⁺) cells than in HepG2 (PSMA) cells. Cell cycle analysis indicated that could induce cell cycle arrest at the S phase.