PDF(Pubmed)
Abstract：
Prostate cancer is the most prevalent cancer among men in the United States and is a leading cause of cancer-related death. Prostate specific membrane antigen (PSMA) has been established as a biomarker for prostate cancer diagnosis and treatment. This study aimed to develop a novel theranostic agent, PSMA-1-MMAE-Pc413, which integrates a PSMA-targeting ligand, the photosensitizer Pc413, and the microtubular inhibitor monomethyl auristatin E (MMAE) for synergistic therapeutic efficacy. In vitro uptake studies revealed that PSMA-1-MMAE-Pc413 demonstrated selective and specific uptake in PSMA-positive PC3pip cells but not in PSMA-negative PC3flu cells, with the uptake in PC3pip cells being approximately three times higher. In vitro cytotoxicity assays showed that, when exposed to light, PSMA-1-MMAE-Pc413 had a synergistic effect, leading to significantly greater cytotoxicity in PSMA-positive cells (IC50 = 2.2 nM) compared to PSMA-1-Pc413 with light irradiation (IC50 = 164.9 nM) or PSMA-1-MMAE-Pc413 without light irradiation (IC50 = 12.6 nM). In vivo imaging studies further demonstrated the selective uptake of PSMA-1-MMAE-Pc413 in PC3pip tumors. In in vivo studies, PSMA-1-MMAE-Pc413 dramatically improves the therapeutic outcome for prostate cancer by providing a synergistic effect that surpasses the efficacy of each treatment modality alone in PC3pip tumors. These findings suggest that PSMA-1-MMAE-Pc413 has strong potential for clinical application in improving prostate cancer treatment.
摘要：
前列腺癌是美国男性中最普遍的癌症,并且是癌症相关死亡的主要原因。前列腺特异性膜抗原（PSMA）已被确立为前列腺癌诊断和治疗的生物标志物。本研究旨在开发一种新型的治疗仪，PSMA-1-MMAE-Pc413，它整合了一个PSMA靶向配体，光敏剂Pc413和微管抑制剂单甲基奥瑞他汀E（MMAE）具有协同治疗功效。体外摄取研究表明，PSMA-1-MMAE-Pc413在PSMA阳性PC3pip细胞中表现出选择性和特异性摄取，而在PSMA阴性PC3flu细胞中没有。PC3pip细胞的摄取大约高出三倍。体外细胞毒性试验表明,当暴露在光线下时，PSMA-1-MMAE-Pc413具有协同作用，与光照射的PSMA-1-Pc413（IC50=164.9nM）或无光照射的PSMA-1-MMAE-Pc413（IC50=12.6nM）相比，导致PSMA阳性细胞（IC50=2.2nM）的细胞毒性明显更大。体内成像研究进一步证明了PSMA-1-MMAE-Pc413在PC3pip肿瘤中的选择性摄取。在体内研究中，PSMA-1-MMAE-Pc413通过提供超过单独在PC3pip肿瘤中的每种治疗方式的功效的协同作用来显著改善前列腺癌的治疗结果。这些发现表明PSMA-1-MMAE-Pc413在改善前列腺癌治疗方面具有很强的临床应用潜力。
