Department of Chemistry, College of Arts and Sciences, Washington State University, Pullman, Washington 99164, United States.
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington 99202, United States.
Biomacromolecules. 2024 Sep 9;25(9):6164-6180. doi: 10.1021/acs.biomac.4c00878. Epub 2024 Aug 20.
Prostate cancer (PC) is the fifth leading cause of cancer-related deaths among men worldwide. Prostate-specific membrane antigen (PSMA), a molecular target of PC, is clinically used for the treatment and diagnosis of PC using radioligand approaches. However, no PSMA-based chemotherapies have yet been approved by the FDA. Here, we present a novel therapeutic approach using PSMA-targeted 2-deoxyglucose-dendrimer (PSMA-2DG-D) for targeted delivery of a potent tyrosine kinase inhibitor, cabozantinib (Cabo), selectively to PC cells. PSMA-2DG-D demonstrates intracellular localization in PSMA (+) PC cells through PSMA-mediated internalization. This PSMA-specific targeting translates to enhanced efficacy of Cabo compared to the free drug when conjugated to PSMA-2DG-D. Furthermore, systemically administered fluorescently labeled PSMA-2DG-D-Cy5 specifically targets PSMA (+) tumors with minimal off-target accumulation in the PC3-PIP tumor xenograft mouse model. This demonstrates that the PSMA-2DG-D platform is a promising new delivery system for potent chemotherapeutics, where systemic side effects are a significant concern.
前列腺癌（PC）是全球男性癌症相关死亡的第五大主要原因。前列腺特异性膜抗原（PSMA）是 PC 的分子靶标，临床上用于使用放射性配体方法治疗和诊断 PC。然而，还没有 FDA 批准的基于 PSMA 的化疗药物。在这里，我们提出了一种使用 PSMA 靶向 2-脱氧葡萄糖-树枝状聚合物（PSMA-2DG-D）的新型治疗方法，用于将有效的酪氨酸激酶抑制剂卡博替尼（Cabo）选择性递送至 PC 细胞。PSMA-2DG-D 通过 PSMA 介导的内化在 PSMA（+）PC 细胞中表现出细胞内定位。与游离药物相比，当与 PSMA-2DG-D 缀合时，PSMA 特异性靶向可提高 Cabo 的疗效。此外，荧光标记的 PSMA-2DG-D-Cy5 经系统给药后可特异性靶向 PSMA（+）肿瘤，在 PC3-PIP 肿瘤异种移植小鼠模型中几乎没有非靶标蓄积。这表明 PSMA-2DG-D 平台是一种有前途的新型递送系统，用于强效化疗药物，其中全身副作用是一个重大问题。
