Prostate-Specific Membrane Antigen Targeted Therapy of Prostate Cancer Using a DUPA–Paclitaxel Conjugate,Molecular Pharmaceutics

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Prostate-Specific Membrane Antigen Targeted Therapy of Prostate Cancer Using a DUPA–Paclitaxel Conjugate
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-04-02 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00026
Qingzhi Lv ₁ , Jincheng Yang , Ruoshi Zhang , Zimeng Yang , Zhengtao Yang , Yongjun Wang , Youjun Xu , Zhonggui He

Affiliation

Prostate cancer (PCa) is the most prevalent cancer among men in the United States and remains the second-leading cause of cancer mortality in men. Paclitaxel (PTX) is the first line chemotherapy for PCa treatment, but its therapeutic efficacy is greatly restricted by the nonspecific distribution in vivo. Prostate-specific membrane antigen (PSMA) is overexpressed on the surface of most PCa cells, and its expression level increases with cancer aggressiveness, while being present at low levels in normal cells. The high expression level of PSMA in PCa cells offers an opportunity for target delivery of nonspecific cytotoxic drugs to PCa cells, thus improving therapeutic efficacy and reducing toxicity. PSMA has high affinity for DUPA, a glutamate urea ligand. Herein, a novel DUPA–PTX conjugate is developed using DUPA as the targeting ligand to deliver PTX specifically for treatment of PSMA expressing PCa. The targeting ligand DUPA enhances the transport capability and selectivity of PTX to tumor cells via PSMA mediated endocytosis. Besides, DUPA is conjugated with PTX via a disulfide bond, which facilitates the rapid and differential drug release in tumor cells. The DUPA–PTX conjugate exhibits potent cytotoxicity in PSMA expressing cell lines and induces a complete cessation of tumor growth with no obvious toxicity. Our findings give new insight into the PSMA-targeted delivery of chemotherapeutics and provide an opportunity for the development of novel active targeting drug delivery systems for PCa therapy.

中文翻译：

DUPA-紫杉醇偶联物对前列腺癌的膜特异性抗原靶向治疗

前列腺癌（PCa）是美国男性中最普遍的癌症，并且仍然是男性癌症死亡率的第二大诱因。紫杉醇（PTX）是PCa治疗的一线化疗，但其体内非特异性分布极大地限制了其治疗效果。前列腺特异性膜抗原（PSMA）在大多数PCa细胞的表面过度表达，其表达水平随着癌症的侵袭而增加，而在正常细胞中则较低。PSMA在PCa细胞中的高表达水平提供了将非特异性细胞毒性药物靶向递送至PCa细胞的机会，从而提高了治疗功效并降低了毒性。PSMA对DUPA（谷氨酸尿素配体）具有高亲和力。在本文中，使用DUPA作为靶向配体开发了新型DUPA-PTX共轭物，以递送PTX专门用于表达PSMA的PCa的治疗。靶向配体DUPA通过PSMA介导的内吞作用增强了PTX对肿瘤细胞的转运能力和选择性。此外，DUPA通过二硫键与PTX共轭，这促进了肿瘤细胞中药物的快速和差异释放。DUPA-PTX共轭物在表达PSMA的细胞系中表现出强力的细胞毒性，并诱导肿瘤生长完全停止而没有明显的毒性。我们的发现为以PSMA为靶点的化疗药物的输送提供了新的见识，并为开发用于PCa治疗的新型主动靶向药物输送系统提供了机会。

更新日期：2018-04-02

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