谷氨酸羧肽酶Ⅱ
前列腺癌
紫杉醇
癌症研究
癌症
靶向治疗
医学
细胞毒性T细胞
靶向给药
药理学
化学
内科学
药品
体外
生物化学
作者
Qingzhi Lv,Jincheng Yang,Ruoshi Zhang,Zimeng Yang,Zhengtao Yang,Yongjun Wang,Youjun Xu,Zhonggui He
标识
DOI:10.1021/acs.molpharmaceut.8b00026
摘要
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.
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