Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China; School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China.
Int J Pharm. 2019 Mar 25;559:48-57. doi: 10.1016/j.ijpharm.2019.01.032. Epub 2019 Jan 21.
Gemcitabine (Gem) as an anti-cancer agent has been limited by its short circulation time and rapid metabolism that reflects in low tumor uptake and low therapeutic efficiency. To improve its anti-tumor activity, a novel FAPα enzyme-activated prodrug of Z-GP-Gem modified at 4-amino group of Gem was developed, which could effectively release parent Gem based on the specific cleavage via FAPα enzyme-activation in tumor microenvironment. Compared to Gem, the Z-GP-Gem prodrug exhibited significantly enhanced inhibition of both tumor growth and pulmonary metastasis in BALB/c mice bearing orthotopic breast 4T1 tumors. The Z-GP-Gem prodrug has a prolonged circulation time and a high tumor uptake based on the modification of Z-GP dipeptide at 4-amino group of Gem. These eventually caused a marked improvement in the systemic toxicity and the tumor growth inhibition in 4T1 cells. More interestingly, the unexpected depletion of tumor-associated fibroblast (TAF) was observed during the treatment of Z-GP-Gem prodrug in animal model. Therefore, these findings demonstrated that the FAPα-activated prodrug Z-GP-Gem would be a desirable approach for tumor therapy by intravenous administration.
吉西他滨（Gem）作为一种抗癌药物，由于其循环时间短和代谢迅速，导致肿瘤摄取率低和治疗效率低，从而受到限制。为了提高其抗肿瘤活性，开发了一种新型的 FAPα 酶激活的吉西他滨前药，该前药在肿瘤微环境中通过 FAPα 酶激活特异性切割，对 Gem 的 4-氨基进行了修饰。与 Gem 相比，Z-GP-Gem 前药在荷有原位乳腺癌 4T1 肿瘤的 BALB/c 小鼠中，对肿瘤生长和肺转移的抑制作用显著增强。基于 Z-GP 二肽在 Gem 的 4-氨基上的修饰，Z-GP-Gem 前药具有延长的循环时间和高肿瘤摄取率。这最终导致在 4T1 细胞中全身毒性和肿瘤生长抑制明显改善。更有趣的是，在动物模型中用 Z-GP-Gem 前药治疗时，观察到肿瘤相关成纤维细胞（TAF）的意外耗竭。因此，这些发现表明，FAPα 激活的前药 Z-GP-Gem 通过静脉给药将是一种有前途的肿瘤治疗方法。
