Song Ping, Yao Xin, Zhong Ting, Zhang Shuang, Guo Yang, Ren Wei, Huang Dan, Duan Xiao-Chuan, Yin Yi-Fan, Zhang Shu-Shi, Zhang Xuan
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Oncotarget. 2016 Jul 26;7(30):48467-48480. doi: 10.18632/oncotarget.10310.
Hypoxia is an important microenvironmental pressure present in the majority of solid tumors and, so, tumor hypoxia might be considered an attractive target for tumor therapy. One strategy for targeting hypoxia is to develop bioreductive prodrugs. In the present research, we synthesized a bioreductive paclitaxel prodrug, 3-(2-Nitrophenyl) propionic acid-paclitaxel (NPPA-PTX). The stability of NPPA-PTX in PBS and rat plasma was investigated. The anti-tumor activity of NPPA-PTX was also evaluated in vitro and in vivo. The results of our stability study indicated that NPPA-PTX was stable in PBS and rat plasma as well as in the blood circulation. The in vitro and in vivo anti-tumor activity of NPPA-PTX was confirmed in both KB cells and MDA-MB-231 cells. Our results also indicated that NPPA-PTX could completely convert to active PTX in tumor tissues and produced the anti-tumor activity in both KB and MDA-MB-231 tumor-bearing nude mice. We suggest that the dissociated PTX which converted from NPPA-PTX in tumor tissues played a key role in producing anti-tumor activity. Considering all our results, we suggest that NPPA-PTX is a novel bioreductive PTX prodrug which could undergo further evaluation.
缺氧是大多数实体瘤中存在的一种重要微环境压力，因此肿瘤缺氧可被视为肿瘤治疗的一个有吸引力的靶点。靶向缺氧的一种策略是开发生物还原前药。在本研究中，我们合成了一种生物还原紫杉醇前药，3-(2-硝基苯基)丙酸-紫杉醇（NPPA-PTX）。研究了NPPA-PTX在磷酸盐缓冲液（PBS）和大鼠血浆中的稳定性。还在体外和体内评估了NPPA-PTX的抗肿瘤活性。我们稳定性研究的结果表明，NPPA-PTX在PBS、大鼠血浆以及血液循环中均稳定。NPPA-PTX在KB细胞和MDA-MB-231细胞中的体外和体内抗肿瘤活性均得到证实。我们的结果还表明，NPPA-PTX在肿瘤组织中可完全转化为活性紫杉醇，并在荷KB和MDA-MB-231肿瘤的裸鼠中产生抗肿瘤活性。我们认为，在肿瘤组织中由NPPA-PTX转化而来的游离紫杉醇在产生抗肿瘤活性中起关键作用。综合我们所有的结果，我们认为NPPA-PTX是一种新型的生物还原紫杉醇前药，可进行进一步评估。
