Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Int J Pharm. 2018 Dec 1;552(1-2):16-26. doi: 10.1016/j.ijpharm.2018.09.050. Epub 2018 Sep 22.
In the present study, we have developed the robust nanoparticles (MGC-GNP/PTX), which are TAMs and tumor cells-dual recognizable, for targeting cancer therapy. Of great importance, the developed nano-platforms are glutathione (GSH)-activable, which means it remains structure intact under normal physiological condition and can be disrupted when exposed to certain concentration of GSH. As demonstrated by the drug release assay in vitro, MGC-GNP/PTX exhibited an excellent structure stability under the normal condition with only 10% of cumulative drug release at 72 h. However, after increasing the concentration of GSH to 1 mM or 10 mM, the release of PTX from the nanoparticles was significantly accelerated and approximately 35% or 95% of drugs was released. Cellular experiments and in vivo tumor targeting assay displayed that the developed nanoparticles have a super capacity of tumor cells and TAMs-dual targeting drug delivery, which resulted in much stronger cytotoxicity when compared to the unmodified ones. Finally, the pharmacodynamic evaluation indicated that the mice treated with MGC-GNP/PTX displayed the strongest tumor suppression ability versus other groups. More importantly, the treatment of MGC-GNP/PTX did not significantly influence the body weight and pathological of the mice, indicated that the prepared nanoparticle system had a satisfactory bio-safety for targeting tumor drug delivery.
在本研究中，我们开发了一种稳健的纳米颗粒（MGC-GNP/PTX），它可以同时识别肿瘤相关巨噬细胞（TAMs）和肿瘤细胞，用于靶向癌症治疗。非常重要的是，所开发的纳米平台是谷胱甘肽（GSH）激活型的，这意味着在正常生理条件下它保持结构完整，而当暴露于特定浓度的 GSH 时，它可以被破坏。如体外药物释放实验所示，MGC-GNP/PTX 在正常条件下表现出优异的结构稳定性，在 72 小时内仅释放 10%的累积药物。然而，当 GSH 浓度增加到 1mM 或 10mM 时，PTX 从纳米颗粒中的释放明显加速，约有 35%或 95%的药物被释放。细胞实验和体内肿瘤靶向实验表明，所开发的纳米颗粒具有超强的肿瘤细胞和 TAMs 双重靶向药物递送能力，与未修饰的纳米颗粒相比，其细胞毒性更强。最后，药效学评价表明，用 MGC-GNP/PTX 处理的小鼠表现出最强的肿瘤抑制能力，优于其他组。更重要的是，MGC-GNP/PTX 的治疗并未显著影响小鼠的体重和病理，表明所制备的纳米颗粒系统具有令人满意的生物安全性，可用于靶向肿瘤药物递送。
