Lu Lu, Zhao Xiaojing, Fu Tiwei, Li Ke, He Ye, Luo Zhong, Dai Liangliang, Zeng Rui, Cai Kaiyong
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
College of Stomatology, Chongqing Medical University, Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing, China.
Biomaterials. 2020 Feb;230:119666. doi: 10.1016/j.biomaterials.2019.119666. Epub 2019 Dec 3.
Various obstacles impede the chemotherapy efficiency of glioma in clinic, such as blood brain barrier (BBB) and blood brain tumor barrier (BBTB). Ligand-mediated polymeric micelles have shown great potential for improving the efficiency of glioma treatment. Herein, we developed a disulfide bond-conjugated prodrug polymer consisted of camptothecin (CPT) and polyethylene glycol (PEG) with further modification of iRGD peptide. The polymer of CPT-S-S-PEG-COOH could self-assemble into nanosized polymeric micelles with diameter around 100 nm, and loaded with photosensitizer IR780 for combination therapy. The micelles displayed good stability with controlled drug release under physiological environment. Importantly, the iRGD modified polymeric micelles demonstrated favorable ability to cross the BBB and target glioma cells via αv β integrin and neuropilin-1-mediated ligand transportation in vitro and in vivo. The whole synthesis process is simple and the drug loading content of CPT in the CPT-S-S-PEG-iRGD@IR780 micelles was higher than 10%. Moreover, CPT-S-S-PEG-iRGD@IR780 micelles combined chemotherapy with photodynamic therapy (PDT) displayed more excellent tumor-killing capability than the other groups. Thus, both in vitro and in vivo studies suggested that the targeting prodrug system could not only effectively cross various barriers to reach at glioma site, but also significantly enhance the antitumor effect with laser irradiation. Our findings consequently suggested that CPT-S-S-PEG-iRGD@IR780 micelles with laser irradiation are a promising drug delivery system for glioma therapy.
在临床上，各种障碍阻碍了胶质瘤化疗的效果，如血脑屏障（BBB）和血脑肿瘤屏障（BBTB）。配体介导的聚合物胶束在提高胶质瘤治疗效果方面显示出巨大潜力。在此，我们开发了一种由喜树碱（CPT）和聚乙二醇（PEG）组成的二硫键共轭前药聚合物，并对iRGD肽进行了进一步修饰。CPT-S-S-PEG-COOH聚合物可自组装成直径约100nm的纳米级聚合物胶束，并负载光敏剂IR780用于联合治疗。这些胶束在生理环境下表现出良好的稳定性和可控的药物释放。重要的是，iRGD修饰的聚合物胶束在体外和体内均表现出通过αvβ整合素和神经纤毛蛋白-1介导的配体转运穿过血脑屏障并靶向胶质瘤细胞的良好能力。整个合成过程简单，CPT-S-S-PEG-iRGD@IR７８０胶束中CPT的载药量高于10%。此外，CPT-S-S-PEG-iRGD@IR780胶束联合化疗与光动力疗法（PDT）显示出比其他组更优异的肿瘤杀伤能力。因此，体外和体内研究均表明，靶向前药系统不仅可以有效穿过各种屏障到达胶质瘤部位，而且在激光照射下还能显著增强抗肿瘤效果。我们的研究结果因此表明，经激光照射的CPT-S-S-PEG-iRGD@IR780胶束是一种有前景用于胶质瘤治疗的药物递送系统。
