Zhang Ru, Jiang Yunying, Hao Linkun, Yang Yang, Gao Ying, Zhang Ningning, Zhang Xuecheng, Song Yimin
Pharmaceutical Engineering Laboratory, Department of Pharmaceutical Engineering, Qingdao University of Science and Technology, Qingdao, China.
Pharmaceutical Engineering Laboratory, Colloge of Marines Life Science, Ocean University of China, Qingdao, China.
Front Pharmacol. 2022 Mar 10;13:829590. doi: 10.3389/fphar.2022.829590. eCollection 2022.
In this study, a novel poly (lactic-co-glycolic acid) (PLGA)-based micelle was synthesized, which could improve the therapeutic effect of the antitumor drug doxorubicin hydrochloride (DOX) and reduce its toxic and side effects. The efficient delivery of DOX was achieved by active targeting mediated by double receptors and stimulating the reduction potential in tumor cells. FA-HA-SS-PLGA polymer was synthesized by amidation reaction, and then DOX-loaded micelles were prepared by dialysis method. The corresponding surface method was used to optimize the experimental design. DOX/FA-HA-SS-PLGA micelles with high drug loading rate and encapsulation efficiency were prepared. The results of hydrophilic experiment, critical micelle concentration determination, and hemolysis test all showed that DOX/FA-HA-SS-PLGA micelles had good physicochemical properties and biocompatibility. In addition, both reduction stimulus response experiment and release experiment showed that DOX/FA-HA-SS-PLGA micelles had reduction sensitivity. Molecular docking experiments showed that it can bind to the target protein. More importantly, cytology studies, human breast cancer cells (MCF-7), human non-small cell lung cancer cells (A549), and mouse colon cancer cells (CT26) were used to demonstrate that the dual receptor-mediated endocytosis pathway resulted in stronger cytotoxicity to tumor cells and more significant apoptosis. In and antitumor experiment, tumor-bearing nude mice were used to further confirm that the micelles with double targeting ligands had better antitumor effect and lower toxicity. These experimental results showed that DOX/FA-HA-SS-PLGA micelles have the potential to be used as chemotherapeutic drugs for precise tumor treatment.
在本研究中，合成了一种新型的基于聚乳酸-羟基乙酸共聚物（PLGA）的胶束，其可提高抗肿瘤药物盐酸多柔比星（DOX）的治疗效果并降低其毒副作用。通过双受体介导的主动靶向和刺激肿瘤细胞中的还原电位实现了DOX的高效递送。通过酰胺化反应合成了FA-HA-SS-PLGA聚合物，然后采用透析法制备了载DOX胶束。使用相应的表面方法优化实验设计。制备了具有高载药率和包封率的DOX/FA-HA-SS-PLGA胶束。亲水实验、临界胶束浓度测定和溶血试验结果均表明，DOX/FA-HA-SS-PLGA胶束具有良好的理化性质和生物相容性。此外，还原刺激响应实验和释放实验均表明，DOX/FA-HA-SS-PLGA胶束具有还原敏感性。分子对接实验表明其可与靶蛋白结合。更重要的是，利用人乳腺癌细胞（MCF-7）、人非小细胞肺癌细胞（A549）和小鼠结肠癌细胞（CT26）进行的细胞学研究表明，双受体介导的内吞途径对肿瘤细胞具有更强的细胞毒性和更显著的凋亡作用。在抗肿瘤实验中，使用荷瘤裸鼠进一步证实，具有双靶向配体的胶束具有更好的抗肿瘤效果和更低的毒性。这些实验结果表明，DOX/FA-HA-SS-PLGA胶束有潜力用作精确肿瘤治疗的化疗药物。
