Ma Hecheng, He Chaoliang, Cheng Yilong, Yang Zhiming, Zang Junting, Liu Jianguo, Chen Xuesi
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun 130022, People's Republic of China.
Department of Orthopaedics, The First Hospital of Jilin University , Changchun 130021, People's Republic of China.
ACS Appl Mater Interfaces. 2015 Dec 16;7(49):27040-8. doi: 10.1021/acsami.5b09112. Epub 2015 Dec 1.
Localized cancer treatments with combination drugs have recently emerged as crucial approaches for effective inhibition of tumor growth and reoccurrence. In this study, we present a new strategy for the osteosarcoma treatment by localized co-delivery of multiple drugs, including doxorubicin (DOX), cisplatin (CDDP) and methotraxate (MTX), using thermosensitive PLGA-PEG-PLGA hydrogels. The release profiles of the drugs from the hydrogels were investigated in vitro. It was found that the multidrug coloaded hydrogels exhibited synergistic effects on cytotoxicity against osteosarcoma Saos-2 and MG-63 cells in vitro. After a single peritumoral injection of the drug-loaded hydrogels into nude mice bearing human osteosarcoma Saos-2 xenografts, the hydrogels coloaded with DOX, CDDP, and MTX displayed the highest tumor suppression efficacy in vivo for up to 16 days, as well as led to enhanced tumor apoptosis and increased regulation of the expressions of apoptosis-related genes. Moreover, the monitoring on the mice body change and the ex vivo histological analysis of the key organs indicated that the localized treatments caused less systemic toxicity and no obvious damage to the normal organs. Therefore, the approach of localized co-delivery of DOX, CDDP, and MTX by the thermosensitive hydrogels may be a promising approach for enhanced osteosarcoma treatment.
联合用药的局部癌症治疗方法最近已成为有效抑制肿瘤生长和复发的关键手段。在本研究中，我们提出了一种新的骨肉瘤治疗策略，即使用热敏性聚乳酸-聚乙二醇-聚乳酸（PLGA-PEG-PLGA）水凝胶局部共递送多种药物，包括阿霉素（DOX）、顺铂（CDDP）和甲氨蝶呤（MTX）。对水凝胶中药物的释放曲线进行了体外研究。结果发现，载有多药的水凝胶在体外对骨肉瘤Saos-2和MG-63细胞的细胞毒性表现出协同作用。将载药的水凝胶瘤周单次注射到携带人骨肉瘤Saos-2异种移植瘤的裸鼠体内后，载有DOX、CDDP和MTX的水凝胶在体内显示出长达16天的最高肿瘤抑制效果，同时还导致肿瘤凋亡增强以及凋亡相关基因表达调控增加。此外，对小鼠身体变化的监测和关键器官的离体组织学分析表明，局部治疗引起的全身毒性较小，对正常器官无明显损伤。因此，通过热敏性水凝胶局部共递送DOX、CDDP和MTX的方法可能是一种有前景的增强骨肉瘤治疗的方法。
