Department of Orthopedic Surgery, Qilu Hospital of Shandong University, Jinan, 250012, People's Republic of China.
Jinan Center hospital affiliated to Shandong University, Shandong University, Jinan, 250012, People's Republic of China.
Int J Nanomedicine. 2022 Mar 22;17:1309-1322. doi: 10.2147/IJN.S356453. eCollection 2022.
Osteosarcoma is considered as the most common primary malignant bone tumor in children and adolescents, and the treatments including chemotherapy and surgery were far from satisfactory. Localized tumor treatments by hydrogels incorporating combined chemotherapeutic drugs have recently emerged as superior approaches for enhanced anti-tumor effects and reduced systemic toxicity.
A novel injectable thermosensitive poly (lactide-co- glycolide)-poly (ethylene glycol)-poly(lactide-co-glycolide) triblock copolymer hydrogel containing doxorubicin and cisplatin for the localized chemotherapy of osteosarcoma were synthesized and characterized. The in vitro drug release properties of the drugs-loaded hydrogels were investigated. To study the anti-tumor efficacy of hydrogels depots in vitro, the cytotoxicity and apoptosis rate against Saos-2 and MG-63 cells were evaluated by MTT, Annexin V and PCR methods. The in vivo synergistic anti-tumor efficacy of the multi-drugs co-loaded hydrogels was investigated by human osteosarcoma xenografts. Additionally, the systemic toxic side effects were evaluated by ex vivo histological analysis of the major organs of the mice.
The PLGA-PEG-PLGA copolymer solution underwent a sol-gel transition at appropriate temperature and degraded in the PBS, presenting a friendly biocompatibility in vitro. The in vitro cell viability tests demonstrated that DOX and CDDP co-loaded hydrogels exhibited synergistic anti-proliferation effect, due to the sustained release of drugs from the drugs-loaded hydrogel. The treatment with DOX and CDDP co-loaded hydrogel led to the highest efficiency in inhibiting the tumor growth, enhanced tumor necrosis rate and increased regulation of the apoptosis-related gene expressions, indicating a synergistic anti-tumor efficacy in vivo. Additionally, ex vivo histological analysis of the nude mice exhibited low systemic toxicity.
The combination treatment of osteosarcoma by localized, sustained co-delivery of DOX and CDDP by PLGA-PEG-PLGA hydrogel may serve as a promising strategy for efficient clinical treatment of osteosarcoma.
骨肉瘤被认为是儿童和青少年中最常见的原发性恶性骨肿瘤，其化疗和手术治疗效果远不理想。最近，通过水凝胶将联合化疗药物局部递送到肿瘤部位，已成为增强抗肿瘤效果和降低全身毒性的一种更优方法。
设计并合成了一种新型的可注射温敏型聚（丙交酯-乙交酯）-聚（乙二醇）-聚（丙交酯-乙交酯）三嵌段共聚物水凝胶，用于骨肉瘤的局部化疗，其中载有阿霉素和顺铂。考察了载药水凝胶的体外药物释放性能。为了研究水凝胶库在体外的抗肿瘤效果，通过 MTT、Annexin V 和 PCR 方法评价了其对 Saos-2 和 MG-63 细胞的细胞毒性和细胞凋亡率。通过人骨肉瘤异种移植模型研究了多药共载水凝胶的体内协同抗肿瘤效果。此外，通过对小鼠主要器官的离体组织学分析评价了其全身毒性副作用。
PLGA-PEG-PLGA 共聚物溶液在适当的温度下发生溶胶-凝胶转变，并在 PBS 中降解，表现出良好的体外生物相容性。体外细胞活力测试表明，DOX 和 CDDP 共载水凝胶具有协同的抗增殖作用，这是由于药物从载药水凝胶中持续释放。DOX 和 CDDP 共载水凝胶治疗导致肿瘤生长抑制效率最高，肿瘤坏死率增加，凋亡相关基因表达上调，表明体内具有协同抗肿瘤效果。此外，裸鼠的离体组织学分析显示全身毒性较低。
PLGA-PEG-PLGA 水凝胶局部、持续共递 DOX 和 CDDP 联合治疗骨肉瘤可能成为骨肉瘤有效临床治疗的一种有前途的策略。
