Wei Lingyu, Chen Jinjin, Zhao Shuhua, Ding Jianxun, Chen Xuesi
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; Department of Gynaecology and Obstetrics, The Second Hospital of Jilin University, Changchun 130041, PR China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; University of Chinese Academy of Sciences, Beijing 100039, PR China.
Acta Biomater. 2017 Aug;58:44-53. doi: 10.1016/j.actbio.2017.05.053. Epub 2017 May 30.
In the synergistic treatment with cytotoxic drug and vascular disrupting agent, the order of drug release shows great importance to enhance the antitumor efficacy. When vascular disrupting agent is firstly administrated, the reduced blood supply and overexpressed hypoxia-inducible factor-1α greatly limit the efficiency of chemotherapy. In this work, an injectable thermo-sensitive polypeptide hydrogel was firstly developed for the locally sequential delivery of hydrophilic doxorubicin (DOX, a cytotoxic agent) and hydrophobic combretastatin A4 (CA4, a vascular disrupting drug). The aqueous solution of polypeptide at low temperature transformed into hydrogel under the body temperature after subcutaneous injection and completely degraded after four weeks with excellent biocompatibility. DOX and CA4 were co-loaded into the hydrogel, and the release of DOX showed much faster than that of CA4 due to their difference in water solubility. The superior inhibition of tumor volume after treatment with DOX and CA4 co-loaded hydrogel occurred in the treatment of grafted mouse U14 cervical tumor compared with both free drugs and single drug-loaded hydrogels. In addition, the co-loaded hydrogel obtained enhanced apoptosis of tumor cells, significant shutdown of blood vessels, and wholly regional tumor apoptosis, which indicated the eradication of solid tumor. Moreover, treatments with the drug-loaded hydrogels showed negligible damage to normal tissues, suggesting their low systemic toxicity. The locally sequential delivery system had great potential for in situ synergistic chemotherapy.
The release order makes great difference in the synergistic efficacies of cytotoxic drug and vascular disrupting agent. When cytotoxic drug is administrated before vascular disrupting agent, an eradication of tumor might be obtained. On the contrary, the antitumor efficiency will be greatly hindered by limited penetration of later cytotoxic drug and drug resistant induced by vascular disrupting agent. Therefore, the adjustment of the delivery behaviors of such two-pronged agents in one platform was significant for their efficiently synergistic chemotherapy. The present study originally provides a convenient strategy and an advanced sample for sequential administration of cytotoxic drug and vascular disrupting agent in one platform based on their water solubility to achieve upregulated efficacy and safety.
在细胞毒性药物与血管破坏剂的协同治疗中，药物释放顺序对提高抗肿瘤疗效至关重要。当首先给予血管破坏剂时，血液供应减少和缺氧诱导因子-1α过度表达会极大地限制化疗效率。在这项工作中，首次开发了一种可注射的热敏多肽水凝胶，用于亲水性阿霉素（DOX，一种细胞毒性药物）和疏水性康普瑞汀A4（CA4，一种血管破坏药物）的局部顺序递送。多肽水溶液在低温下皮下注射后在体温下转变为水凝胶，并在四周后完全降解，具有优异的生物相容性。DOX和CA4共负载于水凝胶中，由于它们在水溶性上的差异，DOX的释放比CA4快得多。与游离药物和单药负载水凝胶相比，DOX和CA4共负载水凝胶治疗移植小鼠U14宫颈癌后对肿瘤体积的抑制效果更佳。此外，共负载水凝胶可增强肿瘤细胞凋亡、显著关闭血管并实现整个区域的肿瘤凋亡，这表明实体瘤被根除。而且，用载药水凝胶治疗对正常组织的损伤可忽略不计，表明其全身毒性较低。这种局部顺序递送系统在原位协同化疗方面具有巨大潜力。
释放顺序对细胞毒性药物与血管破坏剂的协同疗效有很大影响。当细胞毒性药物在血管破坏剂之前给药时，可能会实现肿瘤根除。相反，后续细胞毒性药物的有限渗透和血管破坏剂诱导的耐药性会极大地阻碍抗肿瘤效率。因此，在一个平台上调节这两种药物的递送行为对于它们的高效协同化疗具有重要意义。本研究最初基于细胞毒性药物和血管破坏剂的水溶性，在一个平台上提供了一种方便的策略和先进的样本，用于顺序给药，以实现疗效和安全性的提高。
