Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University. No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China, PR China.
Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University. No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China, PR China.
Int J Pharm. 2016 Jun 30;507(1-2):50-60. doi: 10.1016/j.ijpharm.2016.04.060. Epub 2016 May 3.
While the complicated pathogenesis of cancer results in limited therapeutic efficacy of current mono-drug treatment, combination therapy by multiple drugs is becoming increasingly attractive due to the decreased side effects and synergistic anti-cancer activities. The recently emerging modality is the co-delivery of traditional chemotherapeutics and anti-angiogenesis agents. Although nanocarriers are frequently utilized for the co-delivery of different drugs, there are still concerns regarding their implementations. Most of the nanocarriers cannot release drugs separately into their different targeted sites of action. Therefore, we have developed a micellar platform for the co-delivery of an antiangiogenesis agent, axitinib (AXI) and a DNA intercalator, doxorubicin (DOX). Our results showed that this cross-linked micelle (DA-CM) could release AXI and DOX in tumor extracellular environment and intracellular lysosome compartments, respectively, in response to the dual pH stimulus. Notably, DA-CM exhibited remarkably improved tumor accumulation, cell internalization, tumor spheroids penetration and cytotoxicity. Ultimately, DA-CM reduced the number of immature vessels within xenograft tumors, demonstrating an effective antiangiogenesis effect. Meanwhile, they inhibited tumor growth by 88%. Our co-delivery micellar system with the dual-pH responsive feature might hold great promises for the combinatory cancer therapy.
虽然癌症复杂的发病机制导致目前单一药物治疗的疗效有限，但由于副作用降低和协同抗癌作用，多种药物联合治疗变得越来越有吸引力。最近出现的新方法是将传统化疗药物和抗血管生成药物联合递药。虽然纳米载体常用于不同药物的联合递送，但它们的应用仍存在一些问题。大多数纳米载体不能将药物分别递送到其不同的作用靶点。因此，我们开发了一种胶束平台，用于联合递送抗血管生成剂阿昔替尼（AXI）和 DNA 嵌入剂多柔比星（DOX）。我们的结果表明，这种交联胶束（DA-CM）可以分别在肿瘤细胞外环境和细胞内溶酶体区室中释放 AXI 和 DOX，以响应双重 pH 刺激。值得注意的是，DA-CM 表现出显著改善的肿瘤积累、细胞内化、肿瘤球体穿透和细胞毒性。最终，DA-CM 减少了异种移植肿瘤内不成熟血管的数量，显示出有效的抗血管生成作用。同时，它们抑制了 88%的肿瘤生长。我们具有双重 pH 响应特性的联合递药胶束系统可能为联合癌症治疗提供了很大的希望。
