Zhu Qian, Jia Lixin, Gao Zhongfei, Wang Chunming, Jiang Haoyang, Zhang Junfeng, Dong Lei
State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University , Nanjing 210093, China.
Mol Pharm. 2014 Oct 6;11(10):3269-78. doi: 10.1021/mp4007776. Epub 2014 Apr 25.
Doxorubicin (DOX) is a potent cancer chemotherapeutic agent, but its clinical use is severely limited by potentially lethal cardiotoxicity. Delivery of DOX by particulate carriers can be an effective way to reduce its distribution in cardiac tissue. In the present study, we developed a self-assembled, tumor-microenvironment-responsive delivery system for DOX. The core of the carrier was built upon the DOX/DNA intercalation, which was further combined with cationic gelatin (C-gel) to form the complex GDD. GDD was then packaged into a complex, namely, HDD, based on the electrostatic interactions between the positively charged C-gel and negatively charged human serum albumin (HSA). The HSA molecules on the surface of the complex HDD effectively helped the particle evade the filtration of the body when injected into the circulation and passively accumulate into the tumor sites. After entering the tumor tissue, where albumin is rapidly consumed, GDD was release from HDD and the C-gel was then digested by the tumor-specific matrix metalloproteinase (MMPs) to free the DOX/DNA intercalation. Deoxyribonucleases (DNases) in the tissue could completely destroy the DNA molecules to release DOX into the microenvironments. After a series of in vitro optimization tests, we evaluated the anticancer capacity and cardiac toxicity of HDD in two animal models with cancer. The results suggested that HDD had a higher anticancer efficacy and a significantly lower cardiotoxicity than free DOX. Additionally, the main components of the carrier are all clinically approved materials. Taken together, our present delivery system is safe and efficient and has high potential for further clinical trials.
阿霉素（DOX）是一种强效的癌症化疗药物，但其临床应用因潜在的致命心脏毒性而受到严重限制。通过颗粒载体递送DOX可能是减少其在心脏组织中分布的有效方法。在本研究中，我们开发了一种用于DOX的自组装、肿瘤微环境响应递送系统。载体的核心基于DOX/DNA插入构建，其进一步与阳离子明胶（C-凝胶）结合形成复合物GDD。然后，基于带正电的C-凝胶与带负电的人血清白蛋白（HSA）之间的静电相互作用，将GDD包装成一种复合物，即HDD。复合物HDD表面的HSA分子在注入循环系统时有效地帮助颗粒避开身体的过滤，并被动地积聚到肿瘤部位。进入肿瘤组织后，白蛋白迅速被消耗，GDD从HDD中释放出来，然后C-凝胶被肿瘤特异性基质金属蛋白酶（MMPs）消化以释放DOX/DNA插入物。组织中的脱氧核糖核酸酶（DNases）可以完全破坏DNA分子，将DOX释放到微环境中。经过一系列体外优化试验后，我们在两种癌症动物模型中评估了HDD的抗癌能力和心脏毒性。结果表明，与游离DOX相比，HDD具有更高的抗癌疗效和显著更低的心脏毒性。此外，载体的主要成分都是临床批准的材料。综上所述，我们目前的递送系统安全有效，具有进一步进行临床试验的巨大潜力。
