State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.
Biomaterials. 2010 Aug;31(24):6309-16. doi: 10.1016/j.biomaterials.2010.04.049. Epub 2010 May 15.
To overcome the cardiotoxicity of doxorubicin, a self-assembled pH/enzyme-responsive system was developed. Cationic gelatin combined polyGC-DOX intercalation tightly to form compact nanoscale complexes (CPX1) which then combined by a pH-sensitive pegylated alginate to form CPX2. CPX2 could be digested and release DOX under the co-digestion of gelatinase (GA) and Dnase I when pH < 6.9. More importantly, tumor homogenate supernatant (THS) could effectively release DOX from CPX2 while the plasma and liver homogenate supernatant (LHS) could not, which was confirmed by an in vivo test. The results indicated that this formulation had the tumor-specific drug-release effect. This effect resulted in an increased drug concentration in tumor tissue and decreased content in heart and liver. The changed bio-distribution of DOX delivered by CPX2 greatly enhanced the anti-cancer activity and reduced the cardiotoxicity of the drug. The anti-cancer efficiency of DOX delivered by CPX2 is more than 2 times of the free doxorubicin, and the mortality caused by the high-dose DOX was completely prevented by CPX2. All results suggested that this easy-manufactured, cost-effective nanocomplex holds great promise to be developed into a formulation of doxorubicin and the other anthracyclines with high anti-cancer activity and low cardiotoxicity.
为了克服阿霉素的心脏毒性，开发了一种自组装的 pH/酶响应系统。阳离子明胶与聚 GC-DOX 紧密结合形成紧密的纳米级复合物 (CPX1)，然后通过 pH 敏感的聚乙二醇化藻酸盐结合形成 CPX2。当 pH < 6.9 时，CPX2 可以在明胶酶 (GA) 和 Dnase I 的共同消化下被消化并释放 DOX。更重要的是，肿瘤匀浆上清液 (THS) 可以有效地从 CPX2 中释放 DOX，而血浆和肝匀浆上清液 (LHS) 则不能，这在体内试验中得到了证实。结果表明，该制剂具有肿瘤特异性的药物释放效果。这种效果导致肿瘤组织中药物浓度增加，心脏和肝脏中的含量降低。CPX2 递送的 DOX 的生物分布改变大大增强了抗癌活性并降低了药物的心脏毒性。CPX2 递送的 DOX 的抗癌效率是游离阿霉素的 2 倍以上，CPX2 完全防止了高剂量 DOX 引起的死亡率。所有结果表明，这种易于制造、具有成本效益的纳米复合物具有很大的潜力，可以开发成具有高抗癌活性和低心脏毒性的阿霉素和其他蒽环类药物的制剂。
