1Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123 P. R. China.
2International Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Jin Ming Avenue, Kaifeng, Henan 475004 China.
Signal Transduct Target Ther. 2018 Dec 14;3:32. doi: 10.1038/s41392-018-0032-7. eCollection 2018.
Lung cancer, with its high mortality and increasing morbidity, has become one of the most lethal malignancies worldwide. Here, we developed cyclic RGD peptide-directed and disulfide-crosslinked polymersomal doxorubicin (cRGD-PS-Dox) as a targeted chemotherapy for human non-small cell lung cancer (NSCLC). Notably, cRGD-PS-Dox exhibited a high Dox loading (15.2 wt.%), small hydrodynamic diameter (96 nm), superb stability, prominent targetability to αβ integrin overexpressing A549 human lung cancer cells, and rapid release of the drug into nuclei, leading to a significantly improved antitumor activity compared with the control groups, i.e., PS-Dox and Lipo-Dox (a liposome injection employed in clinical settings). The pharmacokinetic and biodistribution results for cRGD-PS-Dox revealed similar elimination half-lives but two-fold enhanced tumor accumulation compared with PS-Dox and Lipo-Dox. Intriguingly, cRGD-PS-Dox effectively suppressed the growth of A549 lung tumors in both subcutaneous and orthotopic models with minimal adverse effects at a Dox dose of 12 mg/kg, leading to significant survival benefits compared with PS-Dox and Lipo-Dox. This αβ integrin-targeting multifunctional polymersomal doxorubicin is highly promising for targeted chemotherapy of human NSCLC.
肺癌因其高死亡率和发病率不断增加，已成为全球最致命的恶性肿瘤之一。在这里，我们开发了环精氨酸-甘氨酸-天冬氨酸（cRGD）肽导向的二硫键交联聚合物胶束阿霉素（cRGD-PS-Dox），作为一种针对人非小细胞肺癌（NSCLC）的靶向化疗药物。值得注意的是，cRGD-PS-Dox 具有高阿霉素载药量（15.2wt.%）、小水动力直径（96nm）、极好的稳定性、对αβ整合素过表达的 A549 人肺癌细胞的卓越靶向性，以及药物快速进入细胞核释放，与对照组（即 PS-Dox 和 Lipo-Dox，一种临床应用的脂质体注射剂）相比，显著提高了抗肿瘤活性。cRGD-PS-Dox 的药代动力学和生物分布研究结果表明，其消除半衰期相似，但与 PS-Dox 和 Lipo-Dox 相比，肿瘤积累增加了两倍。有趣的是，cRGD-PS-Dox 以 12mg/kg 的阿霉素剂量在皮下和原位模型中有效抑制了 A549 肺肿瘤的生长，且副作用极小，与 PS-Dox 和 Lipo-Dox 相比，显著提高了生存获益。这种针对αβ整合素的多功能聚合物胶束阿霉素具有很大的潜力，可用于人类 NSCLC 的靶向化疗。
