Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, P. R. China.
International Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Jin Ming Avenue, Kaifeng, Henan 475004, P. R. China.
ACS Appl Mater Interfaces. 2020 Apr 1;12(13):14905-14913. doi: 10.1021/acsami.0c01069. Epub 2020 Mar 18.
Docetaxel (DTX) widely used for treating nonsmall cell lung cancer (NSCLC) patients is associated with dose-limiting side effects, especially neurotoxicity and myelosuppression. Here, we have developed cyclic cNGQGEQc peptide-directed polymersomal docetaxel (cNGQ-PS-DTX) as a targeted and multifunctional formulation for NSCLC. cNGQ-PS-DTX carrying 8.1 wt % DTX had a size of 93 nm, neutral surface charge, high stability, and glutathione-triggered DTX release behavior. Cytotoxicity studies demonstrated a clearly better antitumor activity of cNGQ-PS-DTX in αβ integrin overexpressing A549 human lung cancer cells than free DTX and nontargeted PS-DTX. cNGQ-PS-DTX showed a remarkably high tolerability (over 8 times better than free DTX) and slow elimination in mice. Importantly, cNGQ-PS-DTX exhibited greatly improved tumor accumulation and higher suppression of subcutaneous and orthotopic A549 xenografts as compared to PS-DTX and free DTX controls. αβ integrin-targeting polymersomal docetaxel emerges as an advanced nanotherapeutic for NSCLC treatment.
多西他赛（DTX）广泛用于治疗非小细胞肺癌（NSCLC）患者，但与剂量限制的副作用有关，特别是神经毒性和骨髓抑制。在这里，我们开发了环 cNGQGEQc 肽导向聚合物多西他赛（cNGQ-PS-DTX）作为 NSCLC 的靶向和多功能制剂。携带 8.1wt%DTX 的 cNGQ-PS-DTX 的粒径为 93nm，表面呈中性电荷，具有高稳定性和谷胱甘肽触发的 DTX 释放行为。细胞毒性研究表明，cNGQ-PS-DTX 在过度表达 αβ 整合素的 A549 人肺癌细胞中的抗肿瘤活性明显优于游离 DTX 和非靶向 PS-DTX。cNGQ-PS-DTX 在小鼠中表现出极高的耐受性（比游离 DTX 好 8 倍以上）和缓慢的消除。重要的是，与 PS-DTX 和游离 DTX 对照组相比，cNGQ-PS-DTX 表现出大大改善的肿瘤积累和对皮下和原位 A549 异种移植物的更高抑制作用。αβ 整合素靶向聚合物多西他赛是治疗 NSCLC 的先进纳米治疗方法。
