Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China.
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Chengdu, China.
Biomaterials. 2016 Nov;108:44-56. doi: 10.1016/j.biomaterials.2016.09.001. Epub 2016 Sep 4.
Finding effective cures against aggressive malignancy remains a major challenge in cancer chemotherapy. Here, we report a "tadpole"-like peptide by covalently conjugating the alanine-alanine-asparagine "tail" residual to the cyclic tumor homing peptide iRGD (CCRGDKGPDC) to afford nRGD, which significantly enhanced tumoricidal effects of doxorubicin, by either co-administered as a physical mixture or as a targeting ligand covalently conjugated to the liposomal carrier. Given twice at an equivalent dose of 5 mg/kg, doxorubicin loaded liposomes modified with nRGD (nRGD-Lipo-Dox) showed excellent antitumor efficacy in 4T1 breast cancer mice, of which 44.4% remained alive for over 90 days without recurrence during the period of investigation. The dramatic improvement in antitumor efficacy was attributed to nRGD-Lipo-Dox which appeared to specifically interact with tumor vascular endothelial cells to achieve efficient tumor penetration, and modulate tumor microenvironment with depletion of tumor associated macrophages.
寻找有效的方法来对抗侵袭性恶性肿瘤仍然是癌症化疗的一个主要挑战。在这里，我们报告了一种“蝌蚪”样肽，通过将丙氨酸-丙氨酸-天冬氨酸“尾巴”残基共价连接到环肿瘤归巢肽 iRGD（CCRGDKGPDC）上来获得 nRGD，它通过作为物理混合物共同给药或作为靶向配体共价连接到脂质体载体，显著增强了阿霉素的杀肿瘤作用。以相当于 5mg/kg 的等效剂量两次给药，用 nRGD（nRGD-Lipo-Dox）修饰的载阿霉素脂质体（nRGD-Lipo-Dox）在 4T1 乳腺癌小鼠中表现出优异的抗肿瘤疗效，其中 44.4%的小鼠在 90 天以上的观察期内没有复发，且仍然存活。抗肿瘤疗效的显著提高归因于 nRGD-Lipo-Dox，它似乎可以特异性地与肿瘤血管内皮细胞相互作用，以实现有效的肿瘤穿透，并通过耗尽肿瘤相关巨噬细胞来调节肿瘤微环境。
