Yin Shuang, Wang Yan, Zhang Bingyang, Qu Yiran, Liu Yongdong, Dai Sheng, Zhang Yao, Wang Yingli, Bi Jingxiu
School of Chemical Engineering and Advanced Materials, The University of Adelaide, Adelaide SA5005, Australia.
School of Chinese Medicine and Food Engineering, Shanxi University of Traditional Chinese Medicine, Jinzhong 030619, China.
Pharmaceutics. 2021 Apr 9;13(4):521. doi: 10.3390/pharmaceutics13040521.
Ferritin, one of the most investigated protein nanocages, is considered as a promising drug carrier because of its advantageous stability and safety. However, its short half-life and undesirable tumor targeting ability has limited its usage in tumor treatment. In this work, two types of functional peptides, half-life extension peptide PAS, and tumor targeting peptide RGDK (Arg-Gly-Asp-Lys), are inserted to human heavy-chain ferritin (HFn) at C-terminal through flexible linkers with two distinct enzyme cleavable sites. Structural characterizations show both HFn and engineered HFns can assemble into nanoparticles but with different apparent hydrodynamic volumes and molecular weights. RGDK peptide enhanced the internalization efficiency of HFn and showed a significant increase of growth inhibition against 4T1 cell line in vitro. Pharmacokinetic study in vivo demonstrates PAS peptides extended ferritin half-life about 4.9 times in Sprague Dawley rats. RGDK peptides greatly enhanced drug accumulation in the tumor site rather than in other organs in biodistribution analysis. Drug loaded PAS-RGDK functionalized HFns curbed tumor growth with significantly greater efficacies in comparison with drug loaded HFn.
铁蛋白是研究最为深入的蛋白质纳米笼之一，因其具有良好的稳定性和安全性，被认为是一种很有前景的药物载体。然而，其较短的半衰期和不理想的肿瘤靶向能力限制了它在肿瘤治疗中的应用。在这项研究中，两种功能肽，即半衰期延长肽PAS和肿瘤靶向肽RGDK（精氨酸-甘氨酸-天冬氨酸-赖氨酸），通过具有两个不同酶切位点的柔性接头插入到人类重链铁蛋白（HFn）的C末端。结构表征表明，HFn和工程化的HFn都能组装成纳米颗粒，但具有不同的表观流体力学体积和分子量。RGDK肽提高了HFn的内化效率，并在体外对4T1细胞系的生长抑制作用显著增强。体内药代动力学研究表明，PAS肽在Sprague Dawley大鼠中将铁蛋白的半衰期延长了约4.9倍。在生物分布分析中，RGDK肽极大地增强了肿瘤部位的药物积累，而不是其他器官。与载药HFn相比，载药PAS-RGDK功能化的HFn能更有效地抑制肿瘤生长。
