Abstract

Targeted delivery of antitumor drugs is especially important for tumour therapy. Tumour targeting peptides have been shown to be very effective drug carriers for tumour therapy. Interleukin-4 receptor (IL-4R) is overexpressed on the surface of various human solid tumours. To obtain a better targeting peptide, we first designed a novel targeting peptide derived from interleukin-4 (IL-4), ILBP-b. ILBP-b contains the key high-affinity binding residue E9 of IL-4 to IL-4R. Compared with a reported targeting peptide ILBP-a (containing another key high affinity residue R88), ILBP-b was proved to be a better targeting peptide by the fluorescence experiments. Then, we further fused ILBP-b and ILBP-a to increase the multisite-binding ability of ILBP-b and got a better targeting peptide ILBP-ba. ILBP-ba showed a stronger preferential binding ability to IL-4R high-expressing cells than ILBP-a and ILBP-b. Competitive binding experiments demonstrated ILBP-ba specifically targets IL-4R. By fusing ILBP-ba with drug protein trichosanthin (TCS), in vitro drug carrying experiments showed that ILBP-ba could specifically enhance the killing effect of TCS on IL-4R high-expressing tumour cells (more than 10 folds). These results indicated that ILBP-ba has great potential for drug delivery applications targeting IL-4R and will be beneficial for the development of tumour therapeutic agents.

摘要

抗肿瘤药物的靶向递送对于肿瘤治疗尤其重要。肿瘤靶向肽已被证明是非常有效的肿瘤治疗药物载体。白细胞介素 4 受体 (IL-4R) 在各种人类实体瘤的表面过表达。为了获得更好的靶向肽，我们首先设计了一种源自白细胞介素-4（IL-4）的新型靶向肽，ILBP-b。ILBP-b 包含 IL-4 与 IL-4R 的关键高亲和力结合残基 E9。与报道的靶向肽ILBP-a（含有另一个关键的高亲和力残基R88）相比，荧光实验证明ILBP-b是更好的靶向肽。然后，我们进一步融合ILBP-b和ILBP-a以增加ILBP-b的多位点结合能力，得到更好的靶向肽ILBP-ba。与ILBP-a和ILBP-b相比，ILBP-ba对IL-4R高表达细胞显示出更强的优先结合能力。竞争性结合实验证明 ILBP-ba 特异性靶向 IL-4R。通过将 ILBP-ba 与药物蛋白天花粉 (TCS) 融合，体外载药实验表明，ILBP-ba可特异性增强TCS对IL-4R高表达肿瘤细胞的杀伤作用（10倍以上）。这些结果表明，ILBP-ba 在靶向 IL-4R 的药物递送应用方面具有巨大潜力，将有利于肿瘤治疗药物的开发。