In recent years, targeting tumor angiogenesis has emerged as a prominent research focus in the treatment and prevention of tumor expansion. A7R (ATWLPPR) exhibits high affinity and specificity for VEGFR-2, which is overexpressed in various tumors. To enhance the tumor tissue and cell penetration capabilities of A7R, we substituted its non-critical amino acid with Arginine (R) and Glutamic acid (E), cyclized the mutant peptide, and linked it to the membrane permeation sequence using coordination principles. We designed and synthesized fifteen novel penetrating peptides that target tumor blood vessels and cells, followed by conducting various biological evaluations and cell imaging experiments. The results demonstrated that Cyclo-A7R-RRR and A7R-RLLRLLR exhibited excellent permeability towards tumor cells, with Cyclo-A7R-RRR showing superior serum stability compared to A7R. Furthermore, the modified peptides showed no toxicity towards HeLa cells, U251 cells, HuH-7 cells, and HEK293 cells under 10 μmol/L. Utilizing Cyclo-A7R-RRR or A7R-RLLRLLR for transmembrane delivery of drug molecules could significantly improve their efficacy. Our findings broaden the potential application scenarios of A7R in targeted tumor angiogenesis.

中文翻译：

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肿瘤血管靶向肽 A7R 的跨膜修饰作为分子货物递送工具

近年来，靶向肿瘤血管生成已成为治疗和预防肿瘤扩张的重要研究热点。 A7R (ATWLPPR) 对 VEGFR-2 表现出高亲和力和特异性，VEGFR-2 在多种肿瘤中过度表达。为了增强A7R的肿瘤组织和细胞渗透能力，我们用精氨酸（R）和谷氨酸（E）取代其非关键氨基酸，环化突变肽，并利用配位原理将其与膜渗透序列连接。我们设计并合成了十五种针对肿瘤血管和细胞的新型穿透肽，然后进行了各种生物学评估和细胞成像实验。结果表明，Cyclo-A7R-RRR和A7R-RLRLLR对肿瘤细胞表现出优异的渗透性，其中与A7R相比，Cyclo-A7R-RRR表现出优异的血清稳定性。此外，修饰后的肽在10 μmol/L下对HeLa细胞、U251细胞、HuH-7细胞和HEK293细胞没有毒性。利用Cyclo-A7R-RRR或A7R-RLLRLLR进行药物分子的跨膜递送可以显着提高其功效。我们的研究结果拓宽了 A7R 在靶向肿瘤血管生成中的潜在应用场景。