An optimized integrin α6-targeted peptide capable of delivering toxins for melanoma treatment

作者：Zheng Zhao, Z. Li, Yingbin Huang, Meng-Meng Liu, Fei Cao, Guo‐Long Bu, Peng‐Fei Xu, Qi Fang, Zilun Hu, Di Wu, Guo‐Kai Feng, Xuekui Liu · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-06511-5 · 被引用次数：7 · 研究领域：RNA Interference and Gene Delivery、Cancer Research and Treatments、Immunotherapy and Immune Responses

BACKGROUND: Peptide-based therapeutics for melanoma have received increasing attention in medical research. However, the local delivery of such therapeutics poses unique challenges. Cell-penetrating peptides (CPPs) with the ability to selectively enter cancer cells, with sufficient stability and increased endosomal escape mechanisms, can provide a new and improved delivery strategy for therapeutic agents for treating cancer. METHODS: We developed a new combination strategy for the synthesis of penetrating peptides functionalized with targeting of integrin α6. The linear peptide S5 was multimerized with 4 copies in linear sequential order spaced by GSG between each copy to yield the 4S5 peptide. The multimerized 4S5 peptide coupled with an intracellular delivery peptide (N) and endosomal escape peptide (G) was separated by a GGS spacer. This optimized peptide was called 4S5NG. The 4S5NG, EGFP or PE24 peptide-protein conjugates were purified via a C-terminal His-tag. The uptake efficacy, intracellular distribution and integrin α6-targeting ability of these 4S5NG peptides were systematically characterized via IncuCyte, flow cytometry and in vivo imaging using 4S5NG-Cy5 or 4S5NG-EGFP. Moreover, 4S5NG-incorporated Pseudomonas aeruginosa (PE24) exotoxin A generated therapeutic peptides. The antitumor efficacy and underlying mechanism were studied in cell lines and a mouse model. In addition, the effect of 4S5NG-PE24 on antitumor immunity of a healthy immune system was investigated ...