Chawla Vatan, Roy Soumyajit, Raju John, Bundel Pruthviraj, Pal Durba, Singh Yashveer
Department of Chemistry, Indian Institute of Technology Ropar, Rupnagar-140 001, Punjab India.
Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar-140 001, Punjab India.
ACS Appl Bio Mater. 2025 Apr 21;8(4):2787-2799. doi: 10.1021/acsabm.4c01273. Epub 2025 Mar 19.
An intricate biochemical system of coordinated cellular reactions is involved in restoring damaged tissue after wounds. In chronic wounds, such as diabetic foot ulcers, poor angiogenesis is a common stumbling block due to elevated glucose levels, increased proteolytic enzyme activity, and decreased production of growth factors. While various strategies, including modulation of inflammatory cells, administration of growth factors, and therapies involving stem cells or genes, have been explored to promote angiogenesis, they often suffer from limitations such as poor biodistribution, immunological rejection, administration/dosing, and proteolytic instability. Glycosaminoglycans, such as heparan sulfate, facilitate growth factor interactions with their receptors to induce angiogenic signaling, but their exogenous administration is hindered by poor stability, low serum half-life, and immunogenicity. Cyclic peptides, known for their structural stability and specificity, offer a promising alternative for inducing angiogenesis upon functional modifications. In this work, we developed heparan sulfate (HS)-mimetic cyclic peptide nanotubes (CPNTs) grafted with bioactive groups to enhance angiogenesis without using exogenous growth factors, drugs, or supplements. These CPNTs incorporate glutamic acid, serine, and sulfonated lysine to mimic the functional groups in heparin. The sulfonated cyclic hexapeptide nanotubes developed from Pro-Trp-Leu-Ser-Glu-Lys demonstrated significant proangiogenic activity in HUVECs under hyperglycemic conditions; enhanced endothelial cell motility, invasion, and tube formation; and upregulation of proangiogenic genes and proteins. These HS-mimicking nanotubes have shown a strong potential for promoting impaired angiogenesis, without incorporating exogenous growth factors, and show strong potential in treating diabetic wounds. To the best of our knowledge, this is the first report on the use of HS-mimetic proangiogenic cyclic peptide nanotubes for diabetic wound healing.
一个由协调的细胞反应组成的复杂生化系统参与伤口后受损组织的修复。在慢性伤口中，如糖尿病足溃疡，由于葡萄糖水平升高、蛋白水解酶活性增加和生长因子产生减少，血管生成不良是一个常见的障碍。虽然已经探索了各种策略来促进血管生成，包括调节炎症细胞、施用生长因子以及涉及干细胞或基因的疗法，但它们往往存在生物分布差、免疫排斥、给药/剂量以及蛋白水解不稳定性等局限性。糖胺聚糖，如硫酸乙酰肝素，促进生长因子与其受体相互作用以诱导血管生成信号，但它们的外源性施用受到稳定性差、血清半衰期短和免疫原性的阻碍。环肽以其结构稳定性和特异性而闻名，在功能修饰后为诱导血管生成提供了一种有前景的替代方案。在这项工作中，我们开发了接有生物活性基团的硫酸乙酰肝素（HS）模拟环肽纳米管（CPNTs），以在不使用外源性生长因子、药物或补充剂的情况下增强血管生成。这些CPNTs包含谷氨酸、丝氨酸和磺化赖氨酸以模拟肝素中的官能团。由Pro-Trp-Leu-Ser-Glu-Lys开发的磺化环六肽纳米管在高血糖条件下的人脐静脉内皮细胞（HUVECs）中表现出显著的促血管生成活性；增强了内皮细胞的运动性、侵袭性和管形成；并上调了促血管生成基因和蛋白质。这些模拟HS的纳米管在不掺入外源性生长因子的情况下显示出促进受损血管生成的强大潜力，并且在治疗糖尿病伤口方面显示出强大潜力。据我们所知，这是关于使用模拟HS的促血管生成环肽纳米管用于糖尿病伤口愈合的首次报道。
