School of Chemistry, Pharmacy and Food Biosciences, University of Reading, Whiteknights, Reading RG6 6AH, U.K.
Nanomicroscopy Center, Aalto University, Puumiehenkuja 2, FIN-02150 Espoo, Finland.
ACS Appl Mater Interfaces. 2024 Oct 30;16(43):58417-58426. doi: 10.1021/acsami.4c14162. Epub 2024 Oct 18.
The self-assembly of lipopeptide (peptide amphiphile) molecules bearing single linear lipid chains has been widely studied, as has their diverse range of bioactivities. Here, we introduce lipopeptides bearing one or two cycloalkane chains (cycloheptadecyl or cyclododecyl) conjugated to the collagen-stimulating pentapeptide KTTKS used in Matrixyl formulations. The self-assembly of all four molecules is probed using fluorescence probe measurements to detect the critical aggregation concentration (CAC), and cryogenic-TEM and small-angle X-ray scattering (SAXS) to image the nanostructure. The peptide conformation is studied using circular dichroism (CD) and FTIR spectroscopies. All the cycloalkane lipopeptides show excellent compatibility with dermal fibroblasts. The compounds bearing one or two cyclododecyl chains (denoted as DKT and DDKT, respectively) show wound healing in diabetic rats, the improvement being markedly enhanced for DDKT. Interestingly, the revival of hair follicles and blood vessels in the dermis were observed, which are the critical markers of effective wound repair. Analysis of H&E-stained tissue images (from a rat model) shows that the rat groups treated with DDKT and DKT displayed a significantly increased amount of regenerated hair follicles, indicating a faster healing process for DDKT compared to the control group. Collagen deposition was also enhanced, especially for DDKT, and by day 20, the DDKT-treated groups had developed a dense collagen network accompanied by a regenerated epidermis. At the same time, the number of blood vessels in DDKT-treated diabetic wounds was significantly higher than in control groups and neovascularization was substantially enhanced, as assayed using α-SMA (a marker for vascular smooth muscle cells) and CD31 (a marker specific to vascular endothelial cells). These results suggest that the lead lipopeptide DDKT exhibits a remarkable pro-vascularization capability and shows great promise for future application as a wound-healing biomaterial.
具有单一直线型脂质链的脂肽（肽两亲分子）分子的自组装已得到广泛研究，其具有多种生物活性。在这里，我们介绍了带有一个或两个环烷链（十七烷或环十二烷）的脂肽，这些环烷链与用于 Matrixyl 配方的胶原蛋白刺激五肽 KTTKS 相连。使用荧光探针测量法来探测所有四个分子的自组装以检测临界聚集浓度（CAC），并使用低温透射电子显微镜和小角 X 射线散射（SAXS）来成像纳米结构。使用圆二色性（CD）和傅里叶变换红外光谱（FTIR）光谱研究肽构象。所有的环烷脂肽都与真皮成纤维细胞具有极好的相容性。带有一个或两个环十二烷链的化合物（分别表示为 DKT 和 DDKT）在糖尿病大鼠中显示出良好的伤口愈合作用，DDKT 的改善作用明显增强。有趣的是，在真皮中观察到毛囊和血管的再生，这是有效伤口修复的关键标志。对 H&E 染色组织图像（来自大鼠模型）的分析表明，用 DDKT 和 DKT 处理的大鼠组显示出大量再生的毛囊，表明与对照组相比，DDKT 的愈合过程更快。胶原蛋白沉积也得到了增强，尤其是 DDKT，到第 20 天，DDKT 处理组形成了密集的胶原蛋白网络，并伴有再生的表皮。同时，DDKT 处理的糖尿病伤口中的血管数量明显高于对照组，并且血管生成得到了很大增强，如用α-SMA（血管平滑肌细胞的标志物）和 CD31（血管内皮细胞的标志物）检测到的那样。这些结果表明，先导脂肽 DDKT 表现出显著的促血管生成能力，有望作为一种伤口愈合生物材料得到广泛应用。
