Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
ACS Biomater Sci Eng. 2021 Oct 11;7(10):4859-4869. doi: 10.1021/acsbiomaterials.1c00792. Epub 2021 Sep 21.
KPV (Lys-Pro-Val), which is a tripeptide derived from α-MSH (α-melanocyte-stimulating hormone), has an anti-inflammatory effect on colitis. However, KPV solution is very unstable when rectally administered, compromising its therapeutic efficacy. Herein, cysteamine-grafted γ-polyglutamic acid (SH-PGA) was synthesized by conjugating cysteamine with the carboxyl groups of γ-PGA. The synthesized SH-PGA has the thiol grafting amount of 4.5 ± 0.3 mmol/g. Without the use of the cross-linker, the SH-PGA hydrogel with 4% of the polymer was formed by self-cross-linking of thiol groups. Moreover, the formation of the SH-PGA hydrogel was not affected by KPV. The KPV/SH-PGA hydrogel presented higher elastic modulus (') than the corresponding viscous modulus (″) at 0.01-10 Hz, exhibiting good mechanical stability. The KPV/SH-PGA hydrogel presented a shear-thinning behavior, which was helpful for rectal administration. Only 30% of KPV was released from the KPV/SH-PGA hydrogel within 20 min, followed by a sustained-release behavior. Importantly, the stability of KPV in the SH-PGA hydrogel was obviously enhanced, which was presented by detecting its anti-inflammatory activity and promoting cell migration potential after 2 h of exposure to 37 °C. The enhanced therapeutic effect of the KPV/SH-PGA hydrogel on colitis was confirmed on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced ulcerative colitis rats. The colitis symptoms including body weight loss and the disease activity index score were obviously attenuated by rectally administering the KPV/SH-PGA hydrogel. Besides, the KPV/SH-PGA hydrogel treatment prevented the colon shortening of TNBS-infused rats and decreased the colonic myeloperoxidase level. The morphology of the colon including the epithelial barrier, crypt, and intact goblet cells was recovered after KPV/SH-PGA hydrogel treatment. Besides, the KPV/SH-PGA hydrogel decreased the expression of proinflammatory cytokines such as tumor necrosis factor α and interleukin 6. Collectively, the KPV/SH-PGA hydrogel may provide a promising strategy for the treatment of ulcerative colitis.
KPV（Lys-Pro-Val）是一种源自α-MSH（α-黑色素细胞刺激激素）的三肽，对结肠炎具有抗炎作用。然而，当经直肠给药时，KPV 溶液非常不稳定，从而影响其治疗效果。在此，通过将半胱胺与 γ-PGA 的羧基缀合合成了半胱胺接枝 γ-聚谷氨酸（SH-PGA）。合成的 SH-PGA 的巯基接枝量为 4.5±0.3mmol/g。无需使用交联剂，通过巯基的自交联形成聚合物含量为 4%的 SH-PGA 水凝胶。此外，KPV 的存在并不影响 SH-PGA 水凝胶的形成。在 0.01-10Hz 下，KPV/SH-PGA 水凝胶的弹性模量（'）高于相应的粘性模量（″），表现出良好的机械稳定性。KPV/SH-PGA 水凝胶表现出剪切稀化行为，这有助于直肠给药。在 20 分钟内，只有 30%的 KPV 从 KPV/SH-PGA 水凝胶中释放出来，随后呈现持续释放行为。重要的是，在 37°C 下暴露 2 小时后，检测到其抗炎活性和促进细胞迁移潜力，KPV 在 SH-PGA 水凝胶中的稳定性明显增强。通过对 2,4,6-三硝基苯磺酸（TNBS）诱导的溃疡性结肠炎大鼠进行研究，证实了 KPV/SH-PGA 水凝胶对结肠炎的治疗效果增强。通过直肠给予 KPV/SH-PGA 水凝胶，明显减轻了结肠炎症状，包括体重减轻和疾病活动指数评分。此外，KPV/SH-PGA 水凝胶治疗可防止 TNBS 灌注大鼠的结肠缩短，并降低结肠髓过氧化物酶水平。KPV/SH-PGA 水凝胶治疗后，结肠的形态包括上皮屏障、隐窝和完整的杯状细胞得到恢复。此外，KPV/SH-PGA 水凝胶降低了肿瘤坏死因子 α 和白细胞介素 6 等促炎细胞因子的表达。总之，KPV/SH-PGA 水凝胶可能为溃疡性结肠炎的治疗提供一种有前途的策略。
