Lee Wonhwa, Park Eun Ji, Kwon Oh Kwang, Kim Hyelim, Yoo Youngbum, Kim Shin-Woo, Seo Young-Kyo, Kim In-San, Na Dong Hee, Bae Jong-Sup
College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu, 41566, Republic of Korea; Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea; D&D Pharmatech, Seongnam, Gyeonggi-do, 13486, Republic of Korea.
Biomaterials. 2020 Jul;246:120000. doi: 10.1016/j.biomaterials.2020.120000. Epub 2020 Mar 28.
Sepsis is a potentially fatal complication of infections and there are currently no effective therapeutic options for severe sepsis. In this study, we revealed the secretion mechanism of transforming growth factor β-induced protein (TGFBIp) that was recently identified as a therapeutic target for sepsis, and designed TGFBIp acetylation inhibitory peptide (TAIP) that suppresses acetylation of lysine 676 in TGFBIp. To improve bioavailability and biodegradation of the peptide, TAIP was conjugated to polyamidoamine (PAMAM) dendrimers. Additionally, the cell-penetrating peptide (CPP) was conjugated to the TAIP-modified PAMAM dendrimers for the intracellular delivery of TGFBIp. The resulting nanostructures, decorated with TAIP and CPP via poly(ethylene glycol) linkage, improved the mortality and organ damage in the septic mouse model and suppressed lipopolysaccharide-activated severe vascular inflammatory responses in endothelial cells. Thus, the dendrimer-based nanostructures for delivery of TAIP using CPP show great promise in practical applications in sepsis therapy.
脓毒症是感染的一种潜在致命并发症，目前对于严重脓毒症尚无有效的治疗选择。在本研究中，我们揭示了转化生长因子β诱导蛋白（TGFBIp）的分泌机制，该蛋白最近被确定为脓毒症的治疗靶点，并设计了抑制TGFBIp中赖氨酸676乙酰化的TGFBIp乙酰化抑制肽（TAIP）。为提高该肽的生物利用度和生物降解性，将TAIP与聚酰胺胺（PAMAM）树枝状大分子偶联。此外，将细胞穿透肽（CPP）与TAIP修饰的PAMAM树枝状大分子偶联，用于TGFBIp的细胞内递送。通过聚乙二醇连接修饰有TAIP和CPP的所得纳米结构，改善了脓毒症小鼠模型中的死亡率和器官损伤，并抑制了内皮细胞中脂多糖激活的严重血管炎症反应。因此，使用CPP递送TAIP的基于树枝状大分子的纳米结构在脓毒症治疗的实际应用中显示出巨大潜力。
