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Ex-vivo generation of drug-eluting islets improves transplant outcomes by inhibiting TLR4-Mediated NFkB upregulation
Biomaterials ( IF 12.8 ) Pub Date : 2017-12-28 , DOI: 10.1016/j.biomaterials.2017.12.020
Charles A. Chang , Babatope Akinbobuyi , Jeremy M. Quintana , Gumpei Yoshimatsu , Bashoo Naziruddin , Robert R. Kane

The systemic administration of immunosuppressive and anti-inflammatory drugs is routinely employed in organ transplantation to minimize graft rejection and improve graft survival. Localized drug delivery has the potential to improve transplant outcomes by providing sustained exposure to efficacious drug concentrations while avoiding systemic immunosuppression and off-target effects. Here, we describe the synthesis of a novel prodrug and its direct covalent conjugation to pancreatic islets via a cleavable linker. Post-transplant, linker hydrolysis results in the release of a potent anti-inflammatory antagonist of TLR4, localized to the site of implantation. This covalent islet modification significantly reduces the time and the minimal effective dose of islets necessary to achieve normoglycemia in a murine transplantation model. In streptozotocin-induced diabetic C57BL/6 mice a syngeneic transplant of ∼100 modified islets achieved a 100% cure rate by the end of a 4-week monitoring period, compared to a 0% cure rate for untreated control islets. Overall, this direct prodrug conjugation to islets is well tolerated and preserves their functionality while affording significantly superior transplant outcomes. The development of drug-eluting tissues that deliver sustained and localized doses of small-molecule therapeutics represents a novel pathway for enhancing success in transplantation.



中文翻译:

通过抑制TLR4介导的NFkB上调,离体产生药物洗脱的胰岛改善了移植结果

免疫抑制和抗炎药的全身给药常规用于器官移植,以最大程度地减少移植物排斥并提高移植物存活率。通过持续暴露于有效药物浓度,同时避免系统性免疫抑制和脱靶效应,局部药物递送具有改善移植结果的潜力。在这里,我们描述了新型前药的合成及其通过可裂解的接头与胰岛的直接共价结合。移植后,接头水解导致释放一种有效的TLR4抗炎拮抗剂,该拮抗剂位于植入位点。这种共价胰岛修饰显着减少了在鼠移植模型中达到正常血糖所需的时间和胰岛的最小有效剂量。在链脲佐菌素诱导的糖尿病C57BL / 6小鼠中,约100个修饰的胰岛的同基因移植物在4周的监测期结束时达到了100%的治愈率,而未治疗的对照胰岛的治愈率为0%。总体而言,这种直接的前药与胰岛的结合具有良好的耐受性,并保留了其功能,同时提供了明显优越的移植效果。递送持续和局部剂量的小分子治疗药物的药物洗脱组织的发展代表了增强移植成功的新途径。这种直接的前药与胰岛的结合具有良好的耐受性,并保留了其功能,同时提供了明显优越的移植效果。递送持续和局部剂量的小分子治疗药物的药物洗脱组织的发展代表了增强移植成功的新途径。这种直接的前药与胰岛的结合具有良好的耐受性,并保留了其功能,同时提供了明显优越的移植效果。递送持续和局部剂量的小分子治疗药物的药物洗脱组织的发展代表了增强移植成功的新途径。

更新日期:2017-12-31
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