Nanotherapeutic Delivery of Resveratrol Analogs as a Pre-Treatment of Allografts in Solid Organ Transplantation

 描述（由申请人提供）：器官移植已成为终末期器官衰竭的治疗方式。长期来看，慢性排斥反应仍然是移植物失功的主要原因。其中一个主要原因是适应性免疫系统发挥着不可或缺的作用，并且刚刚成为器官移植中的关键介质。越来越多的证据表明，适应性免疫系统在器官移植时被激活，并且比最初通过释放炎症触发物（包括氧化应激）而识别的时间更长。各种转化研究工作已经确定了可能通过增强同种异体移植受体的炎症消退和耐受性表型来减轻慢性排斥反应影响的途径和潜在治疗方法。多酚，如白藜芦醇（RSV），减少一系列与器官移植相关的病理，包括炎症。这些化合物的活性是通过各种机制实现的，包括其充分表征的抗氧化作用和免疫抑制作用。RSV的临床使用不是主流;然而，由于关于不良选择性、剂量、毒性和递送方法的问题尚未解决，因此成为主流。在这里，我们提出了一种新的递送方法，其中免疫球蛋白被封装在生物惰性纳米颗粒中，并以靶向方式递送到体内同种异体移植物。本 最后，我们已经产生了RSV类似物以改善RSV的生物利用度和毒性。RSV类似物在胶束纳米颗粒中的包封及其对收获器官的影响需要概念验证研究。我们将设计一种胶束纳米颗粒，其与Arg-Gly-Asp（cRGD）的氨基酸序列缀合，其作为靶向部分，针对内皮细胞上的αvβ3整联蛋白，优化细胞摄取。近红外荧光团也结合到表面，允许胶束吸收和供体器官同种异体移植物的内皮内的细胞定位的分析。我们假设通过冷藏灌注靶向局部递送包装的RSV将增加细胞内RSV的浓度并保留主动脉同种异体移植物的细胞结构。

 DESCRIPTION (provided by applicant): Organ transplantation has become the modality for the treatment of end-stage organ failure. Chronic rejection remains a leading cause of graft loss in the long term. One of the primary reasons for this is that the adaptive immune system plays an integral role and is just emerging as a critical mediator in organ transplantation. Accumulating evidence indicates that the adaptive immune system is activated at the time of organ transplantation and remains in play longer than initially recognized by the release of inflammatory triggers, including oxidative stress. Various translational research efforts have identified pathways and potential therapeutics that may allay the effects of chronic rejection by conferring an enhanced inflammation resolution and a tolerogenic phenotype in allograft recipients. Polyphenols, such as resveratrol (RSV), reduce a range of pathologies associated with organ transplantation, including inflammation. The activities of these compounds are achieved via various mechanisms including their well-characterized antioxidant effects and immunosuppression effects. The clinical use of RSV is not; however, mainstream as issues regarding poor selectivity, dosage, toxicity and delivery methods are unresolved. Here, we propose a novel delivery method wherein an immunotherapeutic is encapsulated in a biologically inert nanoparticle and delivered in a targeted manner to an allograft in vivo. To this end, we have generated RSV analogs to improve bioavailability and toxicity of RSV. The encapsulation of RSV analogs in micelle nanoparticles and its impact on harvested organs requires proof-of-concept studies. We will engineer a micelle nanoparticle which is conjugated to the amino acid sequence of Arg-Gly-Asp (cRGD), which serves as a targeting moiety directed towards the αvβ3 integrin on endothelial cells which optimizes cellular uptake. Near infrared fluorophores are also conjugated to the surface, allowing for analysis of micelle uptake and cellular localization within the endothelium of donor organ allografts. We hypothesize that targeted local delivery of packaged RSV via cold storage perfusion will increase concentrations of RSV intracellular and preserve aortic allograft cytoarchitecture.