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

 描述(申请人提供)：器官移植已成为治疗终末期器官衰竭的方法。从长远来看，慢性排斥仍然是移植物丢失的主要原因。其中一个主要原因是获得性免疫系统在器官移植中扮演着不可或缺的角色，并刚刚成为关键的介体。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，并通过包括氧化应激在内的炎症触发因素的释放，持续发挥作用的时间比最初认识到的更长。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者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的治疗方法。多酚类物质，如白藜芦醇(RSV)，可以减少器官移植相关的一系列病理变化，包括炎症。这些化合物的活性是通过多种机制实现的，包括它们特有的抗氧化作用和免疫抑制作用。然而，RSV的临床应用并不是主流，因为选择性差、剂量、毒性和给药方法等问题尚未解决。在这里，我们提出了一种新的递送方法，其中免疫治疗剂被包裹在生物惰性纳米颗粒中，并以靶向的方式递送到体内的同种异体移植物。对这件事 最后，我们已经产生了RSV类似物来提高RSV的生物利用度和毒性。RSV类似物在胶束纳米颗粒中的包裹及其对采集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，连接到精氨酸-甘氨酸-天冬氨酸(CRGD)的氨基酸序列上，作为针对内皮细胞上αvβ3整合素的靶向部分，从而优化细胞摄取。近红外荧光团也连接到表面，允许分析胶束摄取和细胞在供体器官移植物内皮内的定位。我们假设，通过冷藏灌流定向局部输送包装的RSV将增加RSV在细胞内的浓度，并保留同种异体主动脉的细胞结构。

 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.