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

白藜芦醇类似物的纳米治疗递送作为实体器官移植中同种异体移植物的预处理

• 批准号: 9306943
• 负责人: ANN-MARIE BROOME
• 金额: $ 7.48万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306943
• 关键词: Acute; Adaptive Immune System; Address; Adverse effects; Allografting; Amino Acid Sequence; Anti-Inflammatory Agents; Anti-inflammatory; Antigen Presentation; Antioxidants; Binding; Biological; Biological Availability; Biological Preservation; Cardiac; Cardiac Myocytes; Cell Line; Cell surface; Chronic; Clinical; Cryopreservation; Devices; Drug Delivery Systems; Drug Targeting; Encapsulated; Endothelial Cells; Endothelium; Engineering; Future; Glare; High Pressure Liquid Chromatography; Hour; Human; Image; Imaging Techniques; Immune system; Immunofluorescence Immunologic; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; In Vitro; Inbred BALB C Mice; Inflammation; Inflammatory; Integrin alphaVbeta3; Literature; Longevity; Mainstreaming; Measures; Mediation; Mediator of activation protein; Methods; Micelles; Modality; Mus; Organ Donor; Organ Harvestings; Organ Transplantation; Oxidative Stress; Pathology; Pathway interactions; Perfusion; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; RGD (sequence); Research Personnel; Resolution; Resveratrol; Role; Sampling; Solid; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staining method; Stains; Surface; System; Therapeutic; Thrombosis; Time; Tissues; Toxic effect; Translational Research; Transplantation; Umbilical vein; Universities; Wisconsin; analog; cytokine; dosage; end-stage organ failure; fluorophore; immunoregulation; improved; in vivo; nanoparticle; nanotherapeutic; novel; organ transplant rejection; polyphenol; prevent; public health relevance; receptor mediated endocytosis; targeted delivery; therapeutic target; trafficking; uptake

 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.

 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式。从长远来看，慢性排斥反应仍然是移植物丢失的主要原因。造成这种情况的主要原因之一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，并且通过释放炎症触发物（包括氧化应激）而发挥作用的时间比最初认识到的时间要长。各种转化研究工作已经确定了途径和潜在的治疗方法，可以通过增强同种异体移植受者的炎症消退和耐受表型来减轻慢性排斥反应的影响。多酚，例如白藜芦醇 (RSV)，可以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多种机制实现的，包括其众所周知的抗氧化作用和免疫抑制作用。 RSV 的临床应用不是；然而，由于选择性差、剂量、毒性和递送方法等问题尚未解决，因此成为主流。在这里，我们提出了一种新的递送方法，其中将免疫治疗药物封装在生物惰性纳米颗粒中，并以靶向方式递送至体内同种异体移植物。对此 最后，我们生成了RSV类似物以提高RSV的生物利用度和毒性。 RSV 类似物封装在胶束纳米颗粒中及其对收获器官的影响需要进行概念验证研究。我们将设计一种与 Arg-Gly-Asp (cRGD) 氨基酸序列缀合的胶束纳米颗粒，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。近红外荧光团也缀合到表面，允许分析供体器官同种异体移植物内皮内的胶束摄取和细胞定位。我们假设通过冷藏灌注有针对性地局部递送包装的 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。