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（适用提供）：器官移植已成为治疗终阶段器官衰竭的方式。从长远来看，慢性排斥仍然是谷物丧失的主要原因。造成这种情况的主要原因之一是自适应免疫系统起着不可或缺的作用，并且正成为器官移植中的关键介体。积累的证据表明，在器官移植时激活了自适应免疫系统，并且在炎症触发因素（包括氧化物应激）的释放时，其发挥作用比最初识别的时间更长。各种翻译研究工作已经确定了途径和潜在的治疗，这些途径可能通过在同种批准接受者中赋予增强的感染分辨率和耐受性表型，从而可能对慢性排斥的所有影响。多酚（例如白藜芦醇（RSV））减少了与器官移植有关的一系列病理，包括感染。这些化合物的活性是通过各种机制来实现的，包括其表征良好的抗氧化作用和免疫抑制作用。 RSV的临床使用不是；但是，主流是关于选择性差，剂量，毒性和递送方法的问题。在这里，我们提出了一种新型的递送方法，其中一种免疫治疗性被封装在生物惰性纳米粒子中，并以靶向方式递送给体内的杂物。这 最后，我们生成了RSV类似物，以提高RSV的生物利用度和毒性。胶束纳米颗粒中RSV类似物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，该胶束纳米颗粒与Arg-Gly-Asp（CRGD）的氨基酸序列相结合，该氨基酸序列是针对内皮细胞上αVβ3整合蛋白的靶向部分，从而优化了细胞的摄取。红外荧光团也被缀合到表面，从而可以分析捐赠器官合金的胶束摄取和细胞定位。我们假设通过冷储存灌注对包装的RSV进行瞄准的局部递送将增加RSV内细胞内的浓度并保留主动脉合金的细胞划界。