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 ?v?3 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.
The necessary immunomodulatory and anti-oxidant medications required to prevent organ transplant rejection carry with them a host of harmful systemic side effects and are currently delivered in an untargeted manner. Our group has identified a powerful nanoparticle device and targeting moiety to specifically deliver resveratrol analogs at the level of the organ allograft. These novel Targeted Resveratrol Micelles (TReM) address the glaring problems of global immune system mediation and lack of operational tolerance whilst setting the stage for future systems of therapeutic targeting and delivery in transplantation.
