Development of Novel Adenosine Polymers for Coating Medical Devices

Project SummaryMyocardial infarctionMIoccurs inAmericans annually accounting for a mortality ofWhile percutaneous coronary interventionPCIis invariably successful in restoring epicardial patencysignificant microvascular obstructionMVOresulting in theno reflow phenomenonNRFoccurs frequently which significantly impacts mortality and the development of CHFCurrent devices are only partially effective in mitigating MVO and NRF following PCI for MIAdenosine attenuates many of the mechanisms responsible for MVO and NRFSeminal studies in our laboratory demonstrated that intravenous adenosine resulted in striking vascular and myocardial protection and this was subsequently confirmed in large clinical trialsAdenosine s full potential is compromised due to its ultra short half lifeSince the guidewire is the first PCI device deployed into the coronary vascular bedwe developed a simpletwo step procedure to make a pentameric form of adenosinePAthat can be coated onto guidewiresAdenowireand allows for continuous and sustained elution of adenosine into the coronary circulation during PCIWe validated the structure of PA with NMRits stability by calorimetry and confirmed its safety with biocompatibility testsWe also demonstrated that PA released adenosine in vitro overminsPorcine studies demonstrated that pharmacologically active amounts of adenosine are released as verified by a significant and sustained increase in coronary blood flow following wire insertionSince our initial submission of this grant proposal we have developed strong relationships with industry leading guidewire and coating companies resulting in the production of a viable commercial productThe goal of this Phase II application is to advance this novel technology to the clinical arenaWe will utilize a LDLR knockout swine model which manifests hypercholesterolemia and human like atherosclerotic lesionsTwo important mechanisms of MVO will be testedefficacy of Adenowire to reverse potent smooth muscle vasoconstrictorsandeffect of Adenowire to ameliorate cellular obstruction by endothelial cells and formed elements thereby attenuating NRF following regional ischemia and reperfusionThe data obtained from these studies will be invaluable in advancing this highly novel guidewire device to clinical trialsThe concept is transformative and has a high likelihood of success since it will deliver high concentrations of adenosine directly at the target site throughout the PCI procedureIf clinical trials confirm that Adenowire is effective in preventing MVO and NRF it would represent a major advance in treatment of MI patientsThis would have important societal and economic benefits for MI patients treated with PCI in the US each year