Nanoentrapped polyphenol coatings for sustained release from angioplasty balloons

PROJECT SUMMARYPeripheral artery diseasePADis a serious cardiovascular disease affectingmillion people worldwidePAD is defined by a blockage of arteries in the lower extremitiesand is associated with painpoor wound healingand without interventionlimb loss and deathDrug coated balloonsDCBare an emerging clinical intervention aimed at clearing blocked arteriesparticularly those that are difficult to treatPAD is a particular case for DCB utilityThese arteries are poor candidates for stenting because of a high degree of stent fracture due to flexure and contraction of muscleIn factballoon angioplasty without stenting is the first line of therapy in PADBy coating the balloon with a drugit is possible to limit the re narrowing of the artery that often occurs after angioplastyAll commercial DCB use a chemotherapy agentpaclitaxelapplied directly to the balloon surfacecausing concern about its potential systemic toxicity upon non specific release into the circulationIn facta recent report suggests that use of paclitaxel coated balloons in the lower limbs leads to an increased risk of deathThusalternatives to paclitaxel for DCB are criticalThe PI has shown that two natural productsresveratrol and quercetinsynergize to significantly reduce vessel re narrowingwhile promoting vascular healingSpecificallythey reduce the adverse proliferation of vascular smooth muscle cellsbut also reduce inflammation and platelet activation while promoting the regrowth of the protective endothelial layerIn prior studiestheir use on a drug eluting stent showed dramatic efficacy in small animal modelsHoweverthe design of a DCB presents unique engineering challengesin that the drug must be delivered to target lesions after only a brief balloon inflationThe team has developed an innovative delivery system that entraps the compounds and releases them slowly over timeThe investigators propose a DCB in which drug entrapped polymeric nanoparticlespNPsremain adhered to the surface of a balloonUpon inflation within the arterythe positively charged pNP transfer to the negatively charged phospholipid membrane comprising the artery wallSince we use natural products with high safety profilesour drugs should also exhibit less systemic toxicity if released systemicallyTo finalize development of our prototypein this Phase I proposal we will optimize an electrospray process for achieving a high quality coating of our polyphenol pNP delivery system onto an angioplasty balloon surfaceThe balloon coating will be evaluated for drug loadinguniformity and retention on the balloon surfaceOnce optimizedthe DCB will be inflated in an artery of a rodent model to ensure that appreciable drug levels are achieved within the vessel for several days after angioplastyThe significance of this polyphenol coated DCB is that by promoting vascular healingre endothelializationits use in vascular interventions could reduce the need for anti platelet therapies and repeat interventionMoreoverthe large safety profile of these polyphenols and our use of pNPs for their entrapment and controllable release should provide for less systemic toxicity and safer long term outcomes NARRATIVE Peripheral artery diseasePADis a serious cardiovascular disease affectingmillion patients worldwidePAD is defined by a blockage of arteries in the lower extremitiesand is associated with painpoor wound healingand without interventionlimb loss and deathBalloon angioplastythe inflation of a balloon within a blocked arteryis the first line of therapy for PADBy coating the balloon with a drugit is possible to limit the re narrowing of the artery that often occurs after angioplastyMost commercial drug coated balloons use a toxic chemotherapy agent applied directly to the balloon surfaceWhat we propose here is an innovative delivery system that entraps our drugs of interest and releases them slowly over time in aqueous compartmentsMoreoverwe utilize two natural products with high safety profiles that should be less problematic if released in bloodTo finalize developmentin this proposal we will implement a spray process for uniformly coating these drugs onto the balloon surface