A nanotechnology approach to higher brain penetrance and sustained brain delivery of intranasal oxytocin

Psychostimulant abuse is a significant public health problemwithmillion Americans reporting cocaine use andmillion reporting methamphetamine useCurrentlythere are no FDA approved pharmacotherapies to treat stimulant dependencePrevious cocaine medications development efforts have focused on small molecule drugs as they can readily enter the brainThe lack of brain penetrance by large molecules was seen as a critical barrier to the use of neuropeptides for cocaine addiction and other central nervous systemCNSdisordersThis is unfortunate as a large body of animal studies support the potential of neuropeptides to treat substance use disordersThe physiology of the blood brain barrierBBBpresents an attractive solution to this dilemmaas although under normal conditions most neuropeptides do not enter the brain because their sizeprevents passivethe BBB endothelium is equipped with a variety of molecular active transport systems that use processes such as receptor mediated transcytosis to transport macromolecules like insulin and transferrin between blood and brainWe have validated a procedure to conjugate biocompatiblebiodegradableand FDA approved nanoparticles to state of the art brain targeting ligandsThese brain targeting ligands then allow the nanoparticles to undergo receptor mediated transcytosis into the brainand then release the neuropeptide over a sustained timecourse to act at their central receptorsIn the proposed studieswe will focus on enhancement of the brain penetrance of the hormone oxytocin because of the substantial body of previous studies showing that oxytocin attenuates the abuse related effects of psychostimulantsAlthough we will focus on the development of this technology using oxytocinwe believe that this new technology will be applicable to many other neuropeptidessuch as neuropeptide Ythat have shown promise for substance use disordersDemonstrating the feasibility of our approachwe have collected compelling preliminary data showing our nanoparticles do not exhibit in vitro or in vivo toxicitycan be optimized to achieve sizes on the order ofnmwhich is highly amenable to brain deliveryincrease the brain penetrance of an IR markerof similar molecular size to oxytocinusing bioimagingengender stronger prosocial effects than oxytocin solution given intranasallysuppress the behavioral effects of cocaineand exhibit sustained release effects both in vitro and in vivoWe propose to engage in reproducibility assessments to further characterize the CNS bioavailabilityusing cell culture and bioimagingto further establish the therapeutic efficacy in an animal model of cocaine use disorderand to determine the benefits of nasalvsIP and IV administration of this formulation Psychostimulant abuse is a significant public health problemwithmillion Americans reporting cocaine use andmillion reporting methamphetamine useand currentlythere are no FDA approved pharmacotherapies to treat stimulant dependenceWe propose to engage in reproducibility assessments to further characterize the CNS bioavailabilityusing cell culture and bioimagingto further establish the therapeutic efficacy in an animal model of cocaine use disorderand to determine the benefits of nasalvsIP and IV administration of a state ofthe art nanotechnology drug carrier that we have developed to increase the brain targeting and sustain the delivery of neuropeptides such as oxytocin that are potential pharm acotherapeutics for substanc e use disorders