HLS13-13 Albumin nanoparticle based technology to treat ARDS

DESCRIPTION provided by applicant Severe infections various types of trauma and other etiologic factors can cause ALI that rapidly morphs into ARDS The incidence of ALI ARDS is around in adults in US alone Despite medical advances and better management through ventilation intervention the mortality is still unacceptably high at This problem is likely to escalate given the aging population and can be a severe drain on our healthcare budget There is no formally recommended drug therapy in place for ALI patients except for switching to low volume ventilators Thus there is a pressing need for highly effective therapies for ALI ARDS In ALI ARDS the initial exudative phase is characterized by damage to the pulmonary endothelium and alveolar epithelium that results in leakage of protein rich fluid into the interstitium and alveoli along with inflammatory cells and RBCs At the onset of this phase neutrophils adhere to the activated endothelium and navigate into lung tissue thereby triggering a surge of inflammatory cytokines that cause the damage We propose to combat ALI ARDS by using nanotechnology specifically we will use a proof of principle drug piceatannol a naturally occurring plant stilbene chemically conjugated to albumin nanoparticles PANPs to andquot dis adhereandquot neutrophils tightly adherent to the activated lung vascular endothelium Piceatannol is a metabolite of resveratrol with significant anti inflammatory properties In supporting studies to overcome the solubility issue we conjugated piceatannol to albumin nanoparticles PANPs We observed that PANPs targeted adherent neutrophils and that these neutrophils achieved high effective intra cellular concentrations of the drug Using this innovative approach we demonstrated that PANP prevented ALI induced by i v challenge of TNF and LPS in mice We will therefore under the auspices of this STTR exploit the novel PANP strategy to reverse the course of ALI and thereby prevent ARDS In Phase we will have two following specific aims to develop systematically the therapeutic potential of this novel nanotechnology Specific Aim Determine the efficacy of i v administered PANPs in reversing the progression of endotoxin CLP and P aeruginosa in robust ALI ARDS mouse models causing severe ALI and determine whether the treatment is efficacious without compromising the lungandapos s intrinsic host defense function Specific Aim Determine role of PANPs in andquot dis adheringandquot the adherent neutrophils from activated endothelial cells as a primary mechanism of restoring lung homeostasis and rule out the possibility that the detached neutrophils are injuring distal organs such as the liver PUBLIC HEALTH RELEVANCE ALI ARDS is a disease with high mortality rate with significant disparities in the elderly and African descent and Latino patients who are particularly susceptible ALI ARDS patients also require extensive stays in ICUs and typically receive mechanical ventilation to overcome severe hypoxia and respiratory failure Unfortunately mechanical ventilation itself can exacerbate the lung injury There are no standard pharmacological treatments effective for ALI We propose to determine the efficacy of piceatannol loaded albumin nanoparticles in ALI ARDS mouse models based on our preliminary data showing the potential effectiveness of this nanotechnology approach As described below our nanodrug suppresses the initial steps in inflammation that precedes ALI by andquot de adheringandquot the neutrophils binding to the activated vascular endothelium thereby preventing the development of uncontrolled lung inflammation the root cause of compromised lungs vascular leakiness and edema in lungs