A targeted drug delivery system for reducing neutrophil-mediated damage

There is an urgent need to develop effective therapies directed against specific mediators of acute respiratory distress syndrome ARDS Mortality remains high at to depending on disease severity with annual deaths in the US in Neutrophils have a critical role in early stages of lung injury and development of respiratory failure Pulmonary dysfunction is associated with excessive alveolar neutrophil recruitment with subsequent injury to the alveolar capillary barrier leading to ARDS Adhesion molecules involved in the neutrophil adhesion cascade ICAM VCAM and E selectin are involved in sepsis induced tissue damage Protein kinase C delta PKC is a critical inflammatory regulator of neutrophil recruitment sequestration and activation in the lung and is an important regulator of apoptosis We have preliminary data in a rodent model of sepsis showing that inhibition of PKC by an HIV trans activator of transcription TAT conjugated PKC inhibitory peptide was lung protective Therefore PKC is an important therapeutic target for control of neutrophil mediated lung damage in ARDS No pharmacological therapeutic interventions for sepsis are currently approved by either the US Food and Drug Administration or the European Medicines Evaluation Agency MedVas Concepts LLC proposes to develop an endothelium targeted nanocarrier drug delivery system immunoliposomes loaded with PKC TAT inhibitor using antibodies targeted towards specific adhesion molecules that are upregulated on the surface of endothelial cells in the pulmonary vasculature during sepsis Efficacy of the targeted drug delivery system will be investigated in vitro with a novel microfluidics platform seeded with cultured human lung primary microvascular endothelial cells that mimics physiological conditions in the microcirculation The microfluidics platform allows quantification of neutrophil attachment and transmigration in the device with and without immunoliposome treatment After optimizing the endothelium targeted immunoliposome drug delivery system we will conduct in vivo studies using our established rodent cecal ligation and puncture CLP sepsis model We anticipate that intravenous delivery of drug loaded immunoliposomes will provide a longer therapeutic window and expect to see less damage to the lung and longer survival times for immunoliposome treated animals compared with animals treated by intravenous delivery of free drug Project Narrative Sepsis is one of the leading causes of morbidity and mortality in intensive care units often associate with indirect injury to the lung that can lead to acute respiratory distress syndrome ARDS A key step in neutrophil mediated tissue damage to the lung and other organs with sepsis is the migration of activated neutrophils across the vascular endothelium We propose to develop a nanocarrier drug delivery system targeted to the pulmonary endothelium in order to control a specific enzyme protein kinase C delta PKC to prevent neutrophil mediated tissue injury and offer a unique therapeutic target for the treatment of ARDS