A targeted drug delivery system for reducing neutrophil-mediated damage

Medvas Concepts, Llc, Wynnewood PA

Investigators

Abstract

There is an urgent need to develop effective therapies directed against specific mediators of acute respiratory distress syndrome (ARDS). Mortality remains high, at 27% to 45%, depending on disease severity, with 74,500 annual deaths in the US in 2005. 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-1, VCAM-1 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-1 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.