A targeted drug delivery system for reducing neutrophil-mediated damage

Period of Performance: 08/01/2016 - 07/31/2017

$223K

Phase 1 SBIR

Recipient Firm

Medvas Concepts Company
Wynnewood, PA 19096
Principal Investigator

Abstract

There is an urgent need to develop effective therapies directed against specific mediators of acute respiratorydistress syndrome (ARDS). Mortality remains high, at 27% to 45%, depending on disease severity, with 74,500annual deaths in the US in 2005. Neutrophils have a critical role in early stages of lung injury and development of respiratory failure. Pulmonarydysfunction 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 criticalinflammatory regulator of neutrophil recruitment, sequestration, and activation in the lung and is an importantregulator of apoptosis. We have preliminary data in a rodent model of sepsis showing that inhibition of PKC? byan 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. Nopharmacological therapeutic interventions for sepsis are currently approved by either the US Food and DrugAdministration 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 adhesionmolecules 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 platformseeded with cultured human lung primary microvascular endothelial cells that mimics physiological conditions inthe microcirculation. The microfluidics platform allows quantification of neutrophil attachment and transmigrationin the device with and without immunoliposome treatment. After optimizing the endothelium-targetedimmunoliposome drug delivery system, we will conduct in vivo studies using our established rodent cecal ligationand puncture (CLP) sepsis model. We anticipate that intravenous delivery of drug-loaded immunoliposomes willprovide a longer therapeutic window and expect to see less damage to the lung and longer survival times forimmunoliposome treated animals compared with animals treated by intravenous delivery of free drug.