Targeting of Drugs to ICAM for Treatment of Acute Lung Injury
Abstract
In the second year, we characterized intracellular traffic and final destination of anti-CAM conjugates in endothelial cells (EC) and found that CAM-mediated endocytosis initiates an unusually slow vesicular traffic that delivers conjugates to lysosomes several hours after internalization. Further, auxiliary drugs that regulate these processes can be utilized for prolongation of therapeutic duration of internalized conjugates. We characterized a series of in-house models of human ALI (injection of anti-TM/GOX and hyperoxia in mice), studied dynamics and role of EC cell adhesion molecules and leukocytes in these models and developed a new, clinically relevant and reliable model of ALI, based on combined treatment with anti-TM/GOX and hyperoxia. We synthesized anti-CAM/SOD conjugate with proper targeting size (^200 nm), enzymatic activity and affinity to SC and documented that it accumulates in the pulmonary vasculature after intravenous injection, thus satisfying main requirements for subsequent testing in animal models of ALI. In vitro and in vivo fibrinolysis studies have been employed in order to select the optimal candidate fibrinolytic (a novel tPA derivative, Tenektase) for targeting to endothelial CAM. Design and production of optimized affinity carriers for this purpose is in progress.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2004
- Accession Number
- ADA425905
Entities
People
- Vladimir Muzykantov
Organizations
- University of Pennsylvania