Targeting of Drugs to ICAM for Treatment of Acute Lung Injury
Annual rept. 11 Mar 2004-10 Mar 2005
PENNSYLVANIA UNIV PHILADELPHIA
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In the third year, we experimentally tested and documented that ant I-CAMSOD and anti- CAMSODcatalase tandem conjugates targeted to endothelial cells detoxify diverse reactive oxygen species, thereby protecting cells against oxidative stress and toxicity via apoptotic and necrotic pathways, which permits testing of therapeutic effect of the conjugates in animal models in the fourth year. We designed, synthesized and tested a novel anti-CAM scFvpro-urokinase recombinant fusion protein construct and documented that it is properly assembled and folded, thereby retaining ability to bind to endothelial cells and be activated by plasmin to produce local fibrinolysis. Further, this fusion protein accumulates in the pulmonary vasculature of naive, but not PECAM-deficient mice and markedly enhances dissolution of pulmonary thrombi in vivo. We also tested potential adverse effects of accumulation of stable anti-CAM polymer conjugates inside the endothelial cells and detected no signs of cellular injury or compromised uptake and vesicular traffic inside the endothelial cells. These results imply that CAM-targeted delivery of antioxidant and anti-thrombotic drugs, directed to either intracellular or surface compartment of endothelium, provides safe means for treatment ALIARDS.
- Anatomy and Physiology
- Stress Physiology