@article {Muro1161, author = {Silvia Muro and Thomas Dziubla and Weining Qiu and John Leferovich and Xiumin Cui and Erik Berk and Vladimir R. Muzykantov}, title = {Endothelial Targeting of High-Affinity Multivalent Polymer Nanocarriers Directed to Intercellular Adhesion Molecule 1}, volume = {317}, number = {3}, pages = {1161--1169}, year = {2006}, doi = {10.1124/jpet.105.098970}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Targeting of diagnostic and therapeutic agents to endothelial cells (ECs) provides an avenue to improve treatment of many maladies. For example, intercellular adhesion molecule 1 (ICAM-1), a constitutive endothelial cell adhesion molecule up-regulated in many diseases, is a good determinant for endothelial targeting of therapeutic enzymes and polymer nanocarriers (PNCs) conjugated with anti-ICAM (anti-ICAM/PNCs). However, intrinsic and extrinsic factors that control targeting of anti-ICAM/PNCs to ECs (e.g., anti-ICAM affinity and PNC valency and flow) have not been defined. In this study we tested in vitro and in vivo parameters of targeting to ECs of anti-ICAM/PNCs consisting of either prototype polystyrene or biodegradable poly(lactic-coglycolic) acid polymers (\~{}200 nm diameter spheres carrying \~{}200 anti-ICAM molecules). Anti-ICAM/PNCs, but not control IgG/PNCs 1) rapidly (t1/2 \~{}5 min) and specifically bound to tumor necrosis factor-activated ECs in a dose-dependent manner (Bmax \~{}350 PNC/cell) at both static and physiological shear stress conditions and 2) bound to ECs and accumulated in the pulmonary vasculature after i.v. injection in mice. Anti-ICAM/PNCs displayed markedly higher EC affinity versus naked anti-ICAM (Kd \~{}80 pM versus \~{}8 nM) in cell culture and, probably because of this factor, higher value (185.3 {\textpm} 24.2 versus 50.5 {\textpm} 1.5\% injected dose/g) and selectivity (lung/blood ratio 81.0 {\textpm} 10.9 versus 2.1 {\textpm} 0.02, in part due to faster blood clearance) of pulmonary targeting. These results 1) show that reformatting monomolecular anti-ICAM into high-affinity multivalent PNCs boosts their vascular immuno-targeting, which withstands physiological hydrodynamics and 2) support potential anti-ICAM/PNCs utility for medical applications. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/317/3/1161}, eprint = {https://jpet.aspetjournals.org/content/317/3/1161.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }