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CARDIOVASCULAR

Endothelial Targeting of High-Affinity Multivalent Polymer Nanocarriers Directed to Intercellular Adhesion Molecule 1

Institute for Environmental Medicine (S.M., T.D., W.Q., J.L., X.C., E.B., V.R.M.), Targeted Therapeutics Program of the Institute for Translational Medicine and Therapeutics (S.M., T.D., V.M.), Department of Pharmacology (S.M., V.M.), School of Medicine, and Department of Bioengineering (W.Q.), School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania

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 (t_1/2 5 min) and specifically bound to tumor necrosis factor-activated ECs in a dose-dependent manner (B_max 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 (K_d 80 pM versus 8 nM) in cell culture and, probably because of this factor, higher value (185.3 ± 24.2 versus 50.5 ± 1.5% injected dose/g) and selectivity (lung/blood ratio 81.0 ± 10.9 versus 2.1 ± 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.

Address correspondence to: Dr. Vladimir R. Muzykantov, Institute for Environmental Medicine, 1 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6068. E-mail: muzykant{at}mail.med.upenn.edu

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