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 ± 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 immunotargeting, which withstands physiological hydrodynamics and 2) support potential anti-ICAM/PNCs utility for medical applications.
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jun 2006|
ASJC Scopus subject areas
- Molecular Medicine