Received for publication December 2, 2005.
Revised February 16, 2006.
Accepted for publication February 23, 2006.

Endothelial targeting of high-affinity multivalent polymer nanocarriers directed to ICAM-1

Abstract

Targeting of diagnostic and therapeutic agents to endothelial cells (ECs) provides an avenue to improve treatment of many maladies. For example, 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, PNC valency, 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 PLGA polymers (~100 nm diameter spheres carrying ~200 anti-ICAM molecules). Anti-ICAM/PNCs, but not control IgG/PNCs: i) rapidly (t_1/2 ~5 min) and specifically bound to TNF-activated ECs in a dose-dependent manner (B_max ~350 PNC/cell) at both static and physiological shear stress conditions; and, ii) bound to ECs and accumulated in the pulmonary vasculature after IV injection in mice. Anti-ICAM/PNCs displayed markedly higher EC affinity vs maternal anti-ICAM (Kd ~80 pM vs ~8 nM) in cell culture, and, likely due to this factor, higher value (185.3±24.2 vs 50.5±1.5 %ID/g) and selectivity (lung-to-blood ratio 81.0±10.9 vs 2.1±0.02, in part due to faster blood clearance) of pulmonary targeting. These results: i) show that re-formatting monomolecular anti-ICAM into high-affinity multivalent PNCs boosts their vascular immunotargeting, which withstand physiological hydrodynamics; and, ii) support potential anti-ICAM/PNCs utility for medical applications.

Key words: ICAM-1, Vascular immunotargeting, drug delivery, endothelium, nanotechnology, pulmonary vasculature

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