Endothelial Targeting of High-affinity Multivalent Polymer Nanocarriers Directed to Intercellular Adhesion Molecule 1.
From: Institute for Environmental Medicine, 1 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104-6068, USA.
The Journal of pharmacology and experimental therapeutics
- Publish Date: Jun 2006
- ISSN: 0022-3565
- Volume: 317
- Issue: 3
- Pages: 1161-9
- Medium: Print
- Language: English
- Citation (JAMA): Muro Silvia, Dziubla Thomas, Qiu Weining, et al. Endothelial Targeting of High-affinity Multivalent Polymer Nanocarriers Directed to Intercellular Adhesion Molecule 1.. J. Pharmacol. Exp. Ther. Jun 2006;317:1161-9
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 (approximately 200 nm diameter spheres carrying approximately 200 anti-ICAM molecules). Anti-ICAM/PNCs, but not control IgG/PNCs 1) rapidly (t1/2 approximately 5 min) and specifically bound to tumor necrosis factor-activated ECs in a dose-dependent manner (Bmax approximately 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 approximately 80 pM versus approximately 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.
Mesh Headings (Keywords): Animals, Antibodies, Monoclonal, Antibody Affinity, Drug Carriers, Endothelial Cells, Endothelium, Vascular, Glycolates, Humans, Intercellular Adhesion Molecule-1, Male, Mice, Mice, Inbred C57BL, Nanostructures, Particle Size, Polymers, Polystyrenes, Rats, Rats, Sprague-Dawley
Check for Full Text / PubMed Unique Identifier (PMID): 16505161
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