Reduction of Nanoparticle Avidity Enhances the Selectivity of Vascular Targeting and PET Detection of Pulmonary Inflammation

Abstract

Targeting nanoparticles (NPs) loaded with drugs and probes to precise locations in the body may improve the treatment and detection of many diseases. Generally, to achieve targeting, affinity ligands are introduced on the surface of NPs that can bind to molecules present on the cell of interest. Optimization of ligand density is a critical parameter in controlling NP binding to target cells and a higher ligand density is not always the most effective. In this study, we investigated how NP avidity affects targeting to the pulmonary vasculature, using NPs targeted to ICAM-1. This cell adhesion molecule is expressed by quiescent endothelium at modest levels and is upregulated in a variety of pathological settings. NP avidity was controlled by ligand density, with the expected result that higher avidity NPs demonstrated greater pulmonary uptake than lower avidity NPs in both naïve and pathological mice. However, in comparison with high avidity NPs, low avidity NPs exhibited several-fold higher selectivity of targeting to pathological endothelium. This finding was translated into a PET imaging platform that was more effective in detecting pulmonary vascular inflammation using low avidity NPs. Furthermore, computational modeling revealed that elevated expression of ICAM-1 on the endothelium is critical for multivalent anchoring of NPs with low avidity, while high avidity NPs anchor effectively to both quiescent and activated endothelium. These results provide a paradigm that can be used to optimize NP targeting by manipulating ligand density, and may find biomedical utility for increasing detection of pathological vasculature.

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“…Intercellular adhesion molecule-1 (ICAM-1) is constitutively expressed at a basal level on endothelial cells in quiescent vasculature but its expression is markedly elevated in pathologically activated endothelium. Introduction of reduced quantity of ICAM-1 specific antibody onto a particle surface enhanced the selectivity for binding to inflamed vasculature compared with normal tissues [159].…”

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“…To investigate the role of targeting ligands in tandem with hitchhiking, we utilized a lung inflammation model that induces over expression of ICAM on lung endothelium. By over-expressing ICAM on target tissues, interaction between ICAM-antibodies and lung inflamed endothelium is increased [53]. ICAM is widely explored as an attractive endothelial target in the context of inflammation.…”

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