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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 naive 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.

SUBMITTER: Zern BJ

PROVIDER: S-EPMC3609928 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Reduction of nanoparticle avidity enhances the selectivity of vascular targeting and PET detection of pulmonary inflammation.

Zern Blaine J BJ Chacko Ann-Marie AM Liu Jin J Greineder Colin F CF Blankemeyer Eric R ER Radhakrishnan Ravi R Muzykantov Vladimir V

ACS nano 20130208 3

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 avidi ...[more]

PMID: 23383962

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Project description:UnlabelledInflammation plays important roles at all stages of atherosclerosis. Chemokine systems have major effects on the initiation and progression of atherosclerosis by controlling the trafficking of inflammatory cells in vivo through interaction with their receptors. Chemokine receptor 5 (CCR5) has been reported to be an active participant in the late stage of atherosclerosis and has the potential as a prognostic biomarker for plaque stability. However, its diagnostic potential has not yet been explored. The purpose of this study was to develop a targeted nanoparticle for sensitive and specific PET/CT imaging of the CCR5 receptor in an apolipoprotein E knock-out (ApoE(-/-)) mouse vascular injury model.MethodsThe D-Ala1-peptide T-amide (DAPTA) peptide was selected as a targeting ligand for the CCR5 receptor. Through controlled conjugation and polymerization, a biocompatible poly(methyl methacrylate)-core/polyethylene glycol-shell amphiphilic comblike nanoparticle was prepared and labeled with (64)Cu for CCR5 imaging in the ApoE(-/-) wire-injury model. Immunohistochemistry, histology, and real-time reverse transcription polymerase chain reaction (RT-PCR) were performed to assess the disease progression and upregulation of CCR5 receptor.ResultsThe (64)Cu-DOTA-DAPTA tracer showed specific PET imaging of CCR5 in the ApoE(-/-) mice. The targeted (64)Cu-DOTA-DAPTA-comb nanoparticles showed extended blood signal and optimized biodistribution. The tracer uptake analysis showed significantly higher accumulations at the injury lesions than those acquired from the sham-operated sites. The competitive PET receptor blocking studies confirmed the CCR5 receptor-specific uptake. The assessment of (64)Cu-DOTA-DAPTA-comb in C57BL/6 mice and (64)Cu-DOTA-comb in ApoE(-/-) mice verified low nonspecific nanoparticle uptake. Histology, immunohistochemistry, and RT-PCR analyses verified the upregulation of CCR5 in the progressive atherosclerosis model.ConclusionThis work provides a nanoplatform for sensitive and specific detection of CCR5's physiologic functions in an animal atherosclerosis model.

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Reduction of nanoparticle avidity enhances the selectivity of vascular targeting and PET detection of pulmonary inflammation.

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Reduction of nanoparticle avidity enhances the selectivity of vascular targeting and PET detection of pulmonary inflammation.

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