PET/CT Imaging of Chemokine Receptor CCR5 in Vascular Injury Model Using Targeted Nanoparticle

Abstract

Inflammation 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. Methods The 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 64Cu 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. Results The 64Cu-DOTA-DAPTA tracer showed specific PET imaging of CCR5 in the ApoE−/− mice. The targeted 64Cu-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 64Cu-DOTA-DAPTA-comb in C57BL/6 mice and 64Cu-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. Conclusion This work provides a nanoplatform for sensitive and specific detection of CCR5’s physiologic functions in an animal atherosclerosis model.

Self-assembling peptide-based building blocks in medical applications

“…Other spherical nanoparticles based on amphiphilic peptide conjugates have been tested in vivo for diagnostic applications in vascular injury and cancer [155–158]. Luehmann et al .…”

Nanomedicine for the molecular diagnosis of cardiovascular pathologies

“…Luehmann et al [58] developed PMMA nanoparticles covered with a functionalized PEG shell targeted towards chemokine receptor 5. These nanoparticles were radiolabeled with 64 Cu for PET.…”

The Role of Attractiveness: Imaging the Interaction Between Cardiovascular and Immune System

“…It may, however, also be a disadvantage because minor changes of one chemokine receptor may be masked or even counterregulated by changes in other receptors, making the detection of subtle differences difficult. Other groups and prior work of the same group, for example, chose to focus on specific chemokine receptors such as CXCR4 or CCR5 and explored their role in cardiovascular disease (16,17). Another aspect that is promising and challenging at the same time is the use of nanoparticles and 64 Cu for labeling.…”