CC Chemokine Receptor 5 Targeted Nanoparticles Imaging the Progression and Regression of Atherosclerosis Using Positron Emission Tomography/Computed Tomography

Abstract

Chemokines and chemokine receptors play an important role in the initiation and progression of atherosclerosis by mediating the trafficking of inflammatory cells. Chemokine receptor 5 (CCR5) has major implications in promoting the development of plaques to advanced stage and related vulnerability. CCR5 antagonist has demonstrated the effective inhibition of atherosclerotic progression in mice, making it a potential biomarker for atherosclerosis management. To accurately determine CCR5 in vivo, we synthesized CCR5 targeted Comb nanoparticles through a modular design and construction strategy with control over the physiochemical properties and functionalization of CCR5 targeting peptide D-Ala-peptide T-amide (DAPTA-Comb). In vivo pharmacokinetic evaluation through 64 Cu radiolabeling showed extended blood circulation of 64 Cu-DAPTA-Combs conjugated with 10%, 25%, and 40% DAPTA. The different organ distribution profiles of the three nanoparticles demonstrated the effect of DAPTA on not only physicochemical properties but also targeting efficiency. In vivo positron emission tomography/ computed tomography (PET/CT) imaging in an apolipoprotein E knockout mouse atherosclerosis model (ApoE −/− ) showed that the three 64 Cu-DAPTA-Combs could sensitively and specifically detect CCR5 along the progression of atherosclerotic lesions. In an ApoE-encoding adenoviral vector (AAV) induced plaque regression ApoE −/− mouse model, decreased monocyte recruitment, CD68+ macrophages, CCR5 expression, and plaque size were all associated with reduced PET signals, which not only further confirmed the targeting efficiency of 64 Cu-DAPTA-Combs but also highlighted the potential of these targeted nanoparticles for atherosclerosis imaging. Moreover, the up-regulation of CCR5 and colocalization with CD68+ macrophages in the necrotic core of ex vivo human plaque specimens warrant further investigation for atherosclerosis prognosis.

Advances in Radiopharmaceutical Sciences for Vascular Inflammation Imaging: Focus on Clinical Applications

“…[ 64 Cu]Cu-DOTA-DAPTA-Comb were tested both in an ApoE –/– mouse model and in human carotid endarterectomy specimens. In the ApoE –/– mouse model, results showed sensitive and specific detection of CCR5 in plaques not only along the progression of atherosclerotic lesions, but also during plaque regression and the human ex vivo experiment, which confirmed the potential of CCR5 targeting in human atherosclerosis [ 73 ].…”

PET Imaging Radiotracers of Chemokine Receptors

“…Promising results from PET studies using [ 68 Ga]pentixafor ( 14), [ 64 Cu]DOTA-ECL1i (1), and [ 64 Cu]DOTA-DAPTA-comb (5) expanded the boundaries of cancer and cardiac disorder imaging for CXCR4, CCR2, and CCR5, respectively. In addition, [ 64 Cu]Cu@CuO x -ECL1i-Gem [103] and [ 177 Lu]pentixather [146] may aid the development of suitable theranostic agents for the treatment of chemokine-related cancers. It is important to note that antibody-based PET radiotracers (immunoPET) have garnered attention in recent years because of their superior target specificity and ability to selectively image immune cells and inflammatory processes [147].…”

“…D-Ala1-peptide T-amide (DAPTA) is a synthetic CCR5-specific octapeptide (D-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-NH 2 ) that inhibits the entry of HIV with 0.1 nM antagonist activity [101]. In 2014, Luehmann et al, developed a Cu-64-labeled DOTA-DAPTA ([ 64 Cu]DOTA-DAPTA, 4, Figure 2) and a Cu-64-labeled DOTA-DAPTA-comb nanoparticle (5) [102,103]. The DOTA-DAPTA-comb nanoparticle is a block copolymer of poly(methacrylate) whose ester groups were conjugated to PEG and PEG-DAPTA.…”

PCSK9 Imperceptibly Affects Chemokine Receptor Expression In Vitro and In Vivo

“…Various studies have observed that inhibition of CCR5 reduces the production of inflammatory cytokines [ 44 , 45 ] and atherosclerosis [ 46 ]. Therapeutic targeting of CCR5 facilitates the control of inflammatory situations, especially in the context of cardiac complications.…”