ABSTRACT
PURPOSE: To assess the physicochemical properties, pharmacokinetic profiles, and in vivo positron emission tomography (PET) imaging of natriuretic peptide clearance receptors (NPRC) expressed on atherosclerotic plaque of a series of targeted, polymeric nanoparticles. METHODS: To control their structure, non-targeted and targeted polymeric (comb) nanoparticles, conjugated with various amounts of c-atrial natriuretic peptide (CANF, 0, 5, 10 and 25%), were synthesized by controlled and modular chemistry. In vivo pharmacokinetic evaluation of these nanoparticles was performed in wildtype (WT) C57BL/6 mice after (64)Cu radiolabeling. PET imaging was performed on an apolipoprotein E-deficient (ApoE(-/-)) mouse atherosclerosis model to assess the NPRC targeting efficiency. For comparison, an in vivo blood metabolism study was carried out in WT mice. RESULTS: All three (64)Cu-CANF-comb nanoparticles showed improved biodistribution profiles, including significantly reduced accumulation in both liver and spleen, compared to the non-targeted (64)Cu-comb. Of the three nanoparticles, the 25% (64)Cu-CANF-comb demonstrated the best NPRC targeting specificity and sensitivity in ApoE(-/-) mice. Metabolism studies showed that the radiolabeled CANF-comb was stable in blood up to 9 days. Histopathological analyses confirmed the up-regulation of NPRC along the progression of atherosclerosis. CONCLUSION: The 25% (64)Cu-CANF-comb demonstrated its potential as a PET imaging agent to detect atherosclerosis progression and status.
Subject(s)
Atherosclerosis/metabolism , Atrial Natriuretic Factor/metabolism , Copper Radioisotopes/metabolism , Nanoparticles/metabolism , Polymers/metabolism , Positron-Emission Tomography/methods , Animals , Atherosclerosis/diagnostic imaging , Atrial Natriuretic Factor/administration & dosage , Atrial Natriuretic Factor/chemistry , Copper Radioisotopes/administration & dosage , Copper Radioisotopes/chemistry , Drug Delivery Systems/methods , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Polymers/administration & dosage , Polymers/chemistry , Tissue Distribution/drug effects , Tissue Distribution/physiologyABSTRACT
This work describes the production of high-specific activity 55Co and the evaluation of the stability of 55Co-metal-chelate-peptide complexes in vivo. 55Co was produced via the 58Ni(p,α)55Co reaction and purified using anion exchange chromatography with an average recovery of 92% and an average specific activity of 1.96 GBq/µmol. 55Co-DO3A and 55Co-NO2A peptide complexes were radiolabeled at 3.7 MBq/µg and injected into HCT-116 tumor xenografted mice. Positron emission tomography (PET) and biodistribution studies were performed at 24 and 48 hours postinjection and compared to those of 55CoCl2. Both 55Co-metal-chelate complexes demonstrated good in vivo stability by reducing the radiotracers' uptake in the liver by sixfold at 24 hours with ~ 1% ID/g and at 48 hours with ~ 0.5% ID/g and reducing uptake in the heart by fourfold at 24 hours with ~ 0.7% ID/g and sevenfold at 48 hours with ~ 0.35% ID/g. These results support the use of 55Co as a promising new radiotracer for PET imaging of cancer and other diseases.
