Targeting angiogenesis using a C-type atrial natriuretic factor-conjugated nanoprobe and PET

Yongjian Liu, Eric D. Pressly, Dana R. Abendschein, Craig J. Hawker, Geoffrey E. Woodard, Pamela K. Woodard, Michael J. Welch

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Sensitive, specific, and noninvasive detection of angiogenesis would be helpful in discovering new strategies for the treatment of cardiovascular diseases. Recently, we reported the 64Cu-labeled C-type atrial natriuretic factor (CANF) fragment for detecting the upregulation of natriuretic peptide clearance receptor (NPR-C) with PET on atherosclerosis-like lesions in an animal model. However, it is unknown whether NPR-C is present and overexpressed during angiogenesis. The goal of this study was to develop a novel CANF-integrated nanoprobe to prove the presence of NPR-C and offer sensitive detection with PET during development of angiogenesis in mouse hind limb. Methods: We prepared a multifunctional, core-shell nanoparticle consisting of DOTA chelators attached to a poly(methyl methacrylate) core and CANF-targeting moieties attached to poly(ethylene glycol) chain ends in the shell of the nanoparticle. Labeling of this nanoparticle with 64Cu yielded a high-specific-activity nanoprobe for PET imaging NPR-C receptor in a mouse model of hind limb ischemia-induced angiogenesis. Histology and immunohistochemistry were performed to assess angiogenesis development and NPR-C localization. Results: 15O-H 2O imaging showed blood flow restoration in the previously ischemic hind limb, consistent with the development of angiogenesis. The targeted DOTA-CANF-comb nanoprobe showed optimized pharmacokinetics and biodistribution. PET imaging demonstrated significantly higher tracer accumulation for the targeted DOTA-CANF-comb nanoprobe than for either the CANF peptide tracer or the nontargeted control nanoprobe (P < 0.05, both). Immunohistochemistry confirmed NPR-C upregulation in the angiogenic lesion with colocalization in both endothelial and smooth muscle cells. PET and immunohistochemistry competitive receptor blocking verified the specificity of the targeted nanoprobe to NPR-C receptor. Conclusion: As evidence of its translational potential, this customized DOTA-CANF-comb nanoprobe demonstrated superiority over the CANF peptide alone for imaging NPR-C receptor in angiogenesis.

Original languageEnglish
Pages (from-to)1956-1963
Number of pages8
JournalJournal of Nuclear Medicine
Volume52
Issue number12
DOIs
StatePublished - Dec 1 2011

Keywords

  • Angiogenesis
  • Molecular imaging
  • Nanoparticle
  • Natriuretic peptide clearance receptor
  • Positron emission tomography

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