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 64Cu 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 64Cu-CANF-comb nanoparticles showed improved biodistribution profiles, including significantly reduced accumulation in both liver and spleen, compared to the non-targeted 64Cu-comb. Of the three nanoparticles, the 25% 64Cu-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% 64Cu-CANF-comb demonstrated its potential as a PET imaging agent to detect atherosclerosis progression and status.
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Abbreviations
- %ID/g:
-
Percent injected dose per gram of tissue
- %ID/organ:
-
Percent injected dose per organ of tissue
- °C:
-
Degree celsius
- AIBN:
-
Azobisisobutyronitrile
- ApoE−/− :
-
Apolipoprotein E-deficient
- CANF:
-
C-type atrial natriuretic factor
- DLS:
-
Dynamic light scattering
- DMF:
-
N, N-Dimethylformamide
- DOTA:
-
1,4,7,10-tetraazacyclododecane-1,4,7-tris(t-butyl acetate)
- EDTA:
-
Ethylenediaminetetraacetic acid
- F-FDG:
-
2-deoxy-2-[18F]-fluoro-D-glucose
- FIG:
-
Figure
- FPLC:
-
Fast performance liquid chromatography
- GPC:
-
Gel permeation chromatography
- H&E:
-
Hematoxyline and eosin
- HCD:
-
High cholesterol diet
- HPLC:
-
High pressure liquid chromatography
- I.V.:
-
Intravenous
- ITLC:
-
Instant thin layer chromatography
- MPS:
-
Mononuclear phagocyte system
- NPRC:
-
Natriuretic peptide clearance receptor
- NPRs:
-
Natriuretic peptide receptors
- PDI:
-
Polydispersity index
- PEGMA:
-
Polyethylene glycol methacrylate
- PET/CT:
-
Positron emission tomography/Computed tomography
- PI:
-
Post injection
- PMMA:
-
Poly(methyl methacrylate)
- RAFT:
-
Reversible addition-fragmentation chain-transfer
- RCP:
-
Radiochemical purity
- SPECT:
-
Single photon emission computed tomography
- WT:
-
Wildtype
REFERENCES
Nicolas J, Mura S, Brambilla D, Mackiewicz N, Couvreur P. Design, functionalization strategies and biomedical applications of targeted biodegradable/biocompatible polymer-based nanocarriers for drug delivery. Chem Soc Rev. 2013;42(3):1147–235.
Yang X, Yang M, Pang B, Vara M, Xia Y. Gold nanomaterials at work in biomedicine. Chem Rev. 2015;115(19):10410–88.
Elsabahy M, Heo GS, Lim SM, Sun G, Wooley KL. Polymeric nanostructures for imaging and therapy. Chem Rev. 2015;115(19):10967–1011.
Serra P, Santamaria P. Nanoparticle-based autoimmune disease therapy. Clin Immunol. 2015;160(1):3–13.
Andrade F, Rafael D, Videira M, Ferreira D, Sosnik A, Sarmento B. Nanotechnology and pulmonary delivery to overcome resistance in infectious diseases. Adv Drug Deliv Rev. 2013;65(13–14):1816–27.
Omlor AJ, Nguyen J, Bals R, Dinh QT. Nanotechnology in respiratory medicine. Respir Res. 2015;16:64.
Kemp JA, Shim MS, Heo CY, Kwon YJ. “Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy. Adv Drug Deliv Rev. 2016;98:3–18.
Young SW, Stenzel M, Jia-Lin Y. Nanoparticle-siRNA: a potential cancer therapy? Crit Rev Oncol Hematol. 2016;98:159–69.
Yang Y, Yu C. Advances in silica based nanoparticles for targeted cancer therapy. Nanomedicine. 2016;12(2):317–32.
Hofferberth SC, Grinstaff MW, Colson YL. Nanotechnology applications in thoracic surgery. Eur J Cardiothorac Surg. 2016.
Stendahl JC, Sinusas AJ. Nanoparticles for cardiovascular imaging and therapeutic delivery, part 2: radiolabeled probes. J Nucl Med. 2015;56(11):1637–41.
Min Y, Caster JM, Eblan MJ, Wang AZ. Clinical translation of nanomedicine. Chem Rev. 2015;115(19):11147–90.
Welch MJ, Hawker CJ, Wooley KL. The advantages of nanoparticles for PET. J Nucl Med. 2009;50(11):1743–6.
Elsabahy M, Wooley KL. Design of polymeric nanoparticles for biomedical delivery applications. Chem Soc Rev. 2012;41(7):2545–61.
Shokeen M, Pressly ED, Hagooly A, Zheleznyak A, Ramos N, Fiamengo AL, et al. Evaluation of multivalent, functional polymeric nanoparticles for imaging applications. ACS Nano. 2011;5(2):738–47.
Pressly ED, Rossin R, Hagooly A, Fukukawa K-I, Messmore BW, Welch MJ, et al. Structural Effects on the Biodistribution and Positron Emission Tomography (PET) imaging of well-defined 64Cu-labeled nanoparticles comprised of amphiphilic block graft copolymers. Biomacromolecules. 2007;8(10):3126–34.
Sanz J, Fayad ZA. Imaging of atherosclerotic cardiovascular disease. Nature. 2008;451(7181):953–7.
Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473(7347):317–25.
Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(9):2045–51.
Liu Y, Welch MJ. Nanoparticles labeled with positron emitting nuclides: advantages, methods, and applications. Bioconjug Chem. 2012;23(4):671–82.
Magnoni M, Ammirati E, Camici PG. Non-invasive molecular imaging of vulnerable atherosclerotic plaques. J Cardiol. 2015;65(4):261–9.
Nahrendorf M, Zhang H, Hembrador S, Panizzi P, Sosnovik DE, Aikawa E, et al. Nanoparticle PET-CT imaging of macrophages in inflammatory atherosclerosis. Circulation. 2008;117(3):379–87.
Sadat U, Jaffer FA, van Zandvoort MA, Nicholls SJ, Ribatti D, Gillard JH. Inflammation and neovascularization intertwined in atherosclerosis: imaging of structural and molecular imaging targets. Circulation. 2014;130(9):786–94.
Stacy MR, Sinusas AJ. Novel applications of radionuclide imaging in peripheral vascular disease. Cardiol Clin. 2016;34(1):167–77.
Stendahl JC, Sinusas AJ. Nanoparticles for cardiovascular imaging and therapeutic delivery, part 1: compositions and features. J Nucl Med. 2015;56(10):1469–75.
Tarkin JM, Joshi FR, Rajani NK, Rudd JH. PET imaging of atherosclerosis. Future Cardiol. 2015;11(1):115–31.
Tarkin JM, Joshi FR, Rudd JH. PET imaging of inflammation in atherosclerosis. Nat Rev Cardiol. 2014;11(8):443–57.
Irkle A, Vesey AT, Lewis DY, Skepper JN, Bird JL, Dweck MR, et al. Identifying active vascular microcalcification by (18)F-sodium fluoride positron emission tomography. Nat Commun. 2015;6:7495.
Casco VH, Veinot JP, de Bold Kuroski ML, Masters RG, Stevenson MM, de Bold AJ. Natriuretic peptide system gene expression in human coronary arteries. J Histochem Cytochem. 2002;50(6):799–809.
Liu Y, Abendschein D, Woodard GE, Rossin R, McCommis K, Zheng J, et al. Molecular imaging of atherosclerotic plaque with 64Cu-labeled natriuretic peptide and PET. J Nucl Med. 2010;51(1):85–91.
Pressly ED, Pierce RA, Connal LA, Hawker CJ, Liu Y. Nanoparticle PET/CT imaging of natriuretic peptide clearance receptor in prostate cancer. Bioconjug Chem. 2013;24(2):196–204.
Liu Y, Pressly ED, Abendschein DR, Hawker CJ, Woodard GE, Woodard PK, et al. Targeting angiogenesis using a C-type atrial natriuretic factor-conjugated nanoprobe and PET. J Nucl Med. 2011;52(12):1956–63.
Liu Y, Pierce R, Luehmann HP, Sharp TL, Welch MJ. PET imaging of chemokine receptors in vascular injury-accelerated atherosclerosis. J Nucl Med. 2013;54(7):1135–41.
Perrier S, Takolpuckdee P, Westwood J, Lewis DM. Versatile chain transfer agents for reversible addition fragmentation chain transfer (RAFT) polymerization to synthesize functional polymeric architectures. Macromolecules. 2004;37(8):2709–17.
Liu Y, Ibricevic A, Cohen JA, Cohen JL, Gunsten SP, Frechet JM, et al. Impact of hydrogel nanoparticle size and functionalization on in vivo behavior for lung imaging and therapeutics. Mol Pharm. 2009;6(6):1891–902.
Chen X, Hou Y, Tohme M, Park R, Khankaldyyan V, Gonzales-Gomez I, et al. Pegylated Arg-Gly-Asp peptide: 64Cu labeling and PET imaging of brain tumor alphavbeta3-integrin expression. J Nucl Med. 2004;45(10):1776–83.
Boswell CA, Sun X, Niu W, Weisman GR, Wong EH, Rheingold AL, et al. Comparative in vivo stability of copper-64-labeled cross-bridged and conventional tetraazamacrocyclic complexes. J Med Chem. 2004;47(6):1465–74.
Wang Y, Liu Y, Luehmann H, Xia X, Brown P, Jarreau C, et al. Evaluating the pharmacokinetics and in vivo cancer targeting capability of Au nanocages by positron emission tomography imaging. ACS Nano. 2012;6(7):5880–8.
Majmudar MD, Yoo J, Keliher EJ, Truelove JJ, Iwamoto Y, Sena B, et al. Polymeric nanoparticle PET/MR imaging allows macrophage detection in atherosclerotic plaques. Circ Res. 2013;112(5):755–61.
ACKNOWLEDGMENTS AND DISCLOSURES
This work is supported by the National Heart, Lung and Blood Institute of the National Institutes of Health as a Program of Excellence in Nanotechnology (HHSN268201000046C). The characterization of nanoparticles was performed in the Central Facilities of the UCSB Materials Research Laboratory supported by the MRSEC Program of the National Science Foundation under award no. DMR1121053. No other potential conflict of interest relevant to this article was reported.
We thank Nicole Fettig, Margaret Morris, Amanda Roth, Lori Strong, and Ann Stroncek for their assistance with animals and imaging studies and Tom Voller, Evelyn Madrid, Paul Eisenbies, Efrem Mebrahtu, and Suzanne Lapi for 64Cu production. We thank the helpful discussion and comments from Dr. Richard Pierce.
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Pamela K. Woodard, Yongjian Liu and Eric D. Pressly contributed equally to this work.
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Woodard, P.K., Liu, Y., Pressly, E.D. et al. Design and Modular Construction of a Polymeric Nanoparticle for Targeted Atherosclerosis Positron Emission Tomography Imaging: A Story of 25% 64Cu-CANF-Comb. Pharm Res 33, 2400–2410 (2016). https://doi.org/10.1007/s11095-016-1963-8
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DOI: https://doi.org/10.1007/s11095-016-1963-8