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Theranostics 2018; 8(18):5012-5024. doi:10.7150/thno.24791 This issue Cite

Research Paper

Multimodal imaging of the receptor for advanced glycation end-products with molecularly targeted nanoparticles

Christian J. Konopka^{1,2 *}, Marcin Wozniak^{3,4 *}, Jamila Hedhli^1,2, Agata Ploska^2,3,4, Aaron Schwartz-Duval¹, Anna Siekierzycka³, Dipanjan Pan^1,2, Gnanasekar Munirathinam⁵, Iwona T. Dobrucki², Leszek Kalinowski^{3,4 ✉}, Lawrence W. Dobrucki^{1,2,3,4 ✉}

1. Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL
2. Beckman Institute for Advanced Science and Technology, Urbana, IL
3. Department of Medical Laboratory Diagnostics and Central Bank of Frozen Tissues & Genetic Specimens, Medical University of Gdansk, Gdansk, Poland
4. Biobanking and Biomolecular Resources Research Infrastructure Poland (BBMRI.PL), Gdansk, Poland
5. Department of Biomedical Sciences, University of Illinois College of Medicine, Rockford, IL
^* These authors contributed equally to these studies

✉ Corresponding authors: Lawrence W. Dobrucki, Ph.D. University of Illinois at Urbana-Champaign. 405 N Mathews Ave, MC-251, Urbana, IL 61801. e-mail: dobruckiedu; phone: +1 217-244-3938; Leszek Kalinowski, M.D. Ph.D. Medical University of Gdansk, Poland. Debinki Street 7, 80-211 Gdansk, Poland. e-mail: lekaledu.pl; phone: +48 58 349-2791 More

Abstract

The receptor for advanced glycation end-products (RAGE) is central to multiple disease states, including diabetes-related conditions such as peripheral arterial disease (PAD). Despite RAGE's importance in these pathologies, there remains a need for a molecular imaging agent that can accurately assess RAGE levels in vivo. Therefore, we have developed a multimodal nanoparticle-based imaging agent targeted at RAGE with the well-characterized RAGE ligand, carboxymethyllysine (CML)-modified human serum albumin (HSA).

Methods: A multimodal tracer (⁶⁴Cu-Rho-G4-CML) was developed using a generation-4 (G4) polyamidoamine (PAMAM) dendrimer, conjugated with both rhodamine and copper-64 (⁶⁴Cu) chelator (NOTA) for optical and PET imaging, respectively. First, ⁶⁴Cu-Rho-G4-CML and its non-targeted analogue (⁶⁴Cu-Rho-G4-HSA) were evaluated chemically using techniques such as dynamic light scattering (DLS), electron microscopy and nuclear magnetic resonance (NMR). The tracers' binding capabilities were examined at the cellular level and optimized using live and fixed HUVEC cells grown in 5.5-30 mM glucose, followed by in vivo PET-CT imaging, where the probes' kinetics, biodistribution, and RAGE targeting properties were examined in a murine model of hindlimb ischemia. Finally, histological assessment of RAGE levels in both ischemic and non-ischemic tissues was performed.

Conclusions: Our RAGE-targeted probe demonstrated an average size of 450 nm, a Kd of 340-390 nM, rapid blood clearance, and a 3.4 times greater PET uptake in ischemic RAGE-expressing hindlimbs than their non-ischemic counterpart. We successfully demonstrated increased RAGE expression in a murine model of hindlimb ischemia and the feasibility for non-invasive examination of cellular, tissue, and whole-body RAGE levels with a molecularly targeted tracer.

Keywords: receptor for advanced glycation end-products, PET-CT, hindlimb ischemia, multimodal imaging, inflammation

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