Yaser H Gholami, 1 4 Lee Josephson, 3 Eman A Akam, 5 Peter Caravan, 5 Moses Q Wilks, 3 Xiang-Zuo Pan, 3, 6 Richard Maschmeyer, 1 Aleksandra Kolnick, 3, 7 Georges El Fakhri, 3 Marc D Normandin, 3 Zdenka Kuncic, 1, 4, 8Hushan Yuan 3

1The University of Sydney, Faculty of Science, School of Physics, Sydney, NSW, Australia; 2Bill Walsh Translational Cancer Research Laboratory, The Kolling Institute, Northern Sydney Local Health District, Sydney, Australia; 3Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States; 4Sydney Vital Translational Cancer Research Centre, St Leonards, NSW, Australia; 5The Institute for Innovation in Imaging and the A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States; 6Bouve College of Health Sciences, CaNCURE Program, Northeastern University, Boston, MA, USA; 7Internal Medicine Residency Program, Lahey Hospital and Medical Center, Burlington, MA, USA; 8The University of Sydney Nano Institute, Sydney, NSW, Australia

Correspondence: Hushan YuanGordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 13 th Street, Charlestown, MA 02129, USATel +1 617-643-1963Email hyuan@mgh.harvard.edu

Purpose: Using our chelate-free, heat-induced radiolabeling (HIR) method, we show that a wide range of metals, including those with radioactive isotopologues used for diagnostic imaging and radionuclide therapy, bind to the Feraheme (FH) nanoparticle (NP), a drug approved for the treatment of iron anemia.Material and methods: FH NPs were heated (120C) with nonradioactive metals, the resulting metal-FH NPs were characterized by inductively coupled plasma mass spectrometry (ICP-MS), dynamic light scattering (DLS), and r 1 and r 2 relaxivities obtained by nuclear magnetic relaxation spectrometry (NMRS). In addition, the HIR method was performed with [ 90Y]Y 3+, [ 177Lu]Lu 3+, and [ 64Cu]Cu 2+, the latter with an HIR technique optimized for this isotope. Optimization included modifying reaction time, temperature, and vortex technique. Radiochemical yield (RCY) and purity (RCP) were measured using size exclusion chromatography (SEC) and thin-layer chromatography (TLC).Results: With ICP-MS, metals incorporated into FH at high efficiency were bismuth, indium, yttrium, lutetium, samarium, terbium and europium (> 75% @ 120 oC). Incorporation occurred with a small (less than 20%) but statistically significant increases in size and the r 2 relaxivity. An improved HIR technique (faster heating rate and improved vortexing) was developed specifically for copper and used with the HIR technique and [ 64Cu]Cu 2+. Using SEC and TLC analyses with [ 90Y]Y 3+, [ 177Lu]Lu 3+ and [ 64Cu]Cu 2+, RCYs were greater than 85% and RCPs were greater than 95% in all cases.Conclusion: The chelate-free HIR technique for binding metals to FH NPs has been extended to a range of metals with radioisotopes used in therapeutic and diagnostic applications. Cations with f-orbital electrons, more empty d-orbitals, larger radii, and higher positive charges achieved higher values of RCY and RCP in the HIR reaction. The ability to use a simple heating step to bind a wide range of metals to the FH NP, a widely available approved drug, may allow this NP to become a platform for obtaining radiolabeled nanoparticles in many settings.

Keywords: nanomedicine, radiolabeling, radionuclide therapy, HIR, Feraheme

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