A Chelate-Free Nano-Platform for Incorporation of Diagnostic and Therapeutic Isotopes

A Chelate-Free Nano-Platform for Incorporation of Diagnostic and Therapeutic Isotopes

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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, 8 Hushan Yuan 3 1The University Treatment-Serums 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, AustraliaCorrespondence: 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.eduPurpose: 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 (120°C) 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 King Metal HDBD/FTBD/Rails 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.