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

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 (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 r1 and r2 relaxivities obtained by nuclear magnetic relaxation spectrometry (NMRS). In addition, the HIR method was performed with [90Y]Y3+, [177Lu]Lu3+, and [64Cu]Cu2+, 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 r2 relaxivity. An improved HIR technique (faster heating rate and improved vortexing) was developed specifically for copper and used with the HIR technique and [64Cu]Cu2+. Using SEC and TLC analyses with [90Y]Y3+, [177Lu]Lu3+ and [64Cu]Cu2+, 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.

[1]  Z. Kuncic,et al.  Radio-enhancement effects by radiolabeled nanoparticles , 2019, Scientific Reports.

[2]  Nicolas H Voelcker,et al.  Surface radio-mineralisation mediates chelate-free radiolabelling of iron oxide nanoparticles† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c8sc04895a , 2019, Chemical science.

[3]  M. Shamsipur,et al.  An overview of nanoscale radionuclides and radiolabeled nanomaterials commonly used for nuclear molecular imaging and therapeutic functions. , 2018, Journal of biomedical materials research. Part A.

[4]  Tobias L Ross,et al.  Nanoparticles for SPECT and PET Imaging: Towards Personalized Medicine and Theranostics. , 2018, Current medicinal chemistry.

[5]  Tingting Wang,et al.  Cu-Fe-Se Ternary Nanosheet-Based Drug Delivery Carrier for Multimodal Imaging and Combined Chemo/Photothermal Therapy of Cancer. , 2018, ACS applied materials & interfaces.

[6]  D. Bailey,et al.  Comparison of radiobiological parameters for 90Y radionuclide therapy (RNT) and external beam radiotherapy (EBRT) in vitro , 2018, EJNMMI Physics.

[7]  H. Benveniste,et al.  Simultaneous Preclinical Positron Emission Tomography-Magnetic Resonance Imaging Study of Lymphatic Drainage of Chelator-Free 64Cu-Labeled Nanoparticles. , 2018, Cancer biotherapy & radiopharmaceuticals.

[8]  Jimin Liang,et al.  Intrinsically Zirconium-89-Labeled Manganese Oxide Nanoparticles for In Vivo Dual-Modality Positron Emission Tomography and Magnetic Resonance Imaging. , 2018, Journal of biomedical nanotechnology.

[9]  Georges El Fakhri,et al.  Heat-induced radiolabeling and fluorescence labeling of Feraheme nanoparticles for PET/SPECT imaging and flow cytometry , 2018, Nature Protocols.

[10]  Z. Kuncic,et al.  Nanoparticle radio-enhancement: principles, progress and application to cancer treatment , 2018, Physics in medicine and biology.

[11]  Jason P. Holland,et al.  Advanced Methods for Radiolabeling Multimodality Nanomedicines for SPECT/MRI and PET/MRI , 2017, The Journal of Nuclear Medicine.

[12]  Peng Huang,et al.  Chelator-Free Labeling of Metal Oxide Nanostructures with Zirconium-89 for Positron Emission Tomography Imaging. , 2017, ACS nano.

[13]  Feng Chen,et al.  Target-or-Clear Zirconium-89 Labeled Silica Nanoparticles for Enhanced Cancer-Directed Uptake in Melanoma: A Comparison of Radiolabeling Strategies. , 2017, Chemistry of materials : a publication of the American Chemical Society.

[14]  G. El Fakhri,et al.  Mature B cells accelerate wound healing after acute and chronic diabetic skin lesions , 2017, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[15]  W. Mamdouh,et al.  Comparative study on radiolabeling and biodistribution of core-shell silver/polymeric nanoparticles-based theranostics for tumor targeting. , 2017, International journal of pharmaceutics.

[16]  Yan Xing,et al.  Radiolabeled Dendrimers for Nuclear Medicine Applications , 2017, Molecules.

[17]  R. Bellavia,et al.  Treatment options for unresectable HCC with a focus on SIRT with Yttrium‐90 resin microspheres , 2017, International journal of clinical practice.

[18]  S. Aizawa,et al.  Enantiomeric NMR signal separation behavior and mechanism of samarium(III) and neodymium(III) complexes with (S,S)-ethylenediamine-N,N'-disuccinate. , 2017, Chirality.

[19]  Feng Chen,et al.  Positron emission tomography and nanotechnology: A dynamic duo for cancer theranostics☆ , 2017, Advanced drug delivery reviews.

[20]  H. Wolterbeek,et al.  Separation of nuclear isomers for cancer therapeutic radionuclides based on nuclear decay after-effects , 2017, Scientific Reports.

[21]  Kai Yang,et al.  Chelator-Free Radiolabeling of Nanographene: Breaking the Stereotype of Chelation. , 2017, Angewandte Chemie.

[22]  Kritee Pant,et al.  Radiolabelled Polymeric Materials for Imaging and Treatment of Cancer: Quo Vadis? , 2017, Advanced healthcare materials.

[23]  J. Llop,et al.  Radiolabeled Nanoparticles for Cancer Diagnosis and Therapy. , 2017, Anti-cancer agents in medicinal chemistry.

[24]  L. Josephson,et al.  Heat-induced-radiolabeling and click chemistry: A powerful combination for generating multifunctional nanomaterials , 2017, PloS one.

[25]  R. Korn,et al.  Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study , 2017, Clinical Cancer Research.

[26]  Rubel Chakravarty,et al.  Radiolabeled inorganic nanoparticles for positron emission tomography imaging of cancer: an overview. , 2017, The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of....

[27]  M. Abbasi,et al.  Internal dosimetry for radioembolization therapy with Yttrium‐90 microspheres , 2017, Journal of applied clinical medical physics.

[28]  A. Vomiero,et al.  High performance magneto-fluorescent nanoparticles assembled from terbium and gadolinium 1,3-diketones , 2017, Scientific Reports.

[29]  H. M. Williams,et al.  The application of magnetic nanoparticles in the treatment and monitoring of cancer and infectious diseases , 2017 .

[30]  B. J. Carter.  HEAT STABLE COLLOIDAL IRON OXIDES COATED WITH REDUCED , 2017 .

[31]  A. Larson,et al.  Multimodal Imaging of Nanocomposite Microspheres for Transcatheter Intra-Arterial Drug Delivery to Liver Tumors , 2016, Scientific Reports.

[32]  Ulrich B Wiesner,et al.  Intraoperative mapping of sentinel lymph node metastases using a clinically translated ultrasmall silica nanoparticle. , 2016, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[33]  Feng Chen,et al.  Engineering Intrinsically Zirconium‐89 Radiolabeled Self‐Destructing Mesoporous Silica Nanostructures for In Vivo Biodistribution and Tumor Targeting Studies , 2016, Advanced science.

[34]  S. Gulec.  Y-90 Radiomicrosphere Therapy for Colorectal Cancer Liver Metastases. , 2016, Seminars in nuclear medicine.

[35]  Georges El Fakhri,et al.  Heat-Induced Radiolabeling of Nanoparticles for Monocyte Tracking by PET. , 2015, Angewandte Chemie.

[36]  B. Långström,et al.  Surface metal cation doping of maghemite nanoparticles: modulation of MRI relaxivity features and chelator-free 68Ga-radiolabelling for dual MRI-PET imaging , 2015 .

[37]  Feng Chen,et al.  In Vivo Integrity and Biological Fate of Chelator-Free Zirconium-89-Labeled Mesoporous Silica Nanoparticles , 2015, ACS nano.

[38]  Jun Zhang,et al.  Theranostic Imaging of Yttrium-90 , 2015, BioMed research international.

[39]  A. Mahnken.  (90)Y-glass microspheres for hepatic neoplasia. , 2015, Future oncology.

[40]  Jun Ling,et al.  Research into europium complexes as magnetic resonance imaging contrast agents (Review). , 2015, Experimental and therapeutic medicine.

[41]  Daniele Marin,et al.  Emerging applications for ferumoxytol as a contrast agent in MRI , 2015, Journal of magnetic resonance imaging : JMRI.

[42]  Jan Grimm,et al.  Silica Nanoparticles as Substrates for Chelator-free Labeling of Oxophilic Radioisotopes , 2015, Nano letters.

[43]  Alice M. Bowen,et al.  Chelate-free metal ion binding and heat-induced radiolabeling of iron oxide nanoparticles† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c4sc02778g Click here for additional data file. , 2014, Chemical science.

[44]  Feng Chen,et al.  Intrinsically radiolabeled nanoparticles: an emerging paradigm. , 2014, Small.

[45]  T. Niendorf,et al.  Cerebral blood volume estimation by ferumoxytol‐enhanced steady‐state MRI at 9.4 T reveals microvascular impact of α1‐adrenergic receptor antibodies , 2014, NMR in biomedicine.

[46]  Larissa Miller,et al.  Synthesis, characterization, and biodistribution of multiple 89Zr-labeled pore-expanded mesoporous silica nanoparticles for PET. , 2014, Nanoscale.

[47]  Jan Grimm,et al.  Non-invasive mapping of deep-tissue lymph nodes in live animals using a multimodal PET/MRI nanoparticle , 2014, Nature Communications.

[48]  Chris Orvig,et al.  Matching chelators to radiometals for radiopharmaceuticals. , 2014, Chemical Society reviews.

[49]  Hao Hong,et al.  Chelator-free synthesis of a dual-modality PET/MRI agent. , 2013, Angewandte Chemie.

[50]  C. Batich,et al.  Materials Characterization of Feraheme/Ferumoxytol and Preliminary Evaluation of Its Potential for Magnetic Fluid Hyperthermia , 2013, International journal of molecular sciences.

[51]  E. Frenkel,et al.  Using iron oxide nanoparticles to diagnose CNS inflammatory diseases and PCNSL , 2013, Neurology.

[52]  Brendan J. McCullough,et al.  Ferumoxytol in clinical practice: Implications for MRI , 2013, Journal of magnetic resonance imaging : JMRI.

[53]  Heather M. Hennkens,et al.  Radiometals for combined imaging and therapy. , 2013, Chemical reviews.

[54]  Evan Phillips,et al.  Clinically-translated silica nanoparticles as dual-modality cancer-targeted probes for image-guided surgery and interventions. , 2012, Integrative biology : quantitative biosciences from nano to macro.

[55]  Z. Gu,et al.  Controllable preparation of ternary superparamagnetic nanoparticles dual-doped with Mn and Zn elements. , 2012, Journal of nanoscience and nanotechnology.

[56]  Yongmin Chang,et al.  Paramagnetic nanoparticle T1 and T2 MRI contrast agents. , 2012, Physical chemistry chemical physics : PCCP.

[57]  Oliver T. Bruns,et al.  A simple and widely applicable method to 59Fe-radiolabel monodisperse superparamagnetic iron oxide nanoparticles for in vivo quantification studies. , 2012, ACS nano.

[58]  Q. Vuong,et al.  Paramagnetic nanoparticles as potential MRI contrast agents: characterization, NMR relaxation, simulations and theory , 2012, Magnetic Resonance Materials in Physics, Biology and Medicine.

[59]  C. Apostolidis,et al.  Bismuth-213 and actinium-225 -- generator performance and evolving therapeutic applications of two generator-derived alpha-emitting radioisotopes. , 2012, Current radiopharmaceuticals.

[60]  A. Louie,et al.  Rapid size-controlled synthesis of dextran-coated, 64Cu-doped iron oxide nanoparticles. , 2012, ACS nano.

[61]  Yuko Okamoto,et al.  Generalized-Ensemble Algorithms for Simulations of Complex Molecular Systems , 2012 .

[62]  R. Weissleder,et al.  89Zr-labeled dextran nanoparticles allow in vivo macrophage imaging. , 2011, Bioconjugate chemistry.

[63]  E. Dósa,et al.  Comparative analysis of ferumoxytol and gadoteridol enhancement using T1- and T2-weighted MRI in neuroimaging. , 2011, AJR. American journal of roentgenology.

[64]  I. Nabipour,et al.  Nanotechnology and nuclear medicine; research and preclinical applications. , 2011, Hellenic journal of nuclear medicine.

[65]  K. Uvdal,et al.  Magnetic and Electron Spin Relaxation Properties of (GdxY1−x)2O3 (0 ≤ x ≤ 1) Nanoparticles Synthesized by the Combustion Method. Increased Electron Spin Relaxation Times with Increasing Yttrium Content , 2011 .

[66]  Dong Liang,et al.  A chelator-free multifunctional [64Cu]CuS nanoparticle platform for simultaneous micro-PET/CT imaging and photothermal ablation therapy. , 2010, Journal of the American Chemical Society.

[67]  C. Anderson,et al.  Molecular imaging of cancer with copper-64 radiopharmaceuticals and positron emission tomography (PET). , 2009, Accounts of chemical research.

[68]  Shuang Liu.  Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides. , 2008, Advanced drug delivery reviews.

[69]  Sergi Vidal-Sicart,et al.  SPECT-CT and real-time intraoperative imaging: new tools for sentinel node localization and radioguided surgery? , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[70]  G. Chow,et al.  Carboxyl group (–CO2H) functionalized ferrimagnetic iron oxide nanoparticles for potential bio-applications , 2004 .

[71]  R. Weissleder,et al.  Detection of lymph node metastases by contrast‐enhanced MRI in an experimental model , 2002, Magnetic resonance in medicine.

[72]  D. Scheinberg,et al.  Breakthrough of 225Ac and its radionuclide daughters from an 225Ac/213Bi generator: development of new methods, quantitative characterization, and implications for clinical use. , 2001, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[73]  A. Alavi,et al.  Active Macromolecule Uptake by Lymph Node Antigen-Presenting Cells: A Novel Mechanism in Determining Sentinel Lymph Node Status , 2000, Annals of Surgical Oncology.

[74]  G. S. Mijnhout,et al.  Radiopharmaceuticals in sentinel lymph-node detection – an overview , 1999, European Journal of Nuclear Medicine.

[75]  A. Catalá,et al.  MRI dosimetry: a fast quantitative MRI method to determine 3D absorbed dose distributions. , 1999, Investigative radiology.

[76]  R. Foster,et al.  The sentinel node in breast cancer--a multicenter validation study. , 1998, The New England journal of medicine.

[77]  L. Martí-Bonmatí,et al.  High density barium sulphate as an MRI oral contrast. , 1991, Magnetic resonance imaging.

[78]  R Weissleder,et al.  Superparamagnetic iron oxide: pharmacokinetics and toxicity. , 1989, AJR. American journal of roentgenology.

[79]  M. Welch.  Radiopharmaceuticals and other compounds labelled with short-lived radionuclides , 1977 .