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Synthesis of 68Ga Core-doped Iron Oxide Nanoparticles for Dual Positron Emission Tomography /(T1)Magnetic Resonance Imaging

Published: November 20th, 2018



1Nanobiotechnology, Molecular Imaging and Metabolomics Lab, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 2CIC biomaGUNE and CIBER de Enfermedades Respiratorias (CIBERES). Ikerbasque, Basque Foundation for Science, Universidad Complutense de Madrid (UCM), 3Advanced Imaging Unit, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), CIBER de Enfermedades Respiratorias (CIBERES)

Here, we present a protocol to obtain 68Ga core-doped iron oxide nanoparticles via fast microwave-driven synthesis. The methodology renders PET/(T1)MRI nanoparticles with radiolabeling efficiencies higher than 90% and radiochemical purity of 99% in a 20-min synthesis.

Here, we describe a microwave synthesis to obtain iron oxide nanoparticles core-doped with 68Ga. Microwave technology enables fast and reproducible synthetic procedures. In this case, starting from FeCl3 and citrate trisodium salt, iron oxide nanoparticles coated with citric acid are obtained in 10 min in the microwave. These nanoparticles present a small core size of 4.2 ± 1.1 nm and a hydrodynamic size of 7.5 ± 2.1 nm. Moreover, they have a high longitudinal relaxivity (r1) value of 11.9 mM-1·s-1 and a modest transversal relaxivity value (r2) of 22.9 mM-1·s-1, which results in a low r2/r1 ratio of 1.9. These values enable positive contrast generation in magnetic resonance imaging (MRI) instead of negative contrast, commonly used with iron oxide nanoparticles. In addition, if a 68GaCl3 elution from a 68Ge/68Ga generator is added to the starting materials, a nano-radiotracer doped with 68Ga is obtained. The product is obtained with a high radiolabeling yield (> 90%), regardless of the initial activity used. Furthermore, a single purification step renders the nano-radiomaterial ready to be used in vivo.

The combination of imaging techniques for medical purposes has triggered the quest for different methods to synthesize multimodal probes1,2,3. Due to the sensitivity of positron emission tomography (PET) scanners and the spatial resolution of MRI, PET/MRI combinations seem to be one of the most attractive possibilities, providing anatomical and functional information at the same time4. In MRI, T2-weighted sequences can be used, darkening the tissues in which they accumulate. T1-weighted sequences may also be used, producing the br....

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1. Reagent Preparation

  1. 0.05 M HCl
    1. Prepare 0.05 M HCl by adding 208 µL of 37% HCl to 50 mL of distilled water.
  2. High-performance liquid chromatography eluent
    1. Prepare high-performance liquid chromatography (HPLC) eluent by dissolving 6.9 g of sodium dihydrogen phosphate monohydrate, 7.1 g of disodium hydrogen phosphate, 8.7 g of sodium chloride, and 0.7 g of sodium azide in 1 L of water. Mix well and check the pH. Pass the elu.......

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68Ga-C-IONP were synthesized by combining FeCl3, 68GaCl3, citric acid, water, and hydrazine hydrate. This mixture was introduced into the microwave for 10 min at 120 °C and 240 W under controlled pressure. Once the sample had cooled down to room temperature, the nanoparticles were purified by gel filtration to eliminate unreacted species (FeCl3, citrate, hydrazine hydrate) and free 68Ga (Figure 1

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Iron oxide nanoparticles are a well-established contrast agent for T2-weighted MRI. However, due to the drawbacks of this type of contrast for the diagnosis of certain pathologies, T1-weighted or bright contrast is many times preferred. The nanoparticles presented here not only overcome these limitations by offering positive contrast in MRI but also offer a signal in a functional imaging technique, such as PET, via 68Ga incorporation in their core. Microwave technology enhances t.......

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This study was supported by a grant from the Spanish Ministry for Economy and Competitiveness (MEyC) (grant number: SAF2016-79593-P) and from the Carlos III Health Research Institute (grant number: DTS16/00059). The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades) and the Pro CNIC Foundation and is a Severo Ochoa Centre of Excellence (MEIC award SEV-2015-0505).


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Name Company Catalog Number Comments
Iron (III) chloride hexahydrate POCH 2317294
Citric acid, trisodium salt dihydrate 99% Acros organics 227130010
Hydrazine hydrate Aldrich 225819
Hydrochloric acid 37% Fisher Scientific 10000180
Sodium dihydrogen phosphate monohydrate Aldrich S9638
Disodium phosphate dibasic Aldrich S7907
Sodium chloride Aldrich 746398
Sodium Azide Aldrich S2002
Sodium dihydrogen phosphate anhydrous POCH 799200119
68Ga Chloride  ITG Isotope Technologies Garching GmbH, Germany 68Ge/68Ga generator system
Microwave Anton Paar Monowave 300
Centrifuge Hettich Universal 320
Size Exclusion columns GE Healthcare PD-10

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