^99mTc-Bisphosphonate-Iron Oxide Nanoparticle Conjugates for Dual-Modality Biomedical Imaging

Abstract

The combination of radionuclide-based imaging modalities such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) with magnetic resonance imaging (MRI) is likely to become the next generation of clinical scanners. Hence, there is a growing interest in the development of SPECT- and PET-MRI agents. To this end, we report a new class of dual-modality imaging agents based on the conjugation of radiolabeled bisphosphonates (BP) directly to the surface of superparamagnetic iron oxide (SPIO) nanoparticles. We demonstrate the high potential of BP-iron oxide conjugation using (⁹⁹m)Tc-dipicolylamine(DPA)-alendronate, a BP-SPECT agent, and Endorem/Feridex, a liver MRI contrast agent based on SPIO. The labeling of SPIOs with (⁹⁹m)Tc-DPA-alendronate can be performed in one step at room temperature if the SPIO is not coated with an organic polymer. Heating is needed if the nanoparticles are coated, as long as the coating is weakly bound as in the case of dextran in Endorem. The size of the radiolabeled Endorem (⁹⁹m)Tc-DPA-ale-Endorem) was characterized by TEM (5 nm, Fe₃O₄ core) and DLS (106 ± 60 nm, Fe₃O₄ core + dextran). EDX, Dittmer-Lester, and radiolabeling studies demonstrate that the BP is bound to the nanoparticles and that it binds to the Fe₃O₄ cores of Endorem, and not its dextran coating. The bimodal imaging capabilities and excellent stability of these nanoparticles were confirmed using MRI and nanoSPECT-CT imaging, showing that (⁹⁹m)Tc and Endorem co-localize in the liver and spleen In Vivo, as expected for particles of the composition and size of (⁹⁹m)Tc-DPA-ale-Endorem. To the best of our knowledge, this is the first example of radiolabeling SPIOs with BP conjugates and the first example of radiolabeling SPIO nanoparticles directly onto the surface of the iron oxide core, and not its coating. This work lays down the basis for a new generation of SPECT/PET-MR imaging agents in which the BP group could be used to attach functionality to provide targeting, stealth/stability, and radionuclides to Fe₃O₄ nanoparticles using very simple methodology readily amenable to GMP.

Tunable and noncytotoxic PET/SPECT-MRI multimodality imaging probes using colloidally stable ligand-free superparamagnetic iron oxide nanoparticles

“…Iron oxide magnetic nanoparticles, due to their inherent magnetic properties and feasibility to produce iron oxide cores, are the most common negative (T2 weighted) contrast agents and have been widely applied to in vitro and in vivo studies. [8][9][10][11][12] Among the dual-modality approaches, positron emission tomography/single-photon emission computed tomography (PET/SPECT)-MRI technologies offer high spatial resolution (~50 μm), 13 the best soft tissue contrast, the highest sensitivity, and detection limit. 14 The most common radionuclide probes applied as radiotracers or therapeutic agents in preclinical and clinical practice are 18 F, 64 Cu, 67 Ga, 68 Ga, 89 Zr, 90 Y, 124 I, 99m Tc, 111 In, and 177 Lu.…”

“…14 The most common radionuclide probes applied as radiotracers or therapeutic agents in preclinical and clinical practice are 18 F, 64 Cu, 67 Ga, 68 Ga, 89 Zr, 90 Y, 124 I, 99m Tc, 111 In, and 177 Lu. 12,[15][16][17][18] These radionuclides have been incorporated into nanoparticles via coordination bonds with suitable functional groups or chelating ligands on the nanoparticles.…”

New horizons in multimodality molecular imaging and novel radiotracers

“…13 A question to be resolved in the next few years is under what circumstances the contrast agents for each modality are better combined into one, or administered separately. The combination of multiple modality contrast into a single agent is challenging but an example is the recent development of superparamagnetic iron oxide particles, which provide negative MRI contrast radiolabelled with positron 14 or gamma 15 emitting radionuclides and indeed incorporating optical contrast as well. 16 A potential application of such particles is locating sentinel lymph nodes (eg in breast cancer or melanoma) by taking advantage of the sensitivity offered by the radionuclide, while overcoming its poor resolution by simultaneously imaging with MRI.…”

How Can Nanoparticles be used in Sentinel Node Detection?

“…This has led to the development of dual probes to allow for the benefits of multimodal imaging. Magnetic tracers have been conjugated with radiolabeled bisphosphonates in order to allow simultaneous, excellent anatomical visualization on MRI and computerized tomography (CT) scanning, in addition to functional categorization on positron emission tomography [12]. Triple-modal imaging magnetic nanocapsules, encapsulating hydrophobic SPIO to magnetically target solid tumors after intravenous administration have been developed [13].…”