A Novel Metal-Based Imaging Probe for Targeted Dual-Modality SPECT/MR Imaging of Angiogenesis

Abstract

Superparamagnetic iron oxide nanoparticles with well-integrated multimodality imaging properties have generated increasing research interest in the past decade, especially when it comes to the targeted imaging of tumors. Bevacizumab (BCZM) on the other hand is a well-known and widely applied monoclonal antibody recognizing VEGF-A, which is overexpressed in angiogenesis. The aim of this proof-of-concept study was to develop a dual-modality nanoplatform for in vivo targeted single photon computed emission tomography (SPECT) and magnetic resonance imaging (MRI) of tumor vascularization. Iron oxide nanoparticles (IONPs) have been coated with dimercaptosuccinic acid (DMSA), for consequent functionalization with the monoclonal antibody BCZM radiolabeled with 99mTc, via well-developed surface engineering. The IONPs were characterized based on their size distribution, hydrodynamic diameter and magnetic properties. In vitro cytotoxicity studies showed that our nanoconstruct does not cause toxic effects in normal and cancer cells. Fe3O4-DMSA-SMCC-BCZM-99mTc were successfully prepared at high radiochemical purity (>92%) and their stability in human serum and in PBS were demonstrated. In vitro cell binding studies showed the ability of the Fe3O4-DMSA-SMCC-BCZM-99mTc to bind to the VEGF-165 isoform overexpressed on M-165 tumor cells. The ex vivo biodistribution studies in M165 tumor-bearing SCID mice showed high uptake in liver, spleen, kidney and lungs. The Fe3O4-DMSA-SMCC-BCZM-99mTc demonstrated quick tumor accumulation starting at 8.9 ± 1.88%ID/g at 2 h p.i., slightly increasing at 4 h p.i. (16.21 ± 2.56%ID/g) and then decreasing at 24 h p.i. (6.01 ± 1.69%ID/g). The tumor-to-blood ratio reached a maximum at 24 h p.i. (~7), which is also the case for the tumor-to-muscle ratio (~18). Initial pilot imaging studies on an experimental gamma-camera and a clinical MR camera prove our hypothesis and demonstrate the potential of Fe3O4-DMSA-SMCC-BCZM-99mTc for targeted dual-modality imaging. Our findings indicate that Fe3O4-DMSA-SMCC-BCZM-99mTc IONPs could serve as an important diagnostic tool for biomedical imaging as well as a promising candidate for future theranostic applications in cancer.

Magnetic Nanoparticles as MRI Contrast Agents

“…IONPs have been functionalized with epithelial growth factor (EGFR) antibodies for the diagnosis of breast cancer [ 274 ], pancreatic/stomach cancer [ 275 ] and brain cancer [ 276 ]. Because there is an established relationship between mutations involving overexpression or overactivity of EGFR and various types of cancer, this receptor is currently one of the most important targets in cancer research [ 277 – 279 ].…”

DMSA-Coated Cubic Iron Oxide Nanoparticles as Potential Therapeutic Agents

“…This is presumably due to the DMSA molecules attached to the iron oxide's surface through the COOgroup [40]. According to the previous studies [33], the interaction between the carboxylate head and the metal atom was classified as monodentate, chelating bidentate and bridging bidentate structures, and the separation ( ν) between the wave numbers of the [ν s (COO -)] and [ν as (COO -)] infrared bands can be used to determine the type of interaction between the carboxylate groups of the DA and the iron atom. Here, the largest ν values (200-320 cm -1 ) correspond to the monodentate structure, the smallest ν values (<110 cm -1 ) the chelate bidentate structure and the medium range ν values (140-190 cm -1 ) the bridging bidentate structure.…”

“…In vitro and in vivo studies have showed that cell viability and proliferation are not influenced by the DMSA coating of Fe 3 O 4 and Fe 2 O 3 NPs [32]. DMSA-coated IONPs therefore have the potential to be used as magnetic carriers to deliver high concentrations of radioisotopes to certain areas, for example, as single-photon emission computerized tomography (SPECT)/dual-modal MRI contrast agents [33].…”

<p>Ag/Au Bimetallic Nanoparticles Inhibit Tumor Growth and Prevent Metastasis in a Mouse Model</p>

“…The pronounced lung uptake may be attributed to various factors, such as NP size and DMSA coating. 18 – 20 Most importantly, almost 2.5% ID/g of Ag 3 Au 1 Trp 1:2 NPs accumulated to the tumor sites at 30 min post-administration ( Figure 2D ). Generally, the ideal NP has to stay enough time to bloodstream in order to augment the possibility to reach the tissue of interest, after escaping the RES which is one of the major biological barriers that reduce NP accumulation to the target tissue.…”