^99mTc-Labeled Superparamagnetic Iron Oxide Nanoparticles for Multimodality SPECT/MRI of Sentinel Lymph Nodes

Abstract

The purpose of this study was to develop multimodality SPECT/ MRI contrast agents for sentinel lymph node (SLN) mapping in vivo. Methods: Nanoparticles with a solid iron oxide core and a polyethylene glycol coating were labeled with 99m Tc. The labeling efficiency was determined with instant thin-layer chromatography and magnetic separation. The stability of the radiolabeled superparamagnetic iron oxide nanoparticles (SPIONs) was verified in both sterile water and human serum at room temperature 6 and 24 h after labeling. Five Wistar rats were injected subcutaneously in the right hind paw with 99m Tc-SPIONs (25-50 MBq, ;0.2 mg of Fe) and sacrificed 4 h after injection. Two animals were imaged with SPECT/MRI. All 5 rats were dissected; the lymph nodes, liver, kidneys, spleen, and hind paw containing the injection site were removed and weighed; and activity in the samples was measured. The microdistribution within the lymph nodes was studied with digital autoradiography. Results: The efficiency of labeling of the SPIONs was 99% 6 h after labeling in both water and human serum. The labeling yield was 98% in water and 97% in human serum 24 h after labeling. The SLN could be identified in vivo with SPECT/MRI. The accumulation of 99m Tc-SPIONs (as the percentage injected dose/g [%ID/g]) in the SLN was 100 % ID/g, whereas in the liver and spleen it was less than 2 %ID/g. Digital autoradiography images revealed a nonhomogeneous distribution of 99m Tc-SPIONs within the lymph nodes; nanoparticles were found in the cortical, subcapsular, and medullary sinuses. Conclusion: This study revealed the feasibility of labeling SPIONs with 99m Tc. The accumulation of 99m Tc-SPIONs in lymph nodes after subcutaneous injection in animals, verified by SPECT/MRI, is encouraging for applications in breast cancer and malignant melanoma. The sentinel lymph node (SLN) is defined as the first regional lymph node receiving lymphatic drainage from a malignant tumor (1) and the first node to which metastatic cells are likely to anchor. Therefore, accurate detection and characterization of the SLN is of major importance for cancer staging and for the choice of therapy in patients with breast cancer and malignant melanoma. The current gold standard relies on lymphoscintigraphy after intradermal injection of radiolabeled colloids and blue dye to intraoperatively identify the SLN by dissection and histopathologic examination (2). The radiopharmaceuticals most frequently used for SLN imaging are 99m Tc-labeled colloids and macromolecules such as trisulfide, dextran, and human serum albumin (3-5). The current technique, however, is limited because of the nonspecificity of the tracer and the lack of anatomic information in scintigraphic images. Preoperative planning and identification of the SLN often rely on the experience of the surgeon.We propose combining information from high-resolution MRI and high-sensitivity SPECT images to provide more accurate and less invasive identification of the SLN before surgery. The use of radioactivity would help to ...

What is the future of magnetic nanoparticles in the axillary management of breast cancer?

“…In-vivo studies conducted on rats have identified SLNs on MRI using SPIO as contrast agents and confirmed this histologically on SLNB [27]. Studies have also looked at comparing pre-operative SPIO-enhanced MRI with histological findings on SLNB in breast cancer patients.…”

Molecular Imaging with 68Ga Radio-Nanomaterials: Shedding Light on Nanoparticles

“…Madru et al [70] developed chelator-free 68 Ga-labeled SPIONs. To radiolabel their SPIONs, they incubated GaCl 3 with SPIONs in 1M acetate buffer pH 5.5 for different times to assess the best fitting one.…”

“…68 Ga-labeled SPIONs proved to be stable in human serum at 37 • C for 4 h. These SPIONs served as a dual probe for PET/MR imaging of Sentinel Lymph Nodes (SLN), the first node receiving lymphatic drainage from the primary tumor site, in rat models ( Figure 5). Evertsson et al [69] utilized Madru and coworkers' [70] 68 Ga-SPIONs as a contrast agent for magnetomotive ultrasound (MMUS); a novel ultrasound-based method for intra-surgical guidance to localize metastases during cancer surgery. In their study, 68 Ga-SPIONs served as a dual-imaging probe for pre-operative PET/MRI imaging followed by intra-operative MMUS imaging in a SLN rat model.…”

“…To provide signal in PET, IONPs have been radiolabeled with different radioisotopes such as 64 IONP-based 68 Ga nanoradiotracers have been assessed in preclinical models to ensure biocompatibility and study in vivo biodistribution. Lahooti et al [101] radiolabeled PEG-coated iron oxide nanoparticles with 68 Ga using a chelator-free strategy previously described by Madru et al [70], incubating IONPs with GaCl3 eluate for 30 min at room temperature. They obtained a 66.2% post labeling chemical purity that improved to 98.9% after magnetic separation nanoparticle purification (using a MACS column).…”

“…On the other hand, radioisotope desorption from nanoparticle surface is still the main drawback. Some examples in the literature have exploited this property to produce 68 Ge/ 68 Ga generators, to radiolabel nanoparticles with 69 Ge as well as to radiolabel iron oxide nanoparticles with several radioisotopes, including 68 Ga [8,[66][67][68][69][70].…”