Abstract Body:

Background: A diagnosis of lymph node metastasis has significant prognostic value for melanoma, breast cancer, head and neck cancer, and cervical cancer, among others [1-4]. Sentinel lymph node (SLN) biopsy (SLNB) is a standard-of-care diagnostic staging procedure that aims to identify the first draining lymph node from a primary tumor to be evaluated by histopathology to detect metastasis. An SLNB procedure has recently emerged for use in breast cancer that uses superparamagnetic iron oxide (SPIO) nanoparticles to label the SLNs and a magnetometer to detect the magnetized SLNs during surgery [5,6].  However, for cancers affecting complex anatomies with unpredictable lymphatic basins, pre-operative imaging of SLN location is required to plan the operative approach. 

Our objective is to demonstrate that magnetic particle imaging (MPI) can quantitatively and specifically identify SLNs in a murine model by characterizing the pharmacokinetics of SPIOs when administered in multiple regional lymphatic basins. Further, we assess MPI sensitivity for long-term (8 week) in vivo murine SLN detection and lowering iron oxide injected dose by 50%.

Materials and Methods: VivoTrax SPIOs (Magnetic Insight) were administered intradermally to healthy 12-week-old male C57BL/6 mice. In Study I, a clinically scaled dose (56 mg / 83 kg human ~ 0.675 mg Fe/kg) [5] of SPIOs was administered to the mouse tongue (n = 2), forepaw (n = 1), base of tail (n = 1), or hind footpad (n = 1) to image SLNs in various lymphatic pathways by MPI for up to 4-6 days (Figure A). In Study II, mice received a clinical dose (0.675 mgFe/kg) in the right hindpaw and a half-clinical dose (0.337 mgFe/kg) [6] in the left hindpaw and were imaged by MPI at multiple timepoints for 8 weeks (n = 3 mice). 3D MPI was conducted using a preclinical MPI imager (Momentum, Magnetic Insight). At endpoint, SLNs were extracted to verify the MPI signal ex vivo and processed using Perl’s Prussian iron staining.

Results: MPI directly visualizes mouse SLNs draining in multiple lymphatic pathways, including cervical SLNs draining the tongue, axillary SLN draining the forepaw, inguinal SLN draining the tail, and popliteal SLN draining the footpad (Study I, Figure B). Vivotrax accumulate in SLNs within 1 hour and persists in SLNs allowing for MPI detection for up to 8 weeks (Study II, Figure D). MPI detection of SLNs using 50% reduced SPIO dose produces high-SNR MPI signal for the same duration (Figure E). Notably, MPI lymphography with VivoTrax provides specific images of a single SLN, without MPI-detected flow to secondary or higher echelon nodes. Perl’s Prussian staining confirms the presence of iron in the subcapsular space of excised SLNs.

Conclusion: Our data provides strong support for the use of MPI lymphography to guide SLNB procedures in various lymph node basins. Compared to SPECT/99mTc image guidance which is restricted by tracer half-life (6 hours), the persistence of MPI signal in SLNs for several weeks could provide tremendous clinical flexibility [7]. High MPI sensitivity enables detection of SLNs after administration of 50% SPIO dose, which helps to alleviate concerns regarding skin staining and MRI artifacts [8]. Here we image multiple SLNs in healthy mouse models and future work will be focused on imaging and quantification of tumor-induced lymphatic remodeling. This work directly supports indications for human-scale MPI which is forthcoming in 2024.

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