⁶⁸Ga-Sienna+ for PET-MRI Guided Sentinel Lymph Node Biopsy: Synthesis and Preclinical Evaluation in a Metastatic Breast Cancer Model

Abstract

Sentinel lymph node biopsy (SLNB) is commonly performed in cancers that metastasise via the lymphatic system. It involves excision and histology of sentinel lymph nodes (SLNs) and presents two main challenges: (i) sensitive whole-body localisation of SLNs, and (ii) lack of pre-operative knowledge of their metastatic status, resulting in a high number (>70%) of healthy SLN excisions. To improve SLNB, whole-body imaging could improve detection and potentially prevent unnecessary surgery by identifying healthy and metastatic SLNs. In this context, radiolabelled SPIOs and PET-MRI could find applications to locate SLNs with high sensitivity at the whole-body level (using PET) and guide high-resolution MRI to evaluate their metastatic status. Here we evaluate this approach by synthesising a GMP-compatible 68 Ga-SPIO ( 68 Ga-Sienna+) followed by PET-MR imaging and histology studies in a metastatic breast cancer mouse model. Methods. A clinically approved SPIO for SLN localisation (Sienna+) was radiolabelled with 68 Ga without a chelator. Radiochemical stability was tested in human serum. In vitro cell uptake was compared between 3E.Δ.NT breast cancer cells, expressing the hNIS reporter gene, and macrophage cell lines (J774A.1; RAW264.7.GFP). NSG-mice were inoculated with 3E.Δ.NT cells. Left axillary SLN metastasis was monitored by hNIS/SPECT-CT and compared to the healthy right axillary SLN. 68 Ga-Sienna+ was injected into front paws and followed by PET-MRI. Imaging results were confirmed by histology. Results. 68 Ga-Sienna+ was produced in high radiochemical purity (>93%) without the need for purification and was stable in vitro . In vitro uptake of 68 Ga-Sienna+ in macrophage cells (J774A.1) was significantly higher (12 ± 1%) than in cancer cells (2.0 ± 0.1%; P < 0.001). SPECT-CT confirmed metastasis in the left axillary SLNs of tumour mice. In PET, significantly higher 68 Ga-Sienna+ uptake was measured in healthy axillary SLNs (2.2 ± 0.9 %ID/mL), than in metastatic SLNs (1.1 ± 0.2 %ID/mL; P = 0.006). In MRI, 68 Ga-Sienna+ uptake in healthy SLNs was observed by decreased MR signal in T2/T2*-weighted sequences, whereas fully metastatic SLNs appeared unchanged. Conclusion. 68 Ga-Sienna+ in combination with PET-MRI can locate and distinguish healthy from metastatic SLNs and could be a useful preoperative imaging tool to guide SLN biopsy and prevent unnecessary excisions.

Radiolabelling of nanomaterials for medical imaging and therapy

“…An example of this approach was reported by Savolainen et al who radiolabelled Sienna+/Magtrace s (a macrophage-targeted clinically-approved SPIO) with 68 Ga, as a tool for PET-MRI guided sentinel lymph node (SLN) biopsies in metastatic cancer. 720 In this approach, PET provides sensitive wholebody information of the location of the SLNs, while MRI provides information on their different macrophage levels and hence metastatic status (Fig. 35C).…”

Value of Quantitative SPECT/CT Lymphoscintigraphy in Improving Sentinel Lymph Node Biopsy in Breast Cancer

“…Improving the accuracy of SLN detection is our objective. Numerous studies have focused on developing various novel radiotracers or hybrid approaches to improve SLN identification [ 16 – 19 ]; to the best of our knowledge, these methods have not been officially adopted in clinical settings because of their shortcomings. Less attention has been given to the evaluation of the relationship between radioactive uptake in metastatic and healthy SLNs.…”

Advances of functional nanomaterials for magnetic resonance imaging and biomedical engineering applications

“…For Sienna+, the detection rate of SLN was 98.0% in 150 patients, indicating that the detection of SLN by Sienna+ was feasible and not inferior to 99m Tc. Nowadays Sienna+ research in the United States is under way, while the agent has been approved by the European Commission in 2011 (Savolainen et al, 2019).…”