Superparamagnetic iron oxide nanoparticles (SPIONs) as a multimodality imaging probe for sentinel nodes: Design and Preclinical Evaluation

Breast cancer and malignant melanoma disseminate through the lymphatic system and the first metastases arise in one or two regional, sentinel lymph nodes (SLNs) draining the primary tumour site. Therefore, identification and characterization of the SLNs is of major importance for cancer staging and for choice of therapy in patients. The standard clinical procedure relies on lymphoscintigraphy after intradermal injection of radiolabelled colloids (such as 99mTc-Nanocolloid in Europe) and blue dye to identify the SLNs intra-operatively. Resected SLN-biopsies are then sent for histopathological analysis. This technique, however, is limited by the non-specificity of the tracer, lack of anatomical structures as reference in scintigraphic images, and involves a tight schedule between surgery and pathological examination. In Papers I and II, we propose a new generation tracers (probes) based on superparamagnetic iron oxide nanoparticles (SPIONs) radiolabelled with Tc-99m and Cy 5.5 Alexa Fluor. SPIONs have the great advantage to be produced within a narrow size distribution (20-50 nm) optimal for transport via lymphatic vessels and accumulate in SLNs. Owing to their large surface-to-volume ratio and biocompatible coating; a high radiolabelling yield was demonstrated. After subcutaneous injection of the probe in the hind paw of Wistar rats, 99mTc-SPION-Cy 5.5 the SLNs were easily identified SPECT-MRI and optical imaging modalities. In Paper III and V, a fast one-step radiolabelling method was developed to conjugate 68Ga-SPIONs and 64Cu-SPIONs for positron emission tomography (PET), MRI, and Cherenkov luminescence imaging (CLI) of SLNs. After administration of the probes as in the previous papers in rats and mice, quantitative PET and MRI images were acquired simultaneously. The images clearly depicted the SLNs. A benefit of CLI is that they enable intra-operative optical imaging without the use of toxic fluorophores. In Paper IV non-homogeneous activity distribution in SLN was demonstrated by using digital autoradiography images (DARG), and together with data acquired from biodistribution of the agents in rats from Paper I-III and V, the absorbed doses were calculated for the different radionuclides. It has been shown that the common approach of medical intern radiation doses, MIRD, assuming a homogenous activity distribution it may underestimate the absorbed dose in some regions in SLN.