Abstract
Magnetic hyperthermia (MH) harnesses the heat-releasing properties of superparamagnetic iron oxide nanoparticles (SPIONs) and has potential to stimulate immune activation in the tumor microenvironment whilst sparing surrounding normal tissues. To assess feasibility of localized MH in vivo, SPIONs are injected intratumorally and their fate tracked by Zirconium-89-positron emission tomography, histological analysis, and electron microscopy. Experiments show that an average of 49% (21-87%, n= 9) of SPIONs are retained within the tumor or immediately surrounding tissue. In situ heating is subsequently generated by exposure to an externally applied alternating magnetic field and monitored by thermal imaging. Tissue response to hyperthermia, measured by immunohistochemical image analysis, reveals specific and localized heat-shock protein expression following treatment. Tumor growth inhibition is also observed. To evaluate the potential effects of MH on the immune landscape, flow cytometry is used to characterize immune cells from excised tumors and draining lymph nodes. Results show an influx of activated cytotoxic T cells, alongside an increase in proliferating regulatory T cells, following treatment. Complementary changes are found in draining lymph nodes. In conclusion, results indicate that biologically reactive MH is achievable in vivo and can generate localized changes consistent with an anti-tumor immune response.
Highlights
Hyperthermia has been applied clinically for cancer treatment, either as a monotherapy or in combination with other treatment modalities such as ionizing radiation and chemotherapy.[1,2,3,4,5] The approach has met with some success in difficult to treat tumors
The high error measurements, as well as the finding that measurements are lowest at the 48-htime point, likely reflect the small sample sizes and variability in superparamagnetic iron oxide nanoparticles (SPIONs) content between the tissue samples chosen for analysis. These results suggest that SPIONs retained within the tumor at these later time points either possess less superparamagnetic activity or are present in smaller quantities; as shown using 89Zr-perimag-COOH, where the PET image reconstruction demonstrated a gradual fall in tumor SPION content over the first 24 h with a subsequent stabilization at 72 h (Figure 2E)
Promising, large-scale clinical translation of Magnetic hyperthermia (MH) has been limited by a number of persistent challenges: most notably, difficulty in localizing SPIONs within tumors and targeting them to tumor cells in addition to limitations in monitoring and regulation of the target temperatures.[80]
Summary
Hyperthermia has been applied clinically for cancer treatment, either as a monotherapy or in combination with other treatment modalities such as ionizing radiation and chemotherapy.[1,2,3,4,5] The approach has met with some success in difficult to treat tumors. SPION-generated MH has strong potential for use in cancer treatment but administration remains a challenge because intravenously injected SPIONs are rapidly sequestered by the reticuloendothelial system (RES) within the liver and spleen, limiting their delivery to tumor tissue.[23] A number of approaches have been employed to increase tumor delivery, including targeting SPIONs to tumor cells, intra-arterial delivery, modifying SPION surface coatings, and blocking uptake of SPIONs by the RES.[16,22,30,31,32]. Digital image analysis of whole slide scans of heat-shock protein 70 (hsp70) expression was performed, alongside characterization of tumor infiltrating lymphocyte populations, to look for evidence of an anti-tumor immune response following MH treatment
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