Comparative Study of Extracellular and Intracellular Magnetic Hyperthermia Treatments Using Magnetic Particle Imaging

The purpose of this study was to evaluate the effectiveness of intracellular magnetic hyperthermia treatment (MHT) in comparison with that of extracellular MHT using magnetic particle imaging (MPI). Colon-26 cells were implanted subcutaneously into the backs of 8-week-old male BALB/c mice. When the tumor volume reached approximately 100 mm3, the mice were divided into control (n = 10), extracellular MHT (n = 8), and intracellular MHT groups (n = 7). In the control group, MHT was not performed. In the extracellular MHT and intracellular MHT groups, the tumors were injected directly with magnetic nanoparticles (MNPs) (400 mM Resovist®) and were heated for 20 min using an alternating magnetic field. During MHT, the temperatures of the tumor and rectum were measured using optical fiber thermometers. In the extracellular MHT group, MHT was performed 15 min after the injection of MNPs, whereas MHT was performed one day after the injection of MNPs in the intracellular MHT group. In both groups, MPI images were obtained using our MPI scanner immediately before, immediately after, and 7 and 14 days after MHT. After the MPI studies, we drew a region of interest (ROI) on the tumor in the MPI image and calculated the average, maximum, and total MPI values and the number of pixels within the ROI. Transmission electron microscopic (TEM) images were also obtained from resected tumors. In all groups, tumor volume was measured every day and the relative tumor volume growth (RTVG) was calculated. The TEM images showed that almost all the MNPs were aggregated in the extracellular space in the extracellular MHT group, whereas they were contained within the intracellular space in the intracellular MHT group. Although the temperature of the tumor in the intracellular MHT group was significantly lower than that in the extracellular MHT group, the RTVG value in the intracellular MHT group was significantly lower than that in the control group 2 days or more after MHT and that in the extracellular MHT group 3, 4, and 5 days after MHT. The average MPI value normalized by that immediately before MHT in the intracellular MHT group was significantly higher than that in the extracellular MHT group immediately and 7 days after MHT. The maximum and total MPI values normalized by those immediately before MHT in the intracellular MHT group were significantly higher than those in the extracellular MHT group 7 days after MHT, suggesting that the temporal change of MNPs within the tumor in the intracellular MHT group was smaller than that in the extracellular MHT group. Our results suggest that intracellular MHT is more cytotoxic than extracellular MHT in spite of a lower temperature rise of tumors, and that MPI is useful for evaluating the difference in the temporal change of MNPs in the tumor between extracellular MHT and intracellular MHT.

A Novel Therapeutic Strategy Combining Use of Intracellular Magnetic Nanoparticles under an Alternating Magnetic Field and Bleomycin

Purpose: The purpose of this study was to present a novel therapeutic strategy combining use of intracellular magnetic nanoparticles (MNPs) under an alternating magnetic field (AMF) and bleomycin (BLM), and to evaluate its therapeutic effect using tumor-bearing mice. Materials and Methods: MNPs (Resovist?, 1.05 mg iron) were incorporated into the hemagglutinating virus of Japan-envelope (HVJ-E) vector (~5 × 109 particles) (HVJ-E/MNPs) by centrifugation at 10,000 × g for 5 min at 4°C. Tumor-bearing mice were prepared by inoculating Colon-26 cells subcutaneously into the backs of BALB/c mice. When the tumor volume reached ~100 mm3, HVJ-E/MNPs and/or BLM were injected directly into the tumor. The AMF was applied to the mice one hour after the injection of agents (AMF treatment). The mice injected with HVJ-E/MNPs were imaged using our magnetic particle imaging (MPI) scanner immediately (13 min) before, immediately (22 min) after, and 3, 7, and 14 days after the injection of agents, and the temporal changes of the average and maximum MPI pixel values in the tumor were quantitatively evaluated. The therapeutic effect was evaluated by calculating the relative tumor volume growth (RTVG) from the tumor volumes measured each day. Transmission electron microscopic (TEM) observation of resected tumors was also performed to confirm the intracellular distribution of MNPs. Results: The AMF treatment combined with BLM significantly decreased the RTVG value compared with AMF treatment alone at 9 to 14 days, and BLM alone at 3 to 5 days after AMF treatment. The average and maximum MPI pixel values in the tumor were almost constant for 14 days. TEM observation confirmed that most of the HVJ-E/MNPs were internalized into tumor cells within one hour after injection. Conclusion: A novel therapeutic strategy with use of AMF treatment and BLM was presented, and the time-dependent change of MNPs in tumors was evaluated using MPI. The present results suggest that this novel strategy can suppress tumor volume growth over AMF treatment or BLM alone, and can be performed repeatedly with a single injection of HVJ-E/MNPs. They also suggest that HVJ-E is effective for internalizing MNPs into cancer cells and that MPI allows for longitudinal monitoring of the distribution of MNPs in tumors.

细胞内磁热疗研究概述

热疗即加热疗法,是指通过升高肿瘤温度,利用热能杀灭癌细胞和肿瘤组织的一种物理疗法。通过在磁性纳米粒子表面进行各种修饰,提高磁性纳米粒子进入肿瘤细胞的效率及选择性,在体外交变磁场的作用下促使进入细胞内的纳米磁性粒子产热而杀伤肿瘤细胞,这种方法称为细胞内磁热疗。作者就肿瘤细胞内磁热疗的研究进展作一综述。