Immuno-hyperthermia effected by antibody-conjugated nanoparticles selectively targets and eradicates individual cancer cells.

Hyperthermia has been used for cancer therapy for a long period of time, but has shown limited clinical efficacy. Induction-heating hyperthermia using the combination of magnetic nanoparticles (MNPs) and an alternating magnetic field (AMF), termed magnetic hyperthermia (MHT), has previously shown efficacy in an orthotopic mouse model of disseminated gastric cancer. In the present study, superparamagnetic iron oxide nanoparticles (SPIONs), a type of MNP, were conjugated with an anti-HER2 antibody, trastuzumab and termed anti-HER2-antibody-linked SPION nanoparticles (anti-HER2 SPIONs). Anti-HER2 SPIONs selectively targeted HER2-expressing cancer cells co-cultured along with normal fibroblasts and HER2-negative cancer cells and caused apoptosis only in the HER2-expressing individual cancer cells. The results of the present study show proof-of-concept of a novel hyperthermia technology, immuno-MHT for selective cancer therapy, that targets individual cancer cells.Abbreviations: AMF: alternating magnetic field; DDW: double distilled water; DMEM: Dulbecco's Modified Eagle's; Medium; f: frequency; FBS: fetal bovine serum; FITC: Fluorescein isothiocyanate; GFP: green fluorescent protein; H: amplitude; Hsp: heat shock protein; MHT: magnetic hyperthermia; MNPs: magnetic nanoparticles; PI: propidium iodide; RFP: red fluorescent protein; SPION: superparamagnetic iron oxide (Fe3O4) nanoparticle.

Hyperthermia generated by magnetic nanoparticles for effective treatment of disseminated peritoneal cancer in an orthotopic nude-mouse model.

Magnetic hyperthermia (MHT), which combines magnetic nanoparticles (MNPs) with an alternating magnetic field (AMF), holds promise as a cancer therapy. There have been many studies about hyperthermia, most of which have been performed by direct injection of MNPs into tumor tissues. However, there have been no reports of treating peritoneal disseminated disease with MHT to date. In the present study, we treated peritoneal metastasis of gastric cancer with MHT using superparamagnetic iron oxide (Fe3O4) nanoparticle (SPION) coated with carboxydextran as an MNP, in an orthotopic mouse model mimicking early peritoneal disseminated disease of gastric cancer. SPIONs of an optimal size were intraperitoneally administered, and an AMF (390 kHz, 28 kAm-1) was applied for 10 minutes, four times every three days. Three weeks after the first MHT treatment, the peritoneal metastases were significantly inhibited compared with the AMF-alone group or the untreated-control group. The results of the present study show that MHT can be applied as a new treatment option for disseminated peritoneal gastric cancer.Abbreviations: AMF: alternating magnetic field; Cy1: cytology-positive; DMEM: Dulbecco's Modified Eagle's Medium; FBS: fetal bovine serum; H&E: hematoxylin and eosin; HIPEC: hyperthermic intraperitoneal chemotherapy; MEM: Minimum Essential Medium; MHT: magnetic hyperthermia; MNPs: magnetic nanoparticles; P0: macroscopic peritoneal dissemination; RFP: red fluorescent protein; SPION: superparamagnetic iron oxide (Fe3O4) nanoparticle.

Heat generation and transfer behaviors of ti-coated carbon steel rod adaptable for ablation therapy of oral cancer.

For the purpose of developing a novel ablation therapy for oral cancer, the heat generation and transfer properties of a Ti-coated carbon steel rod with 20-mm length and 1.8-mm outer diameter were investigated by means of a high-frequency induction technique at 300 kHz. The heat generation measurement performed using water (15 mL) revealed that the difference of the inclination angles (θ = 0°, 45° and 90°) relative to the magnetic flux direction only slightly affects the heating behavior, exhibiting the overlapped temperature curves during an induction time of 1200 s. These results suggest that the effect of the shape magnetic anisotropy is almost eliminated, being convenient for the precise control of the ablation temperature in clinical use. In the experiments utilizing a tissue-mimicking phantom, the heat transfer concentrically occurred in the lateral direction for both the planar surface and a 10-mm deep cross-section. However, the former exhibited a considerably lower increase in temperature (ΔT), probably due to the effect of heat dissipation to the ambient air. No significant heat transfer was found to occur to the lower side of the inserted Ti-coated carbon steel rod, which is situated in the longitudinal direction.

Tumor local chemohyperthermia using docetaxel-embedded magnetoliposomes: Interaction of chemotherapy and hyperthermia.

BACKGROUND AND AIM: We have studied and reported the usefulness of tumor local chemohyperthermia at a low-grade temperature below 43°C with docetaxel-embedded magnetoliposome (DML) and an applied alternating current magnetic field. However, the mechanisms of this treatment and the dynamics of the injected docetaxel were not investigated in our previous study. Thus, we investigated the interaction of chemotherapy and hyperthermia in the treated tumor. METHODS: Human MKN45 gastric cancer cells were implanted in the hind limbs of Balb-c/nu/nu mice. DML, magnetite-loaded liposome, and docetaxel were injected into the tumors with or without being exposed to an alternating current magnetic field. Docetaxel and tumor necrosis factor-α concentrations, the cell cycle, and cell death rates in the tumor were examined. RESULTS: Docetaxel concentrations were significantly higher in the DML-injected group than in the docetaxel-injected group 3 days after injection. A G2/M peak was observed 1 day after treatment in the DML-injected and exposed group and the docetaxel-injected group, while it was observed 3 days after treatment in the DML-injected without heating group and the magnetite-loaded liposome group. The tumor cell death rate gradually increased in the DML-injected group, with or without being exposed, while it gradually decreased after its peak in other groups. The tumor necrosis factor-α concentration in the tumor treated with DML with heating remained at a high level on the 7th day after treatment, while it decreased after its peak in other groups. CONCLUSION: The antitumor effect of this treatment derives from a combination of hyperthermia and chemotherapy locally in the tumor.

Development of ti-coated ferromagnetic needle, adaptable for ablation cancer therapy by high-frequency induction heating.

To develop a novel ablation therapy for human solid cancer, the heating properties of a ferromagnetic carbon steel rod and a prototype Ti-coated needle using this carbon steel rod, were investigated in several high-frequency outputs at 300 kHz. In the former, the heating property was drastically different among the three inclination angles (θ = 0°, 45° and 90°) relative to the magnetic flux direction as a result of the shape magnetic anisotropy. However, the effect of the inclination angles was completely eliminated in the latter. It is considered that the complete non-oriented heating property relative to the magnetic flux direction allows the precise control of the ablation temperature during minimally invasive thermotherapy without a lead-wire connected to a fiber-optic thermometer. This newly designed Ti-coated device will be suitable for clinical use combined with its superior biocompatibility for ablation treatments using high-frequency induction heating.

Feasibility of chemohyperthermia with docetaxel-embedded magnetoliposomes as minimally invasive local treatment for cancer.

Hyperthermia is a minimally invasive approach to cancer treatment, but it is difficult to heat only the tumor without damaging surrounding tissue. To solve this problem, we studied the effectiveness of chemohyperthermia with docetaxel-embedded magnetoliposomes (DMLs) and an applied alternating current (AC) magnetic field. Human MKN45 gastric cancer cells were implanted in the hind limb of Balb-c/nu/nu mice. Various concentrations of docetaxel-embedded DMLs were injected into the tumors and exposed to an AC magnetic field (n = 6, each). For comparison with hyperthermia alone, magnetite-loaded liposome (ML)-injected tumors were exposed to an AC magnetic field. Furthermore, the results of DML without AC treatment and docetaxel diluted into PBS with AC treatment were also compared (n = 10, each). Tumor surface temperature was maintained between 42 and 43 degrees C. Tumor volume was reduced in the DML group with a docetaxel concentration > 56.8 microg/ml, while a docetaxel concentration > 568.5 microg/ml was required for tumor reduction without hyperthermia. Statistically significant differences in tumor volume and survival rate were observed between the DML group exposed to the magnetic field and the other groups. The tumor disappeared in 3 mice in the DML group exposed to the magnetic field; 2 mice survived over 6 months after treatment, whereas all mice of the other groups died by 15 weeks. Histologically, hyperthermia with DML damaged tumor cells and DML diffused homogeneously. To the best of our knowledge, this is the first report to show that hyperthermia using chemotherapeutic agent-embedded magnetoliposomes has an anticancer effect.

Development of a second-generation radiofrequency ablation using sintered MgFe(2)O(4) needles and alternating magnetic field for human cancer therapy.

Magnetic metal particles are known to induce heat energy under an alternating magnetic field (AMF). We developed a local tumor-heating device incorporating an MgFe(2)O(4) needle for the purpose of mild ablation for cancer treatment. A needle made from sintered MgFe(2)O(4) particles was embedded in the hepatic or breast tumors. Tumors were then heated by the energy dissipated from the needle exposed to an AMF. We sequentially evaluated histological changes, cellular activity of tumors, and the extent of thermal effect using nicotinamide adenine dinucleotide (NADH) diaphorase and terminal deoxynucleotidyl tranferase-mediated digoxigenin-DUTP nick-end labeling (TUNEL) staining. The mean temperature of the tumor tissue during heating was about 60 degrees C. Nuclei of the tumor cells became hyper-chromatin immediately after heating. The injured area spread progressively until 3 days after heating; when the area was surrounded by fibroblasts (meaning is not clear). Tumors disappeared after treatment without complications. This is the first time that the complete death of tumor cells has been realized by raising the tumor temperature above 60 degrees C using the heat generated by magnetic metal particles exposed to AMF. This device may be useful in the future for local hyperthemic treatment of human cancers.

Repeated inductive heating using a sintered MgFe2O4 needle for minimally invasive local control in breast cancer therapy.

PURPOSE: This study investigated the efficacy of repeated thermotherapy for breast cancer utilising a novel sintered MgFe(2)O(4) needle and alternating current (AC) magnetic field in xenograft animal models mimicking human breast cancer. MATERIALS AND METHODS: A sintered MgFe(2)O(4) needle and an apparatus to apply an AC magnetic field were prepared for this study. Animals bearing BT-474 tumours (mean (+/-standard deviation) volume, 471 +/- 153 mm(3)) were divided into four groups. A sintered MgFe(2)O(4) needle (length, 5 mm) was placed in the centre of each tumour. An AC magnetic field (amplitude, 4 kA/m; 2 kW; 540 kHz) was applied for 10 min once, twice or three times for the first, second and third groups, respectively, and was not applied for the control group. Temperature during treatment and tumour volume 8 weeks after first treatment were assessed. RESULTS: Maximum tumour temperature tended to increase in repeated-application groups: group 1, 59.2 +/- 4 degrees C; group 2, 58.9 +/- 3.3 degrees C and 61.2 +/- 8.9 degrees C for the first and second applications; and group 3, 60.4 +/- 4.6 degrees C, 62.1 +/- 7.8 degrees C and 71.1 +/- 6.1 degrees C for the first, second and third applications. Tumour volumes in control, groups 1, 2 and 3 at 8 weeks after treatment were 3633 +/- 2478 mm(3), 3240 +/- 1031 mm(3), 1252 +/- 1289 mm(3) and 0 mm(3), respectively. Tumours were significantly smaller in group 3 than in the control and group 1 at 8 weeks. CONCLUSIONS: The efficacy of repeated inductive heating utilising a sintered MgFe(2)O(4) needle was demonstrated. Thermotherapy using the present method may offer an effective non-surgical treatment for human breast cancer.

Feasibility of induction heating using a sintered MgFe2O4 needle for minimally invasive breast cancer therapy.

BACKGROUND: This study investigated a novel approach for tumor ablation therapy using an alternating magnetic field combined with a sintered MgFe2O4 needle. This method differs from radiofrequency ablation (RFA) by dielectric heating with regard to the heating mechanism and improves some weak points of these conventional thermotherapies. MATERIALS AND METHODS: Nude mice mimicking human breast cancer BT474 were treated using this method. The extent of tumor death was assessed after ablation. RESULTS: Staining with hematoxylin and eosin showed gradual expansion of the pyknotic area until 48 h after ablation. Nicotinamide adenine dinucleotide diaphorase staining also showed complete tumor death by 48 h after treatment. The ablation area was well controlled and reablation was not necessary. The tumor could be completely controlled using this method without any risk of skin burn. CONCLUSION: This novel ablation therapy appeared to be more effective and less invasive for treatment of breast cancer treatment than RFA.