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1.  Hyperthermic treatment of DMBA-induced rat mammary cancer using magnetic nanoparticles 
We have developed magnetite cationic liposomes (MCLs) and applied them as a mediator of local hyperthermia. MCLs can generate heat under an alternating magnetic field (AMF). In this study, the in vivo effect of hyperthermia mediated by MCLs was examined using 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary cancer as a spontaneous cancer model.
MCLs were injected into the mammary cancer and then subjected to an AMF.
Four rats in 20 developed mammary tumors at more than 1 site in the body. The first-developed tumor in each of these 4 rats was selected and heated to over 43°C following administration of MCLs by an infusion pump. After a series of 3 hyperthermia treatments, treated tumors in 3 of the 4 rats were well controlled over a 30-day observation period. One of the 4 rats exhibited regrowth after 2 weeks. In this rat, there were 3 sites of tumor regrowth. Two of these regrowths were reduced in volume and regressed completely after 31 days, although the remaining one grew rapidly. These results indicated hyperthermia-induced immunological antitumor activity mediated by the MCLs.
Our results suggest that hyperthermic treatment using MCLs is effective in a spontaneous cancer model.
PMCID: PMC2266920  PMID: 18298831
2.  Size dependent heat generation of magnetite nanoparticles under AC magnetic field for cancer therapy 
We have developed magnetic cationic liposomes (MCLs) that contained magnetic nanoparticles as heating mediator for applying them to local hyperthermia. The heating performance of the MCLs is significantly affected by the property of the incorporated magnetite nanoparticles. We estimated heating capacity of magnetite nanoparticles by measuring its specific absorption rate (SAR) against irradiation of the alternating magnetic field (AMF).
Magnetite nanoparticles which have various specific-surface-area (SSA) are dispersed in the sample tubes, subjected to various AMF and studied SAR.
Heat generation of magnetite particles under variable AMF conditions was summarized by the SSA. There were two maximum SAR values locally between 12 m2/g to 190 m2/g of the SSA in all ranges of applied AMF frequency and those values increased followed by the intensity of AMF power. One of the maximum values was observed at approximately 90 m2/g of the SSA particles and the other was observed at approximately 120 m2/g of the SSA particles. A boundary value of the SAR for heat generation was observed around 110 m2/g of SSA particles and the effects of the AMF power were different on both hand. Smaller SSA particles showed strong correlation of the SAR value to the intensity of the AMF power though larger SSA particles showed weaker correlation.
Those results suggest that two maximum SAR value stand for the heating mechanism of magnetite nanoparticles represented by hysteresis loss and relaxation loss.
PMCID: PMC2579422  PMID: 18928573
3.  Development of Novel Magnetic Nanoparticles for Hyperthermia Cancer Therapy 
Proceedings of SPIE  2011;7901:790115-.
Advances in magnetic nanoparticle hyperthermia are opening new doors in cancer therapy. As a standalone or adjuvant therapy this new modality has the opportunity significantly advance thermal medicine. Major advantages of using magnetic magnetite (Fe3O4) nanoparticles are their highly localized power deposition and the fact that the alternating magnetic fields (AMF) used to excite them can penetrate deeply into the body without harmful effect. One limitation, however, which hinders the technology, is the problem of inductive heating of normal tissue by the AMF if the frequency and fields strength are not appropriately matched to the tissue. Restricting AMF amplitude and frequency limits the heat dose which can be selectively applied to cancerous tissue via the magnetic nanoparticle, thus lowering therapeutic effect. In an effort to address this problem, particles with optimized magnetic properties must be developed. Using particles with higher saturation magnetizations and coercivity will enhance hysteresis heating increasing particle power density at milder AMF strengths and frequencies. In this study we used oil in water microemulsions to develop nanoparticles with zero-valent Fe cores and magnetite shells. The superior magnetic properties of zero-valent Fe give these particles the potential for improved SAR over pure magnetite particles. Silane and subsequently dextran have been attached to the particle surface in order to provide a biocompatible surfactant coating. The heating capability of the particles was tested in-vivo using a mouse tumor model. Although we determined that the final stage of synthesis, purification of the dextran coated particles, permits significant corrosion/oxidation of the iron core to hematite, the particles can effectively heat tumor tissue. Improving the purification procedure will allow the generation Fe/Fe3O4 with superior SAR values.
PMCID: PMC3947375  PMID: 24619487
Magnetic Nanoparticle; Ferrofluid; Hyperthermia; Tumor; Cancer; Synthesis
4.  Hyperthermia reduces migration of osteosarcoma by suppression of autocrine motility factor 
Oncology Reports  2012;28(6):1953-1958.
Autocrine motility factor (AMF) plays an important role in the development of metastasis by regulating tumor cell motility. The expression of AMF is associated with metastasis in malignant musculoskeletal tumors including osteosarcoma. Recent studies indicated that hyperthermia contributes to the improvement of the prognosis of patients with soft tissue sarcomas; however, few reports have evaluated the impact of hyperthermia on tumor cell motility, which is an important factor of metastasis. The purpose of this study was to evaluate the effect of hyperthermia with or without heat shock protein (HSP) inhibitors on the motility and AMF expression in an osteosarcoma cell line. Hyperthermia was carried out at 41°C for 24 h. According to microarray results, HSP90, HSP70 and HSP27 expression was upregulated in osteosarcoma cells under hyperthermia. The intracellular, secreted AMF, mRNA of AMF and cell motility were evaluated by western blotting, ELISA, RT-PCR, wound healing and phagokinetic track assays, respectively. The protein secretion and mRNA levels of AMF and tumor cell motility were significantly decreased by hyperthermia. Of note, the downregulated AMF expression and motility were recovered by the addition of an HSP27 inhibitor. By contrast, the HSP90 and HSP70/72/105 inhibitors had no effect on AMF expression and motility downregulated by hyperthermia. In conclusion, hyperthermia reduced AMF expression and tumor cell motility via HSP27 and may therefore be applied as osteosarcoma treatment.
PMCID: PMC3583516  PMID: 23027359
autocrine motility factor; heat shock protein; hyperthermia; metastasis; motility; osteosarcoma
5.  Efficient treatment of breast cancer xenografts with multifunctionalized iron oxide nanoparticles combining magnetic hyperthermia and anti-cancer drug delivery 
Tumor cells can effectively be killed by heat, e.g. by using magnetic hyperthermia. The main challenge in the field, however, is the generation of therapeutic temperatures selectively in the whole tumor region. We aimed to improve magnetic hyperthermia of breast cancer by using innovative nanoparticles which display a high heating potential and are functionalized with a cell internalization and a chemotherapeutic agent to increase cell death.
The superparamagnetic iron oxide nanoparticles (MF66) were electrostatically functionalized with either Nucant multivalent pseudopeptide (N6L; MF66-N6L), doxorubicin (DOX; MF66-DOX) or both (MF66-N6LDOX). Their cytotoxic potential was assessed in a breast adenocarcinoma cell line MDA-MB-231. Therapeutic efficacy was analyzed on subcutaneous MDA-MB-231 tumor bearing female athymic nude mice.
All nanoparticle variants showed an excellent heating potential around 500 W/g Fe in the alternating magnetic field (AMF, conditions: H = 15.4 kA/m, f = 435 kHz). We could show a gradual inter- and intracellular release of the ligands, and nanoparticle uptake in cells was increased by the N6L functionalization. MF66-DOX and MF66-N6LDOX in combination with hyperthermia were more cytotoxic to breast cancer cells than the respective free ligands. We observed a substantial tumor growth inhibition (to 40% of the initial tumor volume, complete tumor regression in many cases) after intratumoral injection of the nanoparticles in vivo. The proliferative activity of the remaining tumor tissue was distinctly reduced.
The therapeutic effects of breast cancer magnetic hyperthermia could be strongly enhanced by the combination of MF66 functionalized with N6L and DOX and magnetic hyperthermia. Our approach combines two ways of tumor cell killing (magnetic hyperthermia and chemotherapy) and represents a straightforward strategy for translation into the clinical practice when injecting nanoparticles intratumorally.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0576-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4451751  PMID: 25968050
6.  Comparison of microwave and magnetic nanoparticle hyperthermia radiosensitization in murine breast tumors 
Proceedings of SPIE  2011;7901:10.1117/12.876515.
Hyperthermia has been shown to be an effective radiosensitizer. Its utility as a clinical modality has been limited by a minimally selective tumor sensitivity and the inability to be delivered in a tumor-specific manner. Recent in vivo studies (rodent and human) have shown that cancer cell-specific cytotoxicity can be effectively and safely delivered via iron oxide magnetic nanoparticles (mNP) and an appropriately matched noninvasive alternating magnetic field (AMF). To explore the tumor radiosensitization potential of mNP hyperthermia we used a syngeneic mouse breast cancer model, dextran-coated 110 nm hydrodynamic diameter mNP and a 169 kHz / 450 Oe (35.8 kA/m) AMF. Intradermally implanted (flank) tumors (150 ± 40 mm3) were treated by injection of 0.04 ml mNP (7.5 mg Fe) / cm3 into the tumor and an AMF (35.8 kA/m and 169 kHz) exposure necessary to achieve a CEM (cumulative equivalent minute) thermal dose of 60 (CEM 60). Tumors were treated with mNP hyperthermia (CEM 60), radiation alone (15 Gy, single dose) and in combination. Compared to the radiation and heat alone treatments, the combined treatment resulted in a greater than two-fold increase in tumor regrowth tripling time (tumor treatment efficacy). None of the treatments resulted in significant normal tissue toxicity or morbidity. Studies were also conducted to compare the radiosensitization effect of mNP hyperthermia with that of microwave-induced hyperthermia. The effects of incubation of nanoparticles within tumors (to allow nanoparticles to be endocytosed) before application of AMF and radiation were determined. This preliminary information suggests cancer cell specific hyperthermia (i.e. antibody-directed or anatomically-directed mNP) is capable of providing significantly greater radiosensitization / therapeutic ratio enhancement than other forms of hyperthermia delivery.
PMCID: PMC3877316  PMID: 24392200
Hyperthermia; radiation; nanoparticle; microwave; AMF; radiosensitization; intracellular hyperthermia
7.  Iron Oxide Hyperthermia And Radiation Cancer Treatment 
It is established that heat can enhance the effect of radiation cancer treatment. Due to the ability to localize thermal energy using nanoparticle hyperthermia, as opposed to other, less targeted, hyperthermia modalities, it appears such enhancement could be accomplished without complications normally associated with systemic or regional hyperthermia. This study employs non-curative (suboptimal), doses of heat and radiation, in an effort to determine the therapeutic enhancement potential for IONP hyperthermia and radiation.
MTG-B murine breast adenocarcinoma cell are inoculated into the right flanks of female CH3/HEJ mice and grown to volumes of 150mm3 +/− 40 mm3. A single dose of 15 Gy (6 MeV) radiation was uniformly delivered to the tumor. A pre-defined thermal dose is delivered by direct injection of iron oxide nanoparticles into the tumor. By adjusting the field strength of the 160 KHz alternating magnetic field (AMF) an intra-tumoral temperature between 41.5 and 43 degrees Celsius was maintained for 10min. The alternating magnetic field was delivered by a water-cooled 36mm diameter square copper tube induction coil operating at 160 kHz with variable magnet field strengths up to 450 Oe. The primary endpoint of the study is the number of days required for the tumor to achieve a volume 3 fold greater than the volume at the time of treatment (tumor regrowth delay).
Preliminary results suggest the addition of a modest IONP hyperthermia to 15 Gy radiation achieved an approximate 50% increase in tumor regrowth delay as compared to a 15 Gy radiation treatment alone. The therapeutic effects of IONP heat and radiation combined were considered additive, however in mice that demonstrated complete response (no tumor present after 30 days), the effect was considered superadditive or synergistic. Although this data is very encouraging from a multimodality cancer therapy standpoint, additional temporal and dose related information is clearly necessary to optimize the therapy.
PMCID: PMC4208073  PMID: 25346582
Iron oxide; nanoparticle; AMF; adenocarcinoma; transmission electron microscopy; TEM; murine; MTG-B; HT-29
8.  Preparation, characterization, and efficient transfection of cationic liposomes and nanomagnetic cationic liposomes 
Cationic liposomes (CLs) are composed of phospholipid bilayers. One of the most important applications of these particles is in drug and gene delivery. However, using CLs to deliver therapeutic nucleic acids and drugs to target organs has some problems, including low transfection efficiency in vivo. The aim of this study was to develop novel CLs containing magnetite to overcome the deficiencies.
Materials and methods
CLs and magnetic cationic liposomes (MCLs) were prepared using the freeze-dried empty liposome method. Luciferase-harboring vectors (pGL3) were transferred into liposomes and the transfection efficiencies were determined by luciferase assay. Firefly luciferase is one of most popular reporter genes often used to measure the efficiency of gene transfer in vivo and in vitro. Different formulations of liposomes have been used for delivery of different kinds of gene reporters. Lipoplex (liposome–plasmid DNA complexes) formation was monitored by gel retardation assay. Size and charge of lipoplexes were determined using particle size analysis. Chinese hamster ovary cells were transfected by lipoplexes (liposome-pGL3); transfection efficiency and gene expression level was evaluated by luciferase assay.
High transfection efficiency of plasmid by CLs and novel nanomagnetic CLs was achieved. Moreover, lipoplexes showed less cytotoxicity than polyethyleneimine and Lipofectamine™.
Novel liposome compositions (1,2-dipalmitoyl-sn-glycero-3-phosphocholine [DPPC]/dioctadecyldimethylammonium bromide [DOAB] and DPPC/cholesterol/DOAB) with high transfection efficiency can be useful in gene delivery in vitro. MCLs can also be used for targeted gene delivery, due to magnetic characteristic for conduction of genes or drugs to target organs.
PMCID: PMC3205124  PMID: 22072865
transfection efficiency; magnetic nanoparticles; luciferase; cationic liposome
9.  Comparison of iron oxide nanoparticle and microwave hyperthermia alone or combined with cisplatinum in murine breast tumors 
Proceedings of SPIE  2011;7901:10.1117/12.876535.
Surgery, radiation and chemotherapy are currently the most commonly used cancer therapies. Hyperthermia has been shown to work effectively with radiation and chemotherapy cancer treatments. The major obstacle faced by previous hyperthermia techniques has been the inability to deliver heat to the tumor in a precise manner. The ability to deliver cytotoxic hyperthermia to tumors (from within individual cells) via iron oxide magnetic nanoparticles (mNP) is a promising new technology that has the ability to greatly improve the therapeutic ratio of hyperthermia as an individual modality and as an adjuvant therapy in combination with other modalities. Although the parameters have yet to be conclusively defined, preliminary data suggests mNP hyperthermia can achieve greater cytotoxicity (in vitro) than conventional water bath hyperthermia methods. At this time, our theory is that intracellular nanoparticle heating is more effective in achieving the combined effect than extracellular heating techniques.1 However, understanding the importance of mNP association and uptake is critical in understanding the potential novelty of the heating modality. Our preliminary data suggests that the mNP heating technique, which did not provide time for particle uptake by the cells, resulted in similar efficacy to microwave hyperthermia. mNP hyperthermia/cisplatinum results have shown a tumor growth delay greater than either modality alone at comparable doses
One hour before nanoparticle hyperthermia, CDDP chemotherapy (5mg/kg of body mass) was delivered intraperitoneally (IP). Iron oxide nanoparticles, 7.5mg of iron per gram of tumor, were injected into MTGB flank tumors in female C3H mice immediately before activation. A 170 KHz, 400-450 Oe alternating magnetic field (AMF) was used to induce particle heating. A comparison of nanoparticle induced hyperthermia to non-nanoparticle induced hyperthermia was also made using a 915 MHz microwave generator. Treatment duration was determined by the use of the cumulative equivalent minutes (CEM) algorithm. A CEM 60 was selected as the thermal dose for all experimental groups.
1) Preliminary mNP hyperthermia/cisplatinum results have shown a tumor growth delay greater than either modality alone at comparable doses.
2) mNP hyperthermia delivered 10 minutes post mNP injection and microwave hyperthermia, with the same thermal dose, demonstrate similar treatment efficacy.
PMCID: PMC3877302  PMID: 24386533
Iron oxide; nanoparticle; hyperthermia; microwave; AMF; chemotherapy; cisplatinum; MTGB
10.  Inhibitory effect of vitamin D-binding protein-derived macrophage activating factor on DMBA-induced hamster cheek pouch carcinogenesis and its derived carcinoma cell line 
Oncology Letters  2011;2(4):685-691.
This study investigated the inhibitory effect of vitamin D-binding protein-derived macrophage-activating factor (GcMAF) on carcinogenesis and tumor growth, using a 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced hamster cheek pouch carcinogenesis model, as well as the cytocidal effect of activated macrophages against HCPC-1, a cell line established from DMBA-induced cheek pouch carcinoma. DMBA application induced squamous cell carcinoma in all 15 hamsters of the control group at approximately 10 weeks, and all 15 hamsters died of tumor burden within 20 weeks. By contrast, 2 out of the 14 hamsters with GcMAF administration did not develop tumors and the remaining 12 hamsters showed a significant delay of tumor development for approximately 3.5 weeks. The growth of tumors formed was significantly suppressed and none of the hamsters died within the 20 weeks during which they were observed. When GcMAF administration was stopped at the 13th week of the experiment in 4 out of the 14 hamsters in the GcMAF-treated group, tumor growth was promoted, but none of the mice died within the 20-week period. On the other hand, when GcMAF administration was commenced after the 13th week in 5 out of the 15 hamsters in the control group, tumor growth was slightly suppressed and all 15 hamsters died of tumor burden. However, the mean survival time was significantly extended. GcMAF treatment activated peritoneal macrophages in vitro and in vivo, and these activated macrophages exhibited a marked cytocidal effect on HCPC-1 cells. Furthermore, the cytocidal effect of activated macrophages was enhanced by the addition of tumor-bearing hamster serum. These findings indicated that GcMAF possesses an inhibitory effect on tumor development and growth in a DMBA-induced hamster cheek pouch carcinogenesis model.
PMCID: PMC3406437  PMID: 22848250
vitamin D-binding protein-derived macrophage-activating factor; macrophage; 9,10-dimethyl-1,2-benzanthracene; hamster cheek pouch carcinogenesis
11.  Effect of magnetic fluid hyperthermia on lung cancer nodules in a murine model 
Oncology Letters  2011;2(6):1161-1164.
The purpose of the present study was to investigate the therapeutic effect of magnetic fluid hyperthermia (MFH) induced by an alternating magnetic field (AMF) on human carcinoma A549 xenograft in nude mice. An animal model of human lung cancer was established by subcutaneous injection of human lung cancer A549 cells in BALB/c nude mice. The xenograft mice were randomly divided into four groups and each group was treated with an injection of a different concentration of magnetic fluid: control, low-dose (67.5 mg/ml), medium-dose (90.0 mg/ml) and high-dose group (112.5 mg/ml), respectively. Following the injection (24 h), the tumor was heated in an AMF for 30 min. Tumor volumes were then measured every week. The therapeutic effect was assessed by measuring the tumor volume and weight. Pathological examination was performed with a light and electronic microscope following treatment. The temperature at the surface of the tumor in the low-, medium- and high-dose groups increased to 41.3, 44.5 and 46.8°C, respectively. The tumor grew significantly slower in the medium- and high-dose groups (both p<0.05) compared to the control group. Cytoclasis and apoptosis were detected under light and electron microscopy. In conclusion, MFH induced by AMF inhibited tumor growth and promoted apoptosis of human carcinoma A549 cells in a xenograft mice model.
PMCID: PMC3406544  PMID: 22848282
magnetic fluid; hyperthermia; lung cancer
12.  Comparison of magnetic nanoparticle and microwave hyperthermia cancer treatment methodology and treatment effect in a rodent breast cancer model 
The purpose of this study was to compare the efficacy of iron oxide/magnetic nanoparticle hyperthermia (mNPH) and 915 MHz microwave hyperthermia at the same thermal dose in mouse mammary adenocarcinoma model.
Materials and Methods
A thermal dose equivalent to 60 minutes at 43°C (CEM 60) was delivered to a syngeneic mouse mammary adenocarcinoma flank tumor (MTGB) via mNPH or locally delivered 915 MHz microwaves. mNPH was generated with ferromagnetic, hydroxyethyl starch coated magnetic nanoparticles. Following mNP delivery, the mouse/tumor was exposed to an alternating magnetic field (AMF). The microwave hyperthermia treatment was delivered by a 915 MHz microwave surface applicator. Time required for the tumor to reach three times the treatment volume was used as the primary study endpoint. Acute pathological effects of the treatments were determined using conventional histopathological techniques.
Locally delivered mNPH resulted in a modest improvement in treatment efficacy as compared to microwave hyperthermia (p=0.09) when prescribed to the same thermal dose. Tumors treated with mNPH also demonstrated reduced peritumoral normal tissue damage.
Our results demonstrate similar tumor treatment efficacy when tumor heating is delivered by locally delivered mNPs and 915 MHz microwaves at the same measured thermal dose. However, mNPH treatments did not result in the same type or level of peritumoral damage seen with the microwave hyperthermia treatments. These data suggest that mNP hyperthermia is capable of improving the therapeutic ratio for locally delivered tumor hyperthermia. These results further indicate that this improvement is due to improved heat localization in the tumor.
PMCID: PMC4167009  PMID: 24219799
Nanoparticle; Hyperthermia; Iron Oxide; Microwave; Cumulative Equivalent; Minutes
13.  Long-term carcinogenicity study in Syrian golden hamster of particulate emissions from coal- and oil-fired power plants. 
Male Syrian golden hamsters were given 15 weekly intratracheal instillations with suspensions of coal fly ash or oil fly ash. Controls were instilled with saline containing gelatine (0.5 g/100 mL) or to check particle effects with suspensions of hematite (Fe2O3). The common weekly dose was 4.5 mg/hamster. In addition, one subgroup of hamsters was treated with oil fly ash at a weekly dose of 3.0 mg/hamster and another with coal fly ash at a weekly dose of 6.0 mg/hamster. Other groups of hamsters were treated with suspensions of benzo[a]pyrene (BaP) or with suspensions on coal fly ash, oil fly ash, or Fe2O3 coated with BaP. The mass median aerodynamic diameters of the coal and oil fly ashes were 4.4 microns and 28 microns, respectively. Hamsters treated with oil fly ash showed a higher frequency of bronchiolar-alveolar hyperplasia than hamsters in the other treatment groups. Squamous dysplasia and squamous metaplasia were most frequent in animals treated with suspensions of BaP or BaP-coated particles. The earliest appearance of a tumor, the highest incidence of tumors, and the highest incidence of malignant tumors were observed in hamsters treated with oil fly ash coated with BaP. Squamous cell carcinoma and adenosquamous carcinoma were the most frequent malignant tumors. No malignant tumors and only few benign tumors were observed in hamsters instilled with suspensions of fly ash not coated with BaP. The present study gives no indication that coal fly ash could create more serious health problems than oil fly ash.
PMCID: PMC1474526  PMID: 3383816
14.  Iron oxide nanoparticle hyperthermia and chemotherapy cancer treatment 
The benefit of combining hyperthermia and chemotherapy to treat cancer is well established. However, combined therapy has not yet achieved standard of care status. The reasons are numerous and varied, however the lack of significantly greater tumor cell sensitivity to heat (as compared to normal cells) and the inability to deliver heat to the tumor in a precise manner have been major factors. Iron oxide nanoparticle (IONP) hyperthermia, alone and combined with other modalities, offers a new direction in hyperthermia cancer therapy via improved tumor targeting and an improved therapeutic ratio. Our preliminary studies have demonstrated tumor cell cytotoxicity (in vitro and in vivo) with IONP heat and cisplatinum (CDDP) doses lower than those necessary when using conventional heating techniques or cisplatinum alone. Ongoing studies suggest such treatment could be further improved through the use of targeted nanoparticles.
In vivo: IONPs (5mg of iron per gram of tumor) were administered into MTG-B flank tumors in female C3H-HEJ mice directly after cisplatinum chemotherapy (0.1ml/kg of body mass) was intraperitoneally injected. An 160 KHz, 350–450 Oe AMF (alternating magnetic field) was used to induce particle heating.
In vitro: Mouse mammary adenocarcinoma cells (MTG-B) cells were grown and exposed to IONP hyperthermia and cisplatinum. IONPs not associated with cells were removed by washing prior to heat induction by an AMF field. Acute cell survival, via trypan blue assay, was used to quantify the level of cytotoxicity.
In vitro studies, using IONP + cisplatinum, have demonstrated promising cytotoxicity enhancement. Ongoing studies are being pursued to further define the mechanism of action, temporal associations and pathophysiology of combined IONP hyperthermia and chemotherapy treatment. Preliminary in vivo IONP /cisplatinum studies have shown a tumor growth delay/volume reduction greater than either modality alone at comparable doses. Further enhancement of this treatment success appears to depend on a better understanding of IONP dose and tumor cell association, chemotherapy dose and administration technique, the spatial and temporal treatment relationship of the two modalities and optimal AMF - IONP coupling.
PMCID: PMC4208066  PMID: 25346581
Iron oxide; nanoparticle; AMF; chemotherapy; cisplatinum; murine; MTG-B; HT-29
15.  Local hyperthermia for esophageal cancer in a rabbit tumor model: Magnetic stent hyperthermia versus magnetic fluid hyperthermia 
Oncology Letters  2013;6(6):1550-1558.
Magnetic-mediated hyperthermia (MMH) is a promising local thermotherapy approach for cancer treatment. The present study investigated the feasibility and effectiveness of MMH in esophageal cancer using a rabbit tumor model. The therapeutic effect of two hyperthermia approaches, magnetic stent hyperthermia (MSH), in which heat is induced by the clinical stent that is placed inside the esophagus, and magnetic fluid hyperthermia (MFH), where magnetic nanoparticles are applied as the agent, was systematically evaluated. A rabbit esophageal tumor model was established by injecting VX2 carcinoma cells into the esophageal submucosa. The esophageal stent was deployed perorally into the tumor segment of the esophagus. For the MFH, magnetic nanoparticles (MNPs) were administered to the rabbits by intratumoral injection. The rabbits were exposed under a benchtop applicator using an alternative magnetic field (AMF) with 300 kHz frequency for the hyperthermia treatment. The results demonstrated that esophageal stents and MNPs had ideal inductive heating properties upon exposure under an AMF of 300 kHz. MSH, using a thermal dose of 46°C with a 10-min treatment time, demonstrated antitumor effects on the rabbit esophageal cancer. However, the rabbit esophageal wall is not heat-resistant. Therefore, a higher temperature or longer treatment time may lead to necrosis of the rabbit esophagus. MFH has a significant antitumor effect by confining the heat within the tumor site without damaging the adjacent normal tissues. The present study indicates that the two hyperthermia procedures have therapeutic effects on esophageal cancer, and that MFH may be more specific than MSH in terms of temperature control during the treatment.
PMCID: PMC3833863  PMID: 24260045
magnetic mediated hyperthermia; esophageal cancer; magnetic nanoparticles; esophageal stent; alternative magnetic field
16.  Silencing of autocrine motility factor induces mesenchymal to epithelial transition and suppression of osteosarcoma pulmonary metastasis 
Cancer research  2010;70(22):9483-9493.
Phosphoglucose isomerase (PGI) is a multifunctional enzyme that functions in glucose metabolism as a glycolytic enzyme catalyzing an interconversion between glucose and fructose inside the cell, while, PGI acts as cytokine outside the cell, with properties that include autocrine motility factor (AMF) regulating tumor cell motility. Overexpression of AMF/PGI induces epithelial to mesenchymal transition (EMT) with enhanced malignancy. Recent studies have revealed that silencing of AMF/PGI resulted in mesenchymal to epithelial transition (MET) of human lung fibrosarcoma cells and breast cancer cells with reduced malignancy. Here, we constructed a hammerhead ribozyme specific against GUC triplet at the position G390 in the human, mouse, and rat AMF/PGI mRNA sequence. Mesenchymal human osteosarcoma MG-63, H S-Os-1, and murine LM8 cells were stably transfected with the ribozyme specific for AMF/PGI. The stable transfectant cells showed effective down-regulation of AMF/PGI expression and subsequent abrogation of AMF/PGI secretion, which resulted in morphological change with reduced growth, motility, and invasion. Silencing of AMF/PGI induced MET, in which up-regulation of E-cadherin and cytokeratins as well as down-regulation of vimentin were noted. The MET guided by AMF/PGI gene silencing induced osteosarcoma MG-63 to terminally differentiate into mature osteoblasts. Furthermore, The MET completely suppressed tumor growth and pulmonary metastasis of LM8 cells in nude mice. Thus, acquisition of malignancy might be completed in part by up-regulation of AMF/PGI and waiver of malignancy might be also controlled by down-regulation of AMF/PGI.
PMCID: PMC2982894  PMID: 20978190
autocrine-paracrine signaling; cell adhesion; cell adhesion and extracellular matrix; cell motility and migration; inducible gene expression; Metastasis/metastasis genes/metastasis models
17.  Intratumoral Iron Oxide Nanoparticle Hyperthermia and Radiation Cancer Treatment 
The potential synergism and benefit of combined hyperthermia and radiation for cancer treatment is well established, but has yet to be optimized clinically. Specifically, the delivery of heat via external arrays /applicators or interstitial antennas has not demonstrated the spatial precision or specificity necessary to achieve appropriate a highly positive therapeutic ratio. Recently, antibody directed and possibly even non-antibody directed iron oxide nanoparticle hyperthermia has shown significant promise as a tumor treatment modality. Our studies are designed to determine the effects (safety and efficacy) of iron oxide nanoparticle hyperthermia and external beam radiation in a murine breast cancer model.
MTG-B murine breast cancer cells (1 × 106) were implanted subcutaneous in 7 week-old female C3H/HeJ mice and grown to a treatment size of 150 mm3 +/− 50 mm3. Tumors were then injected locally with iron oxide nanoparticles and heated via an alternating magnetic field (AMF) generator operated at approximately 160 kHz and 400 - 550 Oe. Tumor growth was monitored daily using standard 3-D caliper measurement technique and formula. specific Mouse tumors were heated using a cooled, 36 mm diameter square copper tube induction coil which provided optimal heating in a 1 cm wide region in the center of the coil. Double dextran coated 80 nm iron oxide nanoparticles (Triton Biosystems) were used in all studies. Intra-tumor, peri-tumor and rectal (core body) temperatures were continually measured throughout the treatment period.
Preliminary in vivo nanoparticle-AMF hyperthermia (167 KHz and 400 or 550 Oe) studies demonstrated dose responsive cytotoxicity which enhanced the effects of external beam radiation. AMF associated eddy currents resulted in nonspecific temperature increases in exposed tissues which did not contain nanoparticles, however these effects were minor and not injurious to the mice. These studies also suggest that iron oxide nanoparticle hyperthermia is more effective than nonnanoparticle tumor heating techniques when similar thermal doses are applied. Initial electron and light microscopy studies of iron oxide nanoparticle and AMF exposed tumor cells show a rapid uptake of particles and acute cytotoxicity following AMF exposure.
PMCID: PMC4187389  PMID: 25301985
18.  STAT2 Knockout Syrian Hamsters Support Enhanced Replication and Pathogenicity of Human Adenovirus, Revealing an Important Role of Type I Interferon Response in Viral Control 
PLoS Pathogens  2015;11(8):e1005084.
Human adenoviruses have been studied extensively in cell culture and have been a model for studies in molecular, cellular, and medical biology. However, much less is known about adenovirus replication and pathogenesis in vivo in a permissive host because of the lack of an adequate animal model. Presently, the most frequently used permissive immunocompetent animal model for human adenovirus infection is the Syrian hamster. Species C human adenoviruses replicate in these animals and cause pathology that is similar to that seen with humans. Here, we report findings with a new Syrian hamster strain in which the STAT2 gene was functionally knocked out by site-specific gene targeting. Adenovirus-infected STAT2 knockout hamsters demonstrated an accentuated pathology compared to the wild-type control animals, and the virus load in the organs of STAT2 knockout animals was 100- to 1000-fold higher than that in wild-type hamsters. Notably, the adaptive immune response to adenovirus is not adversely affected in STAT2 knockout hamsters, and surviving hamsters cleared the infection by 7 to 10 days post challenge. We show that the Type I interferon pathway is disrupted in these hamsters, revealing the critical role of interferon-stimulated genes in controlling adenovirus infection. This is the first study to report findings with a genetically modified Syrian hamster infected with a virus. Further, this is the first study to show that the Type I interferon pathway plays a role in inhibiting human adenovirus replication in a permissive animal model. Besides providing an insight into adenovirus infection in humans, our results are also interesting from the perspective of the animal model: STAT2 knockout Syrian hamster may also be an important animal model for studying other viral infections, including Ebola-, hanta-, and dengue viruses, where Type I interferon-mediated innate immunity prevents wild type hamsters from being effectively infected to be used as animal models.
Author Summary
The biology of human adenoviruses has been studied extensively; however, much less is known about the replication and pathogenesis of the virus in a permissive host. Our laboratory pioneered the use of Syrian hamsters to study the pathogenesis of human adenoviruses. Syrian hamsters are permissive for species C human adenoviruses, which replicate in these animals and cause illness akin to that in humans. Hereby, we report findings with a new Syrian hamster strain (STAT2 KO hamsters), in which the Type I interferon pathway, an important part of the innate immune response to virus infection, is disrupted. This is the first genetically modified Syrian hamster strain ever reported. We show that these animals are very sensitive to infection with type 5 human adenovirus (Ad5). Ad5 replicates to 100- to 1000-fold higher titers in STAT2 KO hamsters than in wild-type ones, and this increased infection causes enhanced pathology. However, the adaptive immune response to the virus infection seems to be intact with the STAT2 KO hamsters, and surviving animals clear the virus effectively. The data reported here may be of interest to researchers focusing on adenoviruses, and also to those who utilize the Syrian hamster as their animal model for other purposes.
PMCID: PMC4546297  PMID: 26291525
19.  Nanoparticle based cancer treatment: can delivered dose and biological dose be reliably modeled and quantified? 
Proceedings of SPIE  2011;7901:10.1117/12.877026.
Essential developments in the reliable and effective use of heat in medicine include: 1) the ability to model energy deposition and the resulting thermal distribution and tissue damage (Arrhenius models) over time in 3D, 2) the development of non-invasive thermometry and imaging for tissue damage monitoring, and 3) the development of clinically relevant algorithms for accurate prediction of the biological effect resulting from a delivered thermal dose in mammalian cells, tissues, and organs. The accuracy and usefulness of this information varies with the type of thermal treatment, sensitivity and accuracy of tissue assessment, and volume, shape, and heterogeneity of the tumor target and normal tissue. That said, without the development of an algorithm that has allowed the comparison and prediction of the effects of hyperthermia in a wide variety of tumor and normal tissues and settings (cumulative equivalent minutes/ CEM), hyperthermia would never have achieved clinical relevance. A new hyperthermia technology, magnetic nanoparticle-based hyperthermia (mNPH), has distinct advantages over the previous techniques: the ability to target the heat to individual cancer cells (with a nontoxic nanoparticle), and to excite the nanoparticles noninvasively with a non-injurious magnetic field, thus sparing associated normal cells and greatly improving the therapeutic ratio. As such, this modality has great potential as a primary and adjuvant cancer therapy. Although the targeted and safe nature of the noninvasive external activation (hysteretic heating) are a tremendous asset, the large number of therapy based variables and the lack of an accurate and useful method for predicting, assessing and quantifying mNP dose and treatment effect is a major obstacle to moving the technology into routine clinical practice. Among other parameters, mNPH will require the accurate determination of specific nanoparticle heating capability, the total nanoparticle content and biodistribution in the target cells/tissue, and an effective and matching alternating magnetic field (AMF) for optimal and safe excitation of the nanoparticles. Our initial studies have shown that appropriately delivered and targeted nanoparticles are capable of achieving effective tumor cytotoxicity at measured thermal doses significantly less than the understood thermal dose values necessary to achieve equivalent treatment effects using conventional heat delivery techniques. Therefore conventional CEM based thermal dose - tissues effect relationships will not hold for mNPH. The goal of this effort is to provide a platform for determining the biological and physical parameters that will be necessary for accurately planning and performing safe and effective mNPH, creating a new, viable primary or adjuvant cancer therapy.
PMCID: PMC3877314  PMID: 24392199
Iron oxide; nanoparticle; hyperthermia; dosimetry; treatment plan; CEM; thermal therapy; thermal dose; tissue assessment
20.  Oleanane triterpenoid CDDO-Me induces apoptosis in multidrug resistant osteosarcoma cells through inhibition of Stat3 pathway 
BMC Cancer  2010;10:187.
The activation of signal transducer and activator of transcription 3 (Stat3) pathway correlates with tumor growth, survival, drug resistance and poor prognosis in osteosarcoma. To explore the potential therapeutic values of this pathway, we assessed both the expression and the activation of Stat3 pathway in several pairs of multidrug resistant (MDR) osteosarcoma cell lines, and tissues. To explore the potential therapeutic values of this pathway, we analyzed the ability of the synthetic oleanane triterpenoid, C-28 methyl ester of 2-cyano-3,12-dioxoolen-1,9-dien-28-oic acid (CDDO-Me), to inhibit Stat3 expression and activation as well as its effects on doxorubicin sensitivity in osteosarcoma cells.
Expression of Stat3, phosphorylated Stat3 (pStat3) and Stat3 targeted proteins, including Bcl-XL, Survivin and MCL-1 were determined in drug sensitive and MDR osteosarcoma cell lines and tissues by Western blot analysis. The effect of CDDO-Me on osteosarcoma cell growth was evaluated by MTT and apoptosis by PARP cleavage assay and caspase-3/7 activity.
Stat3 pathway was activated in osteosarcoma tissues and in MDR cell lines. CDDO-Me inhibited growth and induced apoptosis in osteosarcoma cell lines. Treatment with CDDO-Me significantly decreased the level of nuclear translocation and phosphorylation of Stat3. The inhibition of Stat3 pathway correlated with the suppression of the anti-apoptotic Stat3 targeted genes Bcl-XL, survivin, and MCL-1. Furthermore, CDDO-Me increased the cytotoxic effects of doxorubicin in the MDR osteosarcoma cell lines.
Stat3 pathway is overexpressed in MDR osteosarcoma cells. CDDO-Me significantly inhibited Stat3 phosphorylation, Stat3 nuclear translocation and induced apoptosis in osteosarcoma. This study provides the framework for the clinical evaluation of CDDO-Me, either as monotherapy or perhaps even more effectively in combination with doxorubicin to treat osteosarcoma and overcome drug resistance.
PMCID: PMC2874784  PMID: 20459702
21.  Effects of ulinastatin administered at different time points on the pathological morphologies of the lung tissues of rats with hyperthermia 
Hyperthermia not only directly induces cell injury of body tissues, but also causes the body to release large amounts of inflammatory mediators and cells with extensive biological activities to induce a systemic inflammatory response and immune dysfunction. Thus, hyperthermia causes systemic inflammatory response syndrome, aggravating injuries to various organs. This study aimed to observe the effects of ulinastatin (UTI) administered at different time points on the cellular morphologies of the lung tissues of rats with systemic hyperthermia. A total of 40 male Sprague Dawley rats were randomly divided into five groups: The normal control group (C group), the hyperthermia group without medication (H group), the hyperthermia and UTI pre-treatment group (HU group), the group treated with UTI at 1 h after hyperthermia (HU1 group), and the group treated with UTI at 2 h after hyperthermia (HU2 group). The systemic hyperthermia rat model was established in a heating chamber with a biological oxygen supply. For the HU, HU1 and HU2 groups, UTI (5×104 U/kg) was administered at different time points. For the C and H groups, an equivalent volume of normal saline was administered. During heating, the respiratory frequency and rectal temperature were measured and recorded once every 30 min. After 2.5 h of heating, the wet/dry weight (W/D) ratio of the lung tissues of the rats was measured. Additionally, the cellular morphologies of the lung tissues were observed under light and electron microscopes. The respiratory frequencies and lung tissue W/D ratios of the rats in the various hyperthermia groups were significantly higher than those of the rats in the C group (all P<0.05). The respiratory frequencies and lung tissue W/D values of the HU and HU1 groups were significantly lower than those of the H group (all P<0.05). Under the light microscope, the bronchial surrounding tissues of the HU and HU1 groups were loose, and the majority of the pulmonary alveolar structures were normal; the H and HU2 groups presented a number of changes, including pulmonary interstitial hyperemia, alveolar epithelial swelling and emphysema. Under the electron microscope, it was observed in the type II epithelial cells of the pulmonary alveoli of the H group that the mitochondria were swollen, the cell ridges were shortened, the microvilli were thin and increased, and the alveolar wall was thickened. Also, an increased number of infiltrating neutrophils were visible. In addition, the type II epithelial cells of the HU2 group also presented these changes to different extents and the changes in the HU and HU1 groups were the mildest. These results indicate that the early application of UTI relieves edema and the extent of cell injury of the lung tissue in rats with systemic hyperthermia.
PMCID: PMC4043614  PMID: 24926355
ulinastatin; systemic hyperthermia; pulmonary histopathology
22.  Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study 
The lancet oncology  2010;11(6):561-570.
The optimum treatment for high-risk soft-tissue sarcoma (STS) in adults is unclear. Regional hyperthermia concentrates the action of chemotherapy within the heated tumour region. Phase 2 studies have shown that chemotherapy with regional hyperthermia improves local control compared with chemotherapy alone. We designed a parallel-group randomised controlled trial to assess the safety and efficacy of regional hyperthermia with chemotherapy.
Patients were recruited to the trial between July 21, 1997, and November 30, 2006, at nine centres in Europe and North America. Patients with localised high-risk STS (≥5 cm, Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep to the fascia) were randomly assigned to receive either neo-adjuvant chemotherapy consisting of etoposide, ifosfamide, and doxorubicin (EIA) alone, or combined with regional hyperthermia (EIA plus regional hyperthermia) in addition to local therapy. Local progression-free survival (LPFS) was the primary endpoint. Efficacy analyses were done by intention to treat. This trial is registered with, number NCT 00003052.
341 patients were enrolled, with 169 randomly assigned to EIA plus regional hyperthermia and 172 to EIA alone. All patients were included in the analysis of the primary endpoint, and 332 patients who received at least one cycle of chemotherapy were included in the safety analysis. After a median follow-up of 34 months (IQR 20–67), 132 patients had local progression (56 EIA plus regional hyperthermia vs 76 EIA). Patients were more likely to experience local progression or death in the EIA-alone group compared with the EIA plus regional hyperthermia group (relative hazard [RH] 0.58, 95% CI 0.41–0.83; p=0.003), with an absolute difference in LPFS at 2 years of 15% (95% CI 6–26; 76% EIA plus regional hyperthermia vs 61% EIA). For disease-free survival the relative hazard was 0.70 (95% CI 0.54–0.92, p=0.011) for EIA plus regional hyperthermia compared with EIA alone. The treatment response rate in the group that received regional hyperthermia was 28.8%, compared with 12.7% in the group who received chemotherapy alone (p=0.002). In a pre-specified per-protocol analysis of patients who completed EIA plus regional hyperthermia induction therapy compared with those who completed EIA alone, overall survival was better in the combined therapy group (HR 0.66, 95% CI 0.45–0.98, p=0.038). Leucopenia (grade 3 or 4) was more frequent in the EIA plus regional hyperthermia group compared with the EIA-alone group (128 of 165 vs 106 of 167, p=0.005). Hyperthermia-related adverse events were pain, bolus pressure, and skin burn, which were mild to moderate in 66 (40.5%), 43 (26.4%), and 29 patients (17.8%), and severe in seven (4.3%), eight (4.9%), and one patient (0.6%), respectively. Two deaths were attributable to treatment in the combined treatment group, and one death was attributable to treatment in the EIA-alone group.
To our knowledge, this is the first randomised phase 3 trial to show that regional hyperthermia increases the benefit of chemotherapy. Adding regional hyperthermia to chemotherapy is a new effective treatment strategy for patients with high-risk STS, including STS with an abdominal or retroperitoneal location.
Deutsche Krebshilfe, Helmholtz Association (HGF), European Organisation of Research and Treatment of Cancer (EORTC), European Society for Hyperthermic Oncology (ESHO), and US National Institute of Health (NIH).
PMCID: PMC3517819  PMID: 20434400
23.  Localized Hyperthermia with Iron Oxide-Doped Yttrium Microparticles: Steps Towards Image-Guided Thermoradiotherapy in Liver Cancer 
To test whether iron oxide–containing yttrium aluminosilicate microparticles (IO-YAS MPs) can generate localized therapeutic hyperthermia (≥43°C) when injected intra-tumorally in an animal model of liver cancer and whether MP distributions could be visualized with MR imaging.
Twenty-one Sprague-Dawley rats implanted with N1-S1 liver tumors were assigned to alternating magnetic field (AMF) exposure following intra-tumoral injection with IO-YAS MPs (n=7), sham surgery (n=7), or baseline iron quantitation (n=7). Three fiber optic probes allowed spatial and temporal monitoring of temperatures during 24 minutes of AMF. T2-weighted turbo spin echo magnetic resonance imaging was performed within 1 hour post-procedure to detect signal voids due to IO-YAS deposition. Hematoxylin and eosin–stained pathologic slides were also obtained and the presence of IO-YAS was evaluated with inductively coupled plasma optical emission spectroscopy.
Following AMF exposure, intra-tumoral temperatures after IO-YAS MP injection achieved therapeutic hyperthermia while those after sham surgery did not (46.6±1.3 vs. 36.8±0.4°C, P<0.0001). Within the treated group, the normal hepatic parenchyma (NHP) and rectal temperatures were 37.4±0.9 and 36.5±1.0°C (P=0.0809) at the conclusion of AMF exposure, respectively. A T2-weighted signal void at the tumor site was observed in 7/7 treated animals and intra-tumoral IO-YAS visualized on subsequent histopathology in each case. The mean ratio of tumor:NHP Fe concentrations attributable to IO-YAS MPs was 108:1.
AMF exposure of intra-tumoral IO-YAS MPs generates localized therapeutic hyperthermia in an animal model of liver cancer. MR detectability and potential for combination brachytherapy warrants further investigation for thermoradiotherapy in liver cancer.
PMCID: PMC3943613  PMID: 24315666
24.  Growth Inhibition of Re-Challenge B16 Melanoma Transplant by Conjugates of Melanogenesis Substrate and Magnetite Nanoparticles as the Basis for Developing Melanoma-Targeted Chemo-Thermo-Immunotherapy 
Melanogenesis substrate, N-propionyl-cysteaminylphenol (NPrCAP), is selectively incorporated into melanoma cells and inhibits their growth by producing cytotoxic free radicals. Magnetite nanoparticles also disintegrate cancer cells and generate heat shock protein (HSP) upon exposure to an alternating magnetic field (AMF). This study tested if a chemo-thermo-immunotherapy (CTI therapy) strategy can be developed for better management of melanoma by conjugating NPrCAP on the surface of magnetite nanoparticles (NPrCAP/M). We examined the feasibility of this approach in B16 mouse melanoma and evaluated the impact of exposure temperature, frequency, and interval on the inhibition of re-challenged melanoma growth. The therapeutic protocol against the primary transplanted tumor with or without AMF exposure once a day every other day for a total of three treatments not only inhibited the growth of the primary transplant but also prevented the growth of the secondary, re-challenge transplant. The heat-generated therapeutic effect was more significant at a temperature of 43°C than either 41°C or 46°C. NPrCAP/M with AMF exposure, instead of control magnetite alone or without AMF exposure, resulted in the most significant growth inhibition of the re-challenge tumor and increased the life span of the mice. HSP70 production was greatest at 43°C compared to that with 41°C or 46°C. CD8+T cells were infiltrated at the site of the re-challenge melanoma transplant.
PMCID: PMC2760320  PMID: 19830247
25.  High Therapeutic Efficiency of Magnetic Hyperthermia in Xenograft Models Achieved with Moderate Temperature Dosages in the Tumor Area 
Pharmaceutical Research  2014;31(12):3274-3288.
Tumor cells can be effectively inactivated by heating mediated by magnetic nanoparticles. However, optimized nanomaterials to supply thermal stress inside the tumor remain to be identified. The present study investigates the therapeutic effects of magnetic hyperthermia induced by superparamagnetic iron oxide nanoparticles on breast (MDA-MB-231) and pancreatic cancer (BxPC-3) xenografts in mice in vivo.
Superparamagnetic iron oxide nanoparticles, synthesized either via an aqueous (MF66; average core size 12 nm) or an organic route (OD15; average core size 15 nm) are analyzed in terms of their specific absorption rate (SAR), cell uptake and their effectivity in in vivo hyperthermia treatment.
Exceptionally high SAR values ranging from 658 ± 53 W*gFe−1 for OD15 up to 900 ± 22 W*gFe−1 for MF66 were determined in an alternating magnetic field (AMF, H = 15.4 kA*m−1 (19 mT), f = 435 kHz). Conversion of SAR values into system-independent intrinsic loss power (ILP, 6.4 ± 0.5 nH*m2*kg−1 (OD15) and 8.7 ± 0.2 nH*m2*kg−1 (MF66)) confirmed the markedly high heating potential compared to recently published data. Magnetic hyperthermia after intratumoral nanoparticle injection results in dramatically reduced tumor volume in both cancer models, although the applied temperature dosages measured as CEM43T90 (cumulative equivalent minutes at 43°C) are only between 1 and 24 min. Histological analysis of magnetic hyperthermia treated tumor tissue exhibit alterations in cell viability (apoptosis and necrosis) and show a decreased cell proliferation.
Concluding, the studied magnetic nanoparticles lead to extensive cell death in human tumor xenografts and are considered suitable platforms for future hyperthermic studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s11095-014-1417-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4224751  PMID: 24890197
CEM43T90; in vivo; iron oxide nanoparticles; magnetic hyperthermia; temperature dose

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