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Background: In order to explore the possibility of treating breast cancer by local photo-therapy, a photothermal agents loaded in situ hydrogel was established. In detail, The Cu 2 MnS 2 nanoplates were prepared by one-pot synthesis and, the thermosensitive Pluronic F127 was used as the hydrogel matrix. The Cu 2 MnS 2 nanoplates and the hydrogel were characterized by morphous, particle size, serum stability, photothermal performance upon repeated 808 nm laser irradiation as well as the rheology features. The therapeutic effects of the Cu 2 MnS 2 nanoplates and the hydrogel were evaluated qualitatively and quantitatively in 4T1 mouse breast cancer cells. The retention, photothermal efficacy, therapeutic effects and systemic toxicity of the hydrogel were assessed in tumor bearing mouse model., Results: The Cu 2 MnS 2 nanoplates with a diameter of about 35 nm exhibited satisfying serum stability, photo-heat conversion ability and repeated laser exposure stability. The hydrogel encapsulation did not negatively influence the above features of the photothermal agent. The nanoplates loaded in situ hydrogel shows a phase transition at body temperature and, as a result, a long retention in vivo., Conclusions: The photothermal agent embedded hydrogel played a promising photothermal therapeutic effects in tumor bearing mouse model with low systemic toxicity after peritumoral administration.

Near-infrared (NIR) laser-induced photothermal therapy (PTT) uses a photothermal agent to convert optical energy into thermal energy and has great potential as an effective local, minimally invasive treatment modality for killing cancer cells. To improve the efficacy of PTT, we developed poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) encapsulating superparamagnetic iron oxide (Fe 3 O 4 ), indocyanine green (ICG), and perfluoropentane (PFP) as synergistic agents for NIR laser-induced PTT. We fabricated a novel type of phase-shifting fluorescent magnetic NPs, Fe 3 O 4 /ICG@PLGA/PFP NPs, that effectively produce heat in response to NIR laser irradiation for an enhanced thermal ablation effect and a phase-shift thermoelastic expansion effect, and thus, can be used as a photothermal agent. After in vitro treatment of MCF-7 breast cancer cells with Fe 3 O 4 /ICG@PLGA/PFP NPs and NIR laser irradiation, histology and electron microscopy confirmed severe damage to the cells and the formation of many microbubbles with iron particles at the edge or outside of the microbubbles. In vivo experiments in mice with MCF-7 tumors demonstrated that Fe 3 O 4 /ICG@PLGA/PFP NPs could achieve tumor ablation upon NIR laser irradiation with minimal toxicity to non-irradiated tissues. Together, our results indicate that Fe 3 O 4 /ICG@PLGA/PFP NPs can be used as effective nanotheranostic agents for tumor ablation.

Plasmonic photothermal therapy (PPTT) is a cancer therapy in which gold nanorods are injected at the site of a tumor before near-infrared light is transiently applied to the tumor causing localized cell death. Previously, PPTT studies have been carried out on xenograft mice models. Herein, we report a study showing the feasibility of PPTT as applied to natural tumors in the mammary glands of dogs and cats, which more realistically represent their human equivalents at the molecular level. We optimized a regime of three low PPTT doses at 2-week intervals that ablated tumors mainly via apoptosis in 13 natural mammary gland tumors from seven animals. Histopathology, X-ray, blood profiles, and comprehensive examinations were used for both the diagnosis and the evaluation of tumor statuses before and after treatment. Histopathology results showed an obvious reduction in the cancer grade shortly after the first treatment and a complete regression after the third treatment. Blood tests showed no obvious change in liver and kidney functions. Similarly, X-ray diffraction showed no metastasis after 1 year of treatment. In conclusion, our study suggests the feasibility of applying the gold nanorods-PPTT on natural tumors in dogs and cats without any relapse or toxicity effects after 1 year of treatment.

Two-dimensional MoS2 nanosheet has been extensively explored as a photothermal agent for tumor regression; however, its surface modification remains a great challenge. Herein, as an alternative to surface polyethylene glycol modification (PEGylation), a facile approach based on "thin-film" strategy has been proposed for the first time to produce soybean phospholipid-encapsulated MoS2 (SP-MoS2) nanosheets. By simply vacuum-treating MoS2 nanosheets/soybean phospholipid/chloroform dispersion in a rotary evaporator, SP-MoS2 nanosheet was successfully constructed. Owing to the steric hindrance of polymer chains, the surface-coated soybean phospholipid endowed MoS2 nanosheets with excellent colloidal stability. Without showing detectable in vitro and in vivo hemolysis, coagulation, and cyto-/histotoxicity, the constructed SP-MoS2 nanosheets showed good photothermal conversion performance and photothermal stability. SP-MoS2 nanosheet was shown to be a promising platform for in vitro and in vivo breast tumor photothermal therapy. The produced SP-MoS2 nanosheets featured low cost, simple fabrication, and good in vivo hemo-/histocompatibility and hold promising potential for future clinical tumor therapy.

Herein, we present a novel imaging platform to study the biological effects of non-invasive radiofrequency (RF) electric field cancer hyperthermia. This system allows for real-time in vivo intravital microscopy (IVM) imaging of radiofrequency-induced biological alterations such as changes in vessel structure and drug perfusion. Our results indicate that the IVM system is able to handle exposure to high-power electric-fields without inducing significant hardware damage or imaging artifacts. Furthermore, short durations of low-power (< 200 W) radiofrequency exposure increased transport and perfusion of fluorescent tracers into the tumors at temperatures below 41°C. Vessel deformations and blood coagulation were seen for tumor temperatures around 44°C. These results highlight the use of our integrated IVM-RF imaging platform as a powerful new tool to visualize the dynamics and interplay between radiofrequency energy and biological tissues, organs, and tumors.

This paper focuses on the targeting of single-walled carbon nanotubes (SWNTs) for the treatment of breast cancer with minimal side effects using photothermal therapy. The human protein annexin V (AV) binds specifically to anionic phospholipids expressed externally on the surface of tumour cells and endothelial cells that line the tumour vasculature. A 2 h incubation of the SWNT-AV conjugate with proliferating endothelial cells followed by washing and near-infrared (NIR) irradiation at a wavelength of 980 nm was enough to induce significant cell death; there was no significant cell death with irradiation or the conjugate alone. Administration of the same conjugate i.v. in BALB/c female mice with implanted 4T1 murine mammary at a dose of 0.8 mg SWNT kg(-1) and followed one day later by NIR irradiation of the tumour at a wavelength of 980 nm led to complete disappearance of implanted 4T1 mouse mammary tumours for the majority of the animals by 11 days since the irradiation. The combination of the photothermal therapy with the immunoadjuvant cyclophosphamide resulted in increased survival. The in vivo results suggest the SWNT-AV/NIR treatment is a promising approach to treat breast cancer.

In this study, the biological effects of long-term mild hyperthermia treatment on tumor metabolism and growth were investigated using 4T1 murine mammary carcinoma, a common animal model of metastatic breast cancer. Periodic thermal treatment (12 hours per day) was applied to tumors and carried out for 3 days, 7 days, 14 days, and 21 days, respectively. The metabolites of tumor tissues were analyzed by gas chromatography-mass spectrometry. The results showed that the growth rate of thermally treated tumors was inversely related to the abundance of long chain fatty acids and acyl glycerols identified in tumor tissues. In the first two weeks, the growth of thermally treated tumors was significantly inhibited, while there was an obvious accumulation of long chain fatty acids and acyl glycerols in tumor tissues. In the third week, the thermally treated tumors adapted to the thermal environment and started to regrow, while the abundance of long chain fatty acids and acyl glycerols decreased in the tumor tissues. These observations suggested that the blockade of long chain fatty acid synthesis during mild hyperthermia treatment of tumors could improve the long-term treatment effect by limiting the supply of substance and energy for tumor re-growth.

Purpose: Photothermal therapy is an emerging cancer treatment paradigm which involves highly localized heating and killing of tumor cells, due to the presence of nanomaterials that can strongly absorb near-infrared (NIR) light. In addition to having deep penetration depths in tissue, NIR light is innocuous to normal cells. Little is known currently about the fate of nanomaterials post photothermal ablation and the implications thereof. The purpose of this investigation was to define the intratumoral fate of nanoparticles (NPs) after photothermal therapy in vivo and characterize the use of novel multidye theranostic NPs (MDT-NPs) for fractionated photothermal antitumor therapy., Methods: The photothermal and fluorescent properties of MDT-NPs were first characterized. To investigate the fate of nanomaterials following photothermal ablation in vivo, novel MDT-NPs and a murine mammary tumor model were used. Intratumoral injection of MDT-NPs and real-time fluorescence imaging before and after fractionated photothermal therapy was performed to study the intratumoral fate of MDT-NPs. Gross tumor and histological changes were made comparing MDT-NP treated and control tumor-bearing mice., Results: The dual dye-loaded mesoporous NPs (ie, MDT-NPs; circa 100 nm) retained both their NIR absorbing and NIR fluorescent capabilities after photoactivation. In vivo MDT-NPs remained localized in the intratumoral position after photothermal ablation. With fractionated photothermal therapy, there was significant treatment effect observed macroscopically (P = 0.026) in experimental tumor-bearing mice compared to control treated tumor-bearing mice., Conclusion: Fractionated photothermal therapy for cancer represents a new therapeutic paradigm enabled by the application of novel functional nanomaterials. MDT-NPs may advance clinical treatment of cancer by enabling fractionated real-time image guided photothermal therapy.

Tumour relapse is believed to be caused by rare cancer-cells with stem-cell properties (cancer stem cells) that are intrinsically resistant to available treatments. The identification of novel strategies to increase their sensitivity has major clinical implications. Latest clinical trials have shown a positive antitumoral effect of hyperthermia in combination with chemotherapy or radiotherapy. In a recent paper, the combination of increased temperature at the tumour site, generated by laser treatment of intravenously-injected gold nanoshells, and ionizing radiations enhances radiosensitivity of cancer stem cells and tumor response. At the root of the success of hyperthermia in enhancing radio-sensitization of cancer stem cells is the inhibition of their capacity to repair DNA damage, affecting the survival rate of these cells.

Tumor vasculature damage induced by various thermal treatments has been studied in vivo via laser confocal microscopy. Murine mammary carcinoma 4T1 was implanted in the nude mice dorsal skin fold window chamber. The implanted tumor was treated by alternate cooling and heating. Results showed that the treatment was much more effective as compared with that of cooling or heating alone, especially in damaging the tumor vasculature. In general, tumor vascular response to thermal stimuli was heterogeneous. All the treatments of hyperthermia at 42 degrees C (for 1 h), alternate cooling at 1 degrees C and heating at 42 degrees C (for 1/2 h each) and that of -10 degrees C/42 degrees C (for 1/2 h each) enhanced liposome extravasation. Pre-cooling tumor at 1 degrees C preserved most of the vascular integrity but partially inhibited the effect of post-hyperthermia at 42 degrees C. On the other hand, cooling at -10 degrees C for 1/2 h before heating at 42 degrees C caused severe vessel damage. Histo-pathological analyses further confirmed the effect as rare tumor vessel recurrence and large necrotic tumor tissue areas shown on the 7th day after the treatment.

Purpose: To determine an effective triple-agent schedule combining fever-range whole body thermal therapy (FR-WB-TT) with cisplatin and gemcitabine by optimizing the timing of drug with heat, and drug with drug., Materials and Methods: Using an orthotopically implanted syngeneic breast adenocarcinoma in an immunologically normal female Fischer rat model, we investigated various schedules of a thermochemotherapy regimen combining FR-WB-TT with chemotherapy agents, cisplatin and gemcitabine. Differently timed combinations of a) cisplatin with FR-WB-TT, b) gemcitabine with FR-WB-TT, and c) cisplatin with gemcitabine were examined for anti-tumor efficacy and toxicity. A combination of the three agents based on the optimal two-agent schedules was then tested., Results: The greatest primary tumor and axillary metastasis growth delay and lowest toxicity was induced with administration of cisplatin 24 h prior to gemcitabine and cisplatin 24 h prior to simultaneous gemcitabine and FR-WB-TT. Administering cisplatin 24 h prior to gemcitabine was more effective and less toxic than giving the two drugs simultaneously or gemcitabine prior to cisplatin. Survival was greatest when gemcitabine and FR-WB-TT were administered 24 h after cisplatin, even with reduced drug doses. One complete cure resulted from the triple agent treatment., Conclusions: The relative timing of agents in multiple modality treatments is critically important in achieving tumor control or cures, and in reducing toxicity. Optimizing the relative timing of multiple agents in thermochemotherapy allows use of lower drug doses to achieve maximal anti-tumor efficacy and minimal toxicity.

Purpose: Mild hyperthermia can improve tumour oxygenation and enhance radiosensitivity. Imaging the hypoxic fraction of a tumour can guide hyperthermia treatment planning and facilitate treatment optimization. 64Cu-ATSM (Copper-diacetyl-bis(N4-methylthiosemicarbazone)) is a positron emitting compound that has been demonstrated to have rapid uptake and selective retention in hypoxic cells and has been used for imaging human and animal tumours. The purpose of the present report is to establish methodology that will allow one to use Cu-ATSM PET scanning to detect the impact of hyperthermia on tumour physiology in as little time as possible., Materials and Methods: EMT6 tumours (mouse mammary carcinoma) were implanted into the subcutaneous tissue of both thighs of 10 BALB/c mice (one heated, one control tumour per animal). The target thermal dose was 41.5 degrees C x 45 min. Without interrupting heating, 64Cu-ATSM (mean activity 1.8 mCi) was then injected and serial PET scans were obtained. In a sub-group of four animals, a low administered activity (approximately 0.3 mCi) 64Cu-ATSM scan was also conducted before heating to permit a direct comparison of the effects of hyperthermia on the same tumours. In another sub-group of five animals, a low activity (approximately 0.3 mCi) 64Cu-PTSM (pyruvaldehyde-bis(N*-methylthiosemicarbazone)) scan was conducted before heating, to confirm a posited correlation between perfusion and early 64Cu-ATSM uptake., Results: This study corrected for perfusion differences by dividing tumour uptake by the average early (first minute) uptake ('self-normalized uptake'). The 10 heated tumours showed a significantly (p = 0.007) lower self-normalized uptake than control tumours by 2 min. For the four mice with low activity Cu-ATSM scans performed before hyperthermia, the tumours to be heated demonstrated self-normalized uptake consistent with the unheated control tumours and which departed significantly (p < or = 0.02) from their post-hyperthermia scans by 5 min. Comparisons between scans and needle electrode surveys were performed in an additional four animals with eight tumours. For technical reasons electrode surveys were done after the end of hyperthermia-and, therefore, these animals also had comparison scans taken after hyperthermia. Reduced self-normalized uptake on scans was associated with increased pO2 on electrode surveys. These data also suggested a substantial degradation of the effect on tumour hypoxia by approximately 15-45 min after the end of mild hyperthermia., Conclusion: Short imaging times of approximately 5 min with modest (approximately 4-10) numbers of mice can discriminate the effects of mild hyperthermia on tumour physiology. The long-term objective is to use this tool to identify as short and mild a hyperthermia session as possible.

The goal of this study was to investigate the effect of photothermal laser irradiation on rat breast tumor (DMBA-4) vascular contents. An 805-nm diode laser was used in our experiment with a power density ranging from 0.32 to 1.27 W/cm2. The dynamic changes of oxygenated hemoglobin and total hemoglobin concentrations, delta[HbO2] and delta[Hb]total, in rat tumors during photothermal irradiation were noninvasively monitored by a near-infrared spectroscopy system. A multichannel thermal detection system was also used simultaneously to record temperatures at different locations within the tumors. Our experimental results showed that: (1) photoirradiation did have the ability to induce hyperthermic effects inside the rat breast tumors in a single exponential trend; (2) the significant changes (P < 0.005) of delta[HbO2] and delta[Hb]total in response to a low dosage of laser irradiation (0.32 W/cm2) have a single exponential increasing trend, similar to that seen in the tumor interior temperature; and (3) the increase in magnitude of delta[HbO2] is nearly two times greater than that of delta[Hb]total, suggesting that photoirradiation may enhance tumor vascular oxygenation. The last observation may be important to reveal the hidden mechanism of photoirradiation on tumors, leading to improvement of tumor treatment efficiency.

We have investigated the feasibility of enhancing damage induced by hyperthermia in SCK murine tumors by reducing tumor blood perfusion using a new agent, KB-R8498. Within several minutes of an i.v. injection, the tumor perfusion was reduced to less than 20% of the control value, and it recovered to 40-70% of the control value by 1 h after injection. The perfusion in normal tissues decreased or increased soon after drug administration depending on the tissue type. However, by 1 h after drug treatment, perfusion in five of the seven tissues examined had returned to the control level. The tumor pH was also reduced after i.v. drug administration. Control tumors grew to four times the initial volume in 6 days. Tumors that were heated at 42.5 degrees C for 60 min were delayed in growth by 4 days compared to control tumors. There was a growth delay of 14 days when an i.v. injection of KB-R8498 was given and the tumors were heated at 42.5 degrees C either immediately or 1 h later. In drug-alone studies, the tumor growth was delayed by 4 days when the drug was infused continuously at a rate of 30-50 mg/kg day(-1) for 7 days or about 2 days when mice were treated with five daily injections of 30 mg/kg KB-R8498.

Purpose: The aim of our study was to investigate if the efficacy of paclitaxel and paclitaxel-radiation treatments in vivo could be enhanced by hyperthermia., Materials and Methods: Paclitaxel was administered i.p. in doses from 30 to 60 mg/kg b.w. to (C3D2F1) mice bearing spontaneous mammary carcinoma. Local hyperthermia (41 degrees, 42 degrees, 43 degrees C) was carried out by immersing tumor-bearing legs in a water bath for 1 h. Single X-ray treatments from 10 to 90 Gy were performed. Tumor growth delay (TGD) or tumor control dose (TCD(50), radiation dose needed to induce local tumor control in 50% of irradiated animals) were the endpoints., Results: A significant increase of dose-dependent growth delay was observed in paclitaxel and 43 degrees C hyperthermia combined treatments, and a superadditive effect was seen with paclitaxel 45 mg/kg. Combined treatments with hyperthermia at 41 degrees and 42 degrees C were less effective. Administration of paclitaxel 24 h, 4 h, and 15 min before or 15 min and 4 h after hyperthermic treatments produced similar results (TGDs varying from 22.1 to 17 days), and administering paclitaxel 48 h before or 24 h after hyperthermic treatments decreased TGDs (about 10 days). Trimodality treatment (paclitaxel 45 mg/kg, hyperthermia, and X-ray), with a TCD(50) of 14. 1 Gy, in respect to the TCD(50) of 53.1 obtained with X-ray alone, was the most effective., Conclusions: Hyperthermia enhanced the effectiveness of paclitaxel in all the tested protocols. Our results show a superadditive effect of paclitaxel 45 mg/kg combined with a hyperthermic treatment of 1 h at 43 degrees C. Trimodality treatment, evaluated in terms of percentage of cures, shows a very high enhancement ratio.

The in vivo interaction between flavone acetic acid (FAA) and hyperthermia was studied in a C3H mammary carcinoma grown in the feet of female CDF1 mice and in normal foot skin. FAA was intraperitoneally injected prior to local tissue heating in restrained non-anaesthetized animals. Alone, FAA at doses of 100 mg/kg and above, inhibited tumour growth in a dose-dependent fashion. FAA also enhanced the tumour response to heat, the effect being dependent on both the time interval between the two modalities and the FAA dose, the greatest effect occurring when FAA doses of > or = 150 mg/kg preceeded heat by 3-48 h. These effects of FAA correlated with the drug's ability to decrease tumour blood perfusion measured using the RbCl extraction procedure. Injecting 150 mg/kg FAA 3 h before heating (42.7 degrees C) resulted in a 2.2-fold increase in tumour heat damage, but had little effect on the response of normal foot skin in non-tumour-bearing mice. However, this treatment gave a 2.0-fold increase in normal tissue damage when the skin experiments were repeated in tumour-bearing animals. These effects in skin occurred in the absence of any blood perfusion changes, but appeared to be associated with FAA-induced TNF-alpha production.

We previously reported that the thermosensitivity of tumor cells can be increased when the intracellular pH is lowered by inhibiting Na+/H+ exchange through the plasma membrane with amiloride (3,5-diamino-6-chloro-N-(diamino methylene)pyrazinecarboxamide) or its analogues and HCO3-/Cl-exchange with 4,4-diiothiocyanato-stilbene-2,2'-disulfonic acid. In this study, we investigated the effects of (3-amino-6-chloro-5- (1-homopiperidyl)-N-(diaminomethylene)pyrazine-carboxamide) (HMA), an analogue of amiloride and a potent inhibitor of Na+/H+ exchange, and R(+)-[(5,6-dichloro-2,3,9,9a-tetrahydro-3-oxo-9a-propyl-1H-fluoren -7- yl)oxy]acetic acid [B-3(+)], a potent inhibitor of HCO3-/Cl- exchange, on the thermosensitivity of SCK tumor cells in vitro. We observed that 10 microM of HMA could effectively increase the cell death by heating at 43 degrees in pH 6.6 medium but not in pH 7.5 medium. The B-3(+) at 50 microM alone had no effect on the thermosensitivity of cells, but it increased the thermosensitizing effect of HMA in acidic medium. Our results strongly suggested that a combination of HMA and B-3(+) may preferentially thermosensitize tumors in vivo since the interstitial environment in tumors is acidic relative to that in normal tissues.

Amiloride, a diuretic drug, is a potent inhibitor of Na+/H+ exchange through the plasma membrane, and has been reported to enhance thermal damage in tumor cells in vitro. We investigated the possible relationship between changes in the thermal response of SCK mouse mammary tumor cells in vitro and changes in intracellular pH (pHi) due to amiloride in the present study. At a concentration of 0.5 mM, amiloride reduced the shoulder (Dq) without causing significant change in the slope (Do) of the survival curve of SCK cells heated once at 43 degrees C. On the other hand, 0.5 mM of amiloride sensitized thermotolerant cells to heat as shown by a reduction in Do. The presence of amiloride during the interval between the first and second heatings slightly reduced or inhibited the development of thermotolerance. The pHi was measured with the BCECF fluorescence method. The presence of 0.5 mM amiloride significantly reduced pHi in both pH 7.2 and 6.6 medium. Heating the SCK cells at 43 degrees C in pH 7.2 or 6.6 medium also reduced the pHi. The combined effect of heat and amiloride in reducing the pHi of SCK cells was additive. These results suggest that the effects of amiloride on the thermal response of SCK cells might be mediated in part by a decrease in pHi. The possibility that the effects of amiloride on the thermal response of tumor cells are mediated by other biochemical changes, such as inhibition of protein synthesis, however, could not be ruled out.