Thermal Cancer Therapy Research Articles

Ultrasound ablation enhances drug accumulation and survival in mammary carcinoma models

Magnetic resonance-guided focused ultrasound (MRgFUS) facilitates noninvasive image-guided conformal thermal therapy of cancer. Yet in many scenarios, the sensitive tissues surrounding the tumor constrain the margins of ablation; therefore, augmentation of MRgFUS with chemotherapy may be required to destroy remaining tumor. Here, we used 64Cu-PET-CT, MRI, autoradiography, and fluorescence imaging to track the kinetics of long-circulating liposomes in immunocompetent mammary carcinoma-bearing FVB/n and BALB/c mice. We observed a 5-fold and 50-fold enhancement of liposome and drug concentration, respectively, within MRgFUS thermal ablation-treated tumors along with dense accumulation within the surrounding tissue rim. Ultrasound-enhanced drug accumulation was rapid and durable and greatly increased total tumor drug exposure over time. In addition, we found that the small molecule gadoteridol accumulates around and within ablated tissue. We further demonstrated that dilated vasculature, loss of vascular integrity resulting in extravasation of blood cells, stromal inflammation, and loss of cell-cell adhesion and tissue architecture all contribute to the enhanced accumulation of the liposomes and small molecule probe. The locally enhanced liposome accumulation was preserved even after a multiweek protocol of doxorubicin-loaded liposomes and partial ablation. Finally, by supplementing ablation with concurrent liposomal drug therapy, a complete and durable response was obtained using protocols for which a sub-mm rim of tumor remained after ablation.

The tumor-targeting core–shell structured DTX-loaded PLGA@Au nanoparticles for chemo-photothermal therapy and X-ray imaging

In this study, an organic–inorganic hybrid nanocomposite was synthesized by deposition of Au onto the surface of docetaxel (DTX)-loaded poly (lactide-co-glycolide) (PLGA) nanoparticle cores to form the core–shell structured DTX-loaded PLGA@Au nanoparticles. The tumor targeting peptide, angiopep-2, was then introduced onto the gold nanoshell through Au–S bond, achieving drug delivery with active targeting capability. This novel system allowed combined chemotherapy and thermal therapy for cancer, resulting from DTX and gold nanoshell. The formation of tumor-targeting gold nanoshell surrounding PLGA nanocore, designated as ANG/GS/PLGA/DTX NPs, was confirmed by its surface plasmon resonance (SPR) band in the UV–Vis spectrum and by a transmission electron microscope (TEM). The release profiles of DTX from this system showed strong dependence on near-infrared (NIR) laser. Compared with DTX alone, the ANG/GS/PLGA/DTX NPs afforded much higher anti-tumor efficiency without obvious toxic effects. Besides, it also showed potential X-ray imaging ability. These results demonstrated that the tumor-targeting core–shell structured DTX-loaded PLGA@Au nanoparticles could be used as a multifunctional nanomaterial system with NIR-triggered drug-releasing properties for tumor-targeted chemo-photothermal therapy and theranostics.

Optimization of synthesis and peptization steps to obtain iron oxide nanoparticles with high energy dissipation rates

Magnetic Fluid Hyperthermia (MFH) uses heat generated by magnetic nanoparticles exposed to alternating magnetic fields to cause a temperature increase in tumors to the hyperthermia range (43–47°C), inducing apoptotic cancer cell death. As with all cancer nanomedicines, one of the most significant challenges with MFH is achieving high nanoparticle accumulation at the tumor site. This motivates development of synthesis strategies that maximize the rate of energy dissipation of iron oxide magnetic nanoparticles, preferable due to their intrinsic biocompatibility. This has led to development of synthesis strategies that, although attractive from the point of view of chemical elegance, may not be suitable for scale-up to quantities necessary for clinical use. On the other hand, to date the aqueous co-precipitation synthesis, which readily yields gram quantities of nanoparticles, has only been reported to yield sufficiently high specific absorption rates after laborious size selective fractionation. This work focuses on improvements to the aqueous co-precipitation of iron oxide nanoparticles to increase the specific absorption rate (SAR), by optimizing synthesis conditions and the subsequent peptization step. Heating efficiencies up to 1048W/gFe (36.5kA/m, 341kHz; ILP=2.3nHm2kg−1) were obtained, which represent one of the highest values reported for iron oxide particles synthesized by co-precipitation without size-selective fractionation. Furthermore, particles reached SAR values of up to 719W/gFe (36.5kA/m, 341kHz; ILP=1.6nHm2kg−1) when in a solid matrix, demonstrating they were capable of significant rates of energy dissipation even when restricted from physical rotation. Reduction in energy dissipation rate due to immobilization has been identified as an obstacle to clinical translation of MFH. Hence, particles obtained with the conditions reported here have great potential for application in nanoscale thermal cancer therapy.

Fluorescence probe analysis of leukemia cells by modified graphene oxide

Developing a simple and cost-effective strategy to diagnose and treat cancer with a single and minimum dose through noninvasive strategies is highly challenging. Nano-sized graphene and graphene oxide (GO) are promising for biomedical applications, such as drug delivery and the photo thermal therapy of cancer. An acute promyelocytic leukemia line, such as NB4 cells, was detected by modified GO in extracellular and intracellular experiments. Results shows that GO can quench the fluorescence of the ssDNA fluorescent probe and its fluorescence is restored after a PML/RARα fusion gene of NB4 cell lines is added. Therefore, the fusion gene can be detected accurately with this phenomenon. The best detection conditions for the fusion gene are found with assDNA fluorescent probe concentration of 200 nmol/L in the presence of 0.04 mg/L GO at room temperature for 1 h.

One‐pot synthesis and functionalisation of Fe 2 O 3 @C‐NH 2 nanoparticles for imaging and therapy

The authors have prepared amine-modified Fe2O3@C nanoparticles with diameter of 20 nm by decomposing perchlorinated pyrene/Fe(NO3)3 mixture in the presence of ammonia in solvothermal conditions at 180°C for 48 h by a one-step process. NH3 is not only a cocatalyst of Fe(NO3)3 for decomposition of perchlorinated pyrene, but also the source of surface functionalisation group. The effect of synthesis conditions on shape and size of nanoparticles and characterisation of their structure and functionalisation group are investigated in this research. The amino group in the surface of core-shell nanoparticles can be further functionalised with polyethylene glycol and folic acid to improve their solubility in aqueous solution and target cancer cells. The applications of functionalised core-shell nanoparticles in magnetic resonance imaging and cancer thermal therapy are also investigated in this research.

TU‐C‐144‐03: MR Guided Non Thermal Pulsed High Intensity Focused Ultrasound Therapy of Breast Cancer in Vivo

Purpose: High intensity focused ultrasound (HIFU) has been investigated for ablative therapy and drug enhancement for gene therapy and chemotherapy. The aim of this work is to explore the feasibility of pulsed high‐intensity focused ultrasound (pHIFU) for non thermal cancer therapy using an in vivo animal model. Methods: An InSightec ExAblate 2000 with a 1.5T GE MR scanner was used in this study. Suitable ultrasound parameters were investigated to perform non‐thermal sonications. Breast tumor cells (107), MCF‐7 line were injected subcutaneously in the flanks of the female mice (n = 12). When tumors reached the volume of 78 ± 28 mm3 as measured on MRI, the tumor‐bearing mice (n = 6) were treated with pHIFU (1 MHz frequency; 25 W acoustic power; 0.1 duty cycle; 60 sec duration). A total of 4 to 6 sonications were used to cover the entire tumor volume under MR image guidance. The animals were allowed to survive for 4 weeks after the treatment. The tumor volume was measured on MRI weekly post treatment and was compared with that of the control group (n = 6). Results: Significant tumor growth delay was observed in the tumor‐bearing mice treated with pHIFU. The mean tumor volume for the pHIFU treated mice grew 3%, 17%, 11% at 1 week, 3 weeks and 4 weeks after the treatment, respectively, while the mean tumor volume of the control mice grew 25%, 41% and 48%, respectively, over the same time periods. Statistical analyses yielded p values P=0.034, P=0.005 and P=0.017 at 1 week, 3 weeks and 4 weeks post‐treatment respectively. Conclusion: Our results demonstrated that non‐thermal pHIFU has a great potential for cancer therapy. Further experiments are needed to understand the cell killing mechanisms of pHIFU and to derive optimal ultrasound parameters and fractionation schemes to maximize the therapeutic effect of pHIFU; DOD BC102806

Heat localization for targeted tumor treatment with nanoscale near-infrared radiation absorbers

Focusing heat delivery while minimizing collateral damage to normal tissues is essential for successful nanoparticle-mediated laser-induced thermal cancer therapy. We present thermal maps obtained via magnetic resonance imaging characterizing laser heating of a phantom tissue containing a multiwalled carbon nanotube inclusion. The data demonstrate that heating continuously over tens of seconds leads to poor localization (∼ 0.5 cm) of the elevated temperature region. By contrast, for the same energy input, heat localization can be reduced to the millimeter rather than centimeter range by increasing the laser power and shortening the pulse duration. The experimental data can be well understood within a simple diffusive heat conduction model. Analysis of the model indicates that to achieve 1 mm or better resolution, heating pulses of ∼2 s or less need to be used with appropriately higher heating power. Modeling these data using a diffusive heat conduction analysis predicts parameters for optimal targeted delivery of heat for ablative therapy.

Gold nanostars as thermoplasmonic nanoparticles for optical heating

Gold nanostars are theoretically studied as efficient thermal heaters at their corresponding localized surface-plasmon resonances (LSPRs). Numerical calculations are performed through the 3D Green's Theorem method to obtain the absorption and scattering cross sections for Au nanoparticles with star-like shape of varying symmetry and tip number. Their unique thermoplasmonic properties, with regard to their (red-shifted) LSPR wavelentgh, (∼ 30-fold increase) steady-state temperature, and scattering/absorption cross section ratios, make them specially suitable for optical heating and in turn for cancer thermal therapy.

Recent Patents on Biomedical Devices and Nanomaterials for Hyperthermal Therapy of Cancer

Nanomaterial mediated hyperthermia, or termed nano-hyperthermia, is emerging as a very promising approach to innovate conventional cancer thermal therapy. The current industry is witnessing a rapid growth in the numbers of filed and issued patents in this area. Various types of nanomaterials, such as gold nanoparticles, magnetic nanoparticles, carbon nanotubes, and multifunctional particles etc., are being invented as heating enhancers, image contrast agents and drug delivery carriers etc. Meanwhile, tremendous efforts are also made to improve the heating and energy administration modalities and devices in nano-hyperthermia by taking full use of the many unique merits offered by the nanotechnologies and new heating strategies. This article is dedicated to present a comprehensive analysis on the latest advancement made towards finding new materials and devices for nano-hyperthermia. Typical patents throughout the world will be classified and comparatively interpreted. Some important technical issues will be outlined and future directions worth of pursuing will be suggested.

Thermoacoustic molecular tomography with magnetic nanoparticle contrast agents for targeted tumor detection

The primary feasibility steps of demonstrating the ability of microwave-induced thermoacoustic (TA) in phantoms have been previously reported. However, none were shown to target a diseased site in living subjects in thermoacoustic tomography (TAT) field so far. To determine the expressions of oncogenic surface molecules, it is quite necessary to image tumor lesions and acquire pathogenic status on them via TAT. Compared to biological tissues, iron oxide nanoparticles have a much higher microwave absorbance. Fe3O4/polyaniline (PANI) nanoparticles were prepared via polymerization of aniline in the Fe304 superparamagnetic fluids. Then Fe3O4/PANI was conjugated to folic acid (FA), which can bind specifically to the surface of the folate receptor used as a tumor marker. FA-Fe3O4/PANI targeted tumor was irradiated by pulsed microwave at 6 GHz for thermoacoustic detection and imaging. The effect of the Fe3O4/PANI superparamagnetic nanoparticles for enhancing TAT images was successfully investigated in ex vivo human blood and in vivo mouse tail. Intravenous administration of the targeted nanoparticles to mice bearing tumors showed fivefold greater thermoacoustic signal and much longer elimination time than that of mice injected with nontargeted nanoparticles in the tumor. The specific targeting ability of FA-Fe3O4/PANI to tumor was also verified on fluorescence microscopy. Fabricated iron oxide nanoparticles conjugated with tumor ligands for targeted TAT tumor detection at the molecular level was reported for the first time. The results indicate that thermoacoustic molecular imaging with functionalized iron oxide nanoparticles may contribute to targeted and functional early cancer imaging. Also, the modified iron oxide nanoparticles combined with suitable tumor markers may also be used as novel nanomaterials for targeted and guided cancer thermal therapy.

Inflammatory responses may be induced by a single intratracheal instillation of iron nanoparticles in mice

Magnetite iron nanoparticles have been widely used as contrast agents and in thermal therapy for cancer. However, their adverse effects on human health have not been fully investigated. In this study, iron oxide nanoparticles were prepared using inorganic iron chloride (size: 5.3 ± 3.6 nm in phosphate buffered saline, surface charge: 23.14 mV), and their inflammatory responses were investigated. When mice were treated with iron oxide nanoparticles (250 μg/kg, 500 μg/kg, and 1 mg/kg) by a single intratracheal instillation, the level of intracellular reduced glutathione (GSH) was decreased in the cells of bronchoalveolar lavage (BAL) fluid. The arrest of cell cycles in G1 phase was observed, but S-phase was significantly decreased. The concentrations of pro-inflammatory cytokines (IL-1, TNF-α, and IL-6) were dose-dependently increased at day 1 after instillation in the BAL fluid and in the blood. During the experimental period of 28 days, pro-inflammatory cytokines (IL-1, TNF-α, and IL-6), Th0 cytokine (IL-2), Th1 type cytokine (IL-12), Th2 type cytokines (IL-4 and IL-5), TGF-β, and IgE were also elevated. Expressions of many genes related with inflammation or tissue damage such as heat shock protein, matrix metalloproteinase, tissue inhibitors of metalloproteinases, and serum amyloid A were significantly induced. Formation of microgranuloma, which is one of the indicators for chronic inflammatory response, was observed in the alveolar space. In addition, distribution of B cell and CD8+ T cell in blood lymphocytes was increased at day 28. Based on the result, iron oxide nanoparticles may subchronic induce inflammatory responses via oxidative stress in mice by a single intratracheal instillation.

Poly(ethylene glycol)-based magnetic hydrogel nanocomposites for hyperthermia cancer therapy

Hyperthermia, the heating of cancerous tissues to between 41 and 45 degrees Celsius, has been shown to improve the efficacy of cancer therapy when used in conjunction with irradiation and/or chemotherapy. Here a novel method for remotely administering heat is presented, which involves the heating of tumor tissue using hydrogel nanocomposites containing magnetic nanoparticles which can be remotely heated upon exposure to an external alternating magnetic field (AMF). Specifically, this research explores the use of hydrogel nanocomposites based on poly(ethylene glycol) methyl ether methacrylate and dimethacrylate with iron oxide as implantable biomaterials for thermal cancer therapy applications. Swelling analysis of the systems indicated a dependence of ethylene glycol (EG) content and cross-linking density on swelling behavior where greater EG amount and lower cross-linking resulted in higher volume swelling ratios. Both the entrapped iron oxide nanoparticles and hydrogel nanocomposites exhibited high cell viability for murine fibroblasts, indicating potential biocompatibility. The hydrogels were heated in an AMF, and the heating response was shown to be dependent on both iron oxide loading in the gels and the strength of the magnetic field. As proof of concept of these systems as a thermal therapeutic the ability to selectively kill M059K glioblastoma cells in vitro with hydrogel nanocomposites exposed to an AMF was demonstrated.

Pulmonary toxicity and kinetic study of Cy5.5-conjugated superparamagnetic iron oxide nanoparticles by optical imaging

Recent advances in the development of nanotechnology and devices now make it possible to accurately deliver drugs or genes to the lung. Magnetic nanoparticles can be used as contrast agents, thermal therapy for cancer, and be made to concentrate to target sites through an external magnetic field. However, these advantages may also become problematic when taking into account safety and toxicological factors. This study demonstrated the pulmonary toxicity and kinetic profile of anti-biofouling polymer coated, Cy5.5-conjugated thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION) by optical imaging. Negatively charged, 36 nm-sized, Cy5.5-conjugated TCL-SPION was prepared for optical imaging probe. Cy5.5-conjugated TCL-SPION was intratracheally instilled into the lung by a non-surgical method. Cy5.5-conjugated TCL-SPION slightly induced pulmonary inflammation. The instilled nanoparticles were distributed mainly in the lung and excreted in the urine via glomerular filtration. Urinary excretion was peaked at 3 h after instillation. No toxicity was found under the concentration of 1.8 mg/kg and the half-lives of nanoparticles in the lung and urine were estimated to be about 14.4 ± 0.54 h and 24.7 ± 1.02 h, respectively. Although further studies are required, our results showed that Cy5.5-conjugated TCL-SPION can be a good candidate for use in pulmonary delivery vehicles and diagnostic probes.

Size-dependent joule heating of gold nanoparticles using capacitively coupled radiofrequency fields

Capacitively coupled shortwave radiofrequency fields (13.56 MHz) resistively heat low concentrations (∼1 ppm) of gold nanoparticles with a thermal power dissipation of ∼380 kW/g of gold. Smaller diameter gold nanoparticles (< 50 nm) heat at nearly twice the rate of larger diameter gold nanoparticles (≥50 nm), which is attributed to the higher resistivity of smaller gold nanostructures. A Joule heating model has been developed to explain this phenomenon and provides critical insights into the rational design and engineering of nanoscale materials for noninvasive thermal therapy of cancer.

Assessing the Effect of Surface Chemistry on Gold Nanorod Uptake, Toxicity, and Gene Expression in Mammalian Cells

Through the use of various layer-by-layer polyelectrolyte (PE) coating schemes, such as the common poly(diallyldimethylammonium chloride)-poly(4-styrenesulfonic acid) (PDADMAC-PSS) system, the mammalian cellular uptake of gold nanorods can be tuned from very high to very low by manipulating the surface charge and functional groups of the PEs. The toxicity of these nanorods is also examined. Since the PE coatings are individually toxic, the toxicity of nanorods coated in these PEs is measured and cells are found to be greater than 90% viable in nearly all cases, even at very high concentrations. This viability assay may not be a complete indicator of toxicity, and thus gene-expression analysis is used to examine the molecular changes of cells exposed to PDADMAC-coated nanorods, which enter cells at the highest concentrations. Indicators of cell stress, such as heat-shock proteins, are not significantly up- or down-regulated following nanorod uptake, which suggests that PDADMAC-coated gold nanorods have negligible impact on cell function. Furthermore, a very low number of genes experience any significant change in expression (0.35% of genes examined). These results indicate that gold nanorods are well suited for therapeutic applications, such as thermal cancer therapy, due to their tunable cell uptake and low toxicity.

Characterization of superparamagnetic MgxZn1−x Fe2O4 powders

AbstractStructural and magnetic properties of Mgx Zn1−x Fe2O4 powders have been studied with respect to the application for thermal cancer therapy (magnetic hyperthermia). Mgx Zn1−x Fe2O4 (x=0.1–0.5) powders with particle sizes between 5 and 8 nm were produced by citrate method. The X-ray diffraction patterns of the samples correspond to a spinel phase. The lattice constant and the volume of the elementary cell increase when x changes from 0.1 to 0.5. The FTIR-spectra ascertain the spinel phase formation. The Mossbauer studies reveal the presence of extremely small particles, which undergo superparamagnetic relaxation at room temperature. The core-shell model has been applied to explain quadruple doublets. The quadruple splitting at “shells” is bigger than those at “cores” whereas the isomer shifts remain close. Magnetic studies confirm the presence of extremely small particles that behave as superparamagnetic ones.

Ｔｈｅｒｍａｌ ｔｈｅｒａｐｙに用いるマイクロ波アンテナ―臨床応用へ向けた取り組み―

Microwave energy is one of the heating sources used for thermal therapy of cancer. The thermal therapy means the hyperthermia and the coagulation therapy. In the hyperthermic treatment, the target tumor is heated up to 42-45 °C and in the coagulation therapy, it must be heated 60 °C or more to generate the tissue coagulation. In this manner, although therapeutic temperatures of both schemes are different, there are several similarities between them especially from the engineering aspects. Therefore, this paper describes the fundamental characteristics of microwave inside the biological tissue and two types of heating schemes for the hyperthermic treatments. In addition, the actual treatment by use of newly developed microwave antennas is introduced.

Nanotherapeutics for enhancing thermal therapy of cancer

Purpose: The current work describes the synergistic enhancement of hyperthermic cancer therapy by selective thermal sensitization and induction of vascular injury at the tumor site. The specificity of this response was mediated by CYT-6091: a pegylated colloidal gold-based nanotherapeutic designed to selectively deliver an inflammatory cytokine, tumor necrosis factor alpha (TNF), to solid tumors.Materials and methods: FSaII murine fibrosarcoma-bearing C3H mice received an intravenous injection of either soluble TNF or CYT-6091 (50–250 µg/kg TNF). Four hours later the tumors were exposed to localized heating (42.5 or 43.5°C, 60 min). Tumor responses were assessed by growth delay and/or perfusion.Results: Both soluble TNF and CYT-6091 reduced tumor perfusion by 80% of control (no treatment), 4 hours post administration. However, soluble TNF was toxic to the tumor burdened mice and resulted in 40% mortality alone and 100% mortality when combined with hyperthermia. Conversely, no toxicities were noted with CYT-6091 alone or when combined with hyperthermia. Additionally, CYT-6091 combined with heat yielded significant tumor regression in vivo as compared to heat or CYT-6091 alone as demonstrated by tumor growth delay. Pretreatment with soluble TNF or CYT-6091 followed by heating reduced in vitro tumor and endothelial cell survival by 40–50% (TNF) and 70–75% (CYT-6091) of the control cell (i.e. tumor and endothelial) values, respectively.Conclusions: CYT-6091, by selectively delivering TNF to solid tumors, improves the safety of TNF treatment. In addition, the targeted delivery of TNF augments cancer thermal therapy efficacy possibly by inducing a tumor-localized inflammatory response.

Nanostructure-Mediated Thermal Therapy – The Path From Bench to Clinic

Evaluation of: Huang X, El-Sayed IH, Qian W, El-Sayed MA: Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods. J. Amer. Chem. Soc. 128(6), 2115–2120 (2006) [1] . A recent paper, one of several recent studies on the use of nanostructures in thermal cancer therapy, is evaluated here. Functionalized gold nanorods have been used in vitro to selectively destroy cancer cells by converting near infrared radiation to heat. Nanostructures with tunable optical properties and biologically relevant size show great promise in highly selective thermal ablation therapy. Gold nanorods coated with targeting antibodies were demonstrated to be selective agents for the detection and destruction of cancer cells. We present the results of the El-Sayed paper, compare gold nanorods with other near infrared-absorptive nanostructures and discuss challenges of nanostructure-mediated thermal therapy.

Evolving technology for thermal therapy of cancer

This paper is intended as a succinct review of technology used for clinical hyperthermia therapyfor cancer, as culled from a presentation at the special workshop on Thermal Medicine, Heat ShockProteins, and Cancer at the Society for Thermal Medicine conference in Spring 2005. Followinga brief overview of thermal therapy treatment options and available mechanisms for heating tissue,the paper focuses on the evolution of equipment from basic single element heating devices of theearly 1980s to adjustable multi-element heating devices currently in use or in final stages ofdevelopment. Representative devices from the past, present and near future are cited for furtherinvestigation by the interested reader. The paper concludes with a summary of general trends in theevolution of clinical hyperthermia techniques and a statement of current challenges remaining forthe field.