Tiago R. Oliveira

Application of hyperthermia induced by superparamagnetic iron oxide nanoparticles in glioma treatment

Gliomas are a group of heterogeneous primary central nervous system (CNS) tumors arising from the glial cells. Malignant gliomas account for a majority of malignant primary CNS tumors and are associated with high morbidity and mortality. Glioblastoma is the most frequent and malignant glioma, and despite the recent advances in diagnosis and new treatment options, its prognosis remains dismal. New opportunities for the development of effective therapies for malignant gliomas are urgently needed. Magnetic hyperthermia (MHT), which consists of heat generation in the region of the tumor through the application of magnetic nanoparticles subjected to an alternating magnetic field (AMF), has shown positive results in both preclinical and clinical assays. The aim of this review is to assess the relevance of hyperthermia induced by magnetic nanoparticles in the treatment of gliomas and to note the possible variations of the technique and its implication on the effectiveness of the treatment. We performed an electronic search in the literature from January 1990 to October 2010, in various databases, and after application of the inclusion criteria we obtained a total of 15 articles. In vitro studies and studies using animal models showed that MHT was effective in the promotion of tumor cell death and reduction of tumor mass or increase in survival. Two clinical studies showed that MHT could be applied safely and with few side effects. Some studies suggested that mechanisms of cell death, such as apoptosis, necrosis, and antitumor immune response were triggered by MHT. Based on these data, we could conclude that MHT proved to be efficient in most of the experiments, and that the improvement of the nanocomposites as well as the AMF equipment might contribute toward establishing MHT as a promising tool in the treatment of malignant gliomas.

The impact of temperature and urinary constituents on urine viscosity and its relevance to bladder hyperthermia treatment

Abstract Purpose: The aim of this study was to determine the kinematic viscosity of human urine and factors associated with its variability. This value is necessary for accurate modelling of fluid mechanics and heat transfer during hyperthermia treatments of bladder cancer. Materials and methods: Urine samples from 64 patients undergoing routine clinical testing were subject to dipstick urinalysis and measurement of viscosity with a Cannon-Fenske viscometer. Viscosity measurements were taken at relevant temperatures for hyperthermia studies: 20 °C (room temperature), 37 °C (body temperature), and 42 °C (clinical hyperthermia temperature). Factors that might affect viscosity were assessed, including glucosuria, haematuria, urinary tract infection status, ketonuria and proteinuria status. The correlation of urine specific gravity and viscosity was measured with Spearman’s rho. Results: Urine kinematic viscosity at 20 °C was 1.0700 cSt (standard deviation (SD) = 0.1076), at 37 °C 0.8293 cSt (SD = 0.0851), and at 42 °C 0.6928 cSt (SD = 0.0247). Proteinuria appeared to increase urine viscosity, whereas age, gender, urinary tract infection, glucosuria, ketonuria, and haematuria did not affect it. Urine specific gravity was only modestly correlated with urine viscosity at 20 °C (rho = 0.259), 37 °C (rho = 0.266), and 42 °C (rho = 0.255). Conclusions: The kinematic viscosity of human urine is temperature dependent and higher than water. Urine specific gravity was not a good predictor of viscosity. Of factors that might affect urine viscosity, only proteinuria appeared to be clinically relevant. Estimates of urine viscosity provided in this manuscript may be useful for temperature modelling of bladder hyperthermia treatments with regard to correct prediction of the thermal conduction effects.

Magnetic Fluid Hyperthermia for Bladder Cancer: A Preclinical Dosimetry Study

Abstract Purpose: This paper describes a preclinical investigation of the feasibility of thermotherapy treatment of bladder cancer with magnetic fluid hyperthermia (MFH), performed by analysing the thermal dosimetry of nanoparticle heating in a rat bladder model. Materials and methods: The bladders of 25 female rats were instilled with magnetite-based nanoparticles, and hyperthermia was induced using a novel small animal magnetic field applicator (Actium Biosystems, Boulder, CO). We aimed to increase the bladder lumen temperature to 42 °C in <10 min and maintain that temperature for 60 min. Temperatures were measured within the bladder lumen and throughout the rat with seven fibre-optic probes (OpSens Technologies, Quebec, Canada). An MRI analysis was used to confirm the effectiveness of the catheterisation method to deliver and maintain various nanoparticle volumes within the bladder. Thermal dosimetry measurements recorded the temperature rise of rat tissues for a variety of nanoparticle exposure conditions. Results: Thermal dosimetry data demonstrated our ability to raise and control the temperature of rat bladder lumen ≥1 °C/min to a steady state of 42 °C with minimal heating of surrounding normal tissues. MRI scans confirmed the homogenous nanoparticle distribution throughout the bladder. Conclusion: These data demonstrate that our MFH system with magnetite-based nanoparticles provides well-localised heating of rat bladder lumen with effective control of temperature in the bladder and minimal heating of surrounding tissues.

Design and Optimization of an Ultra Wideband and Compact Microwave Antenna for Radiometric Monitoring of Brain Temperature

We present the modeling efforts on antenna design and frequency selection to monitor brain temperature during prolonged surgery using noninvasive microwave radiometry. A tapered log-spiral antenna design is chosen for its wideband characteristics that allow higher power collection from deep brain. Parametric analysis with the software HFSS is used to optimize antenna performance for deep brain temperature sensing. Radiometric antenna efficiency (η) is evaluated in terms of the ratio of power collected from brain to total power received by the antenna. Anatomical information extracted from several adult computed tomography scans is used to establish design parameters for constructing an accurate layered 3-D tissue phantom. This head phantom includes separate brain and scalp regions, with tissue equivalent liquids circulating at independent temperatures on either side of an intact skull. The optimized frequency band is 1.1-1.6 GHz producing an average antenna efficiency of 50.3% from a two turn log-spiral antenna. The entire sensor package is contained in a lightweight and low-profile 2.8 cm diameter by 1.5 cm high assembly that can be held in place over the skin with an electromagnetic interference shielding adhesive patch. The calculated radiometric equivalent brain temperature tracks within 0.4 °C of the measured brain phantom temperature when the brain phantom is lowered 10 °C and then returned to the original temperature (37 °C) over a 4.6-h experiment. The numerical and experimental results demonstrate that the optimized 2.5-cm log-spiral antenna is well suited for the noninvasive radiometric sensing of deep brain temperature.

Non-Invasive Measurement of Brain Temperature with Microwave Radiometry: Demonstration in a Head Phantom and Clinical Case

This study characterizes the sensitivity and accuracy of a non-invasive microwave radiometric thermometer intended for monitoring body core temperature directly in brain to assist rapid recovery from hypothermia such as occurs during surgical procedures. To study this approach, a human head model was constructed with separate brain and scalp regions consisting of tissue equivalent liquids circulating at independent temperatures on either side of intact skull. This test setup provided differential surface/deep tissue temperatures for quantifying sensitivity to change in brain temperature independent of scalp and surrounding environment. A single band radiometer was calibrated and tested in a multilayer model of the human head with differential scalp and brain temperature. Following calibration of a 500MHz bandwidth microwave radiometer in the head model, feasibility of clinical monitoring was assessed in a pediatric patient during a 2-hour surgery. The results of phantom testing showed that calculated radiometric equivalent brain temperature agreed within 0.4°C of measured temperature when the brain phantom was lowered 10°C and returned to original temperature (37°C), while scalp was maintained constant over a 4.6-hour experiment. The intended clinical use of this system was demonstrated by monitoring brain temperature during surgery of a pediatric patient. Over the 2-hour surgery, the radiometrically measured brain temperature tracked within 1–2°C of rectal and nasopharynx temperatures, except during rapid cooldown and heatup periods when brain temperature deviated 2–4°C from slower responding core temperature surrogates. In summary, the radiometer demonstrated long term stability, accuracy and sensitivity sufficient for clinical monitoring of deep brain temperature during surgery.

Structural characterization of the interaction of the polyene antibiotic Amphotericin B with DODAB bicelles and vesicles

Amphotericin B (AmB) is widely used in the treatment of systemic fungal infections, despite its toxic effects. Nephrotoxicity, ascribed as the most serious toxic effect, has been related to the state of aggregation of the antibiotic. In search of the increase in AmB antifungal activity associated with low toxicity, several AmB-amphiphile formulations have been proposed. This work focuses on the structural characterization of a specific AmB formulation: AmB associated with sonicated dioctadecyl dimethylammonium bromide (DODAB) aggregates. Here, it was confirmed that sonicated DODAB dispersion is constituted by DODAB bicelles, and that monomeric AmB is much more soluble in bicelles than in DODAB vesicles. A new optical parameter is proposed for the estimation of the relative amount of amphiphile-bound monomeric AmB. With theoretical simulations of the spectra of spin labels incorporated in DODAB bicelles it was possible to prove that monomeric AmB binds preferentially to lipids located at the edges of DODAB bicelles, rigidifying them, and decreasing the polarity of the region. That special binding of monomeric AmB along the borders of bicelles, where the lipids are highly disorganized, could be used in the formulation of other carriers for the antibiotic, including mixtures of natural lipids which are known to form bicelles.

Stable microwave radiometry system for long term monitoring of deep tissue temperature

Background: There are numerous clinical applications for non-invasive monitoring of deep tissue temperature. We present the design and experimental performance of a miniature radiometric thermometry system for measuring volume average temperature of tissue regions located up to 5cm deep in the body. Methods: We constructed a miniature sensor consisting of EMI-shielded log spiral microstrip antenna with high gain onaxis and integrated high-sensitivity 1.35GHz total power radiometer with 500 MHz bandwidth. We tested performance of the radiometry system in both simulated and experimental multilayer phantom models of several intended clinical measurement sites: i) brown adipose tissue (BAT) depots within 2cm of the skin surface, ii) 3-5cm deep kidney, and iii) human brain underlying intact scalp and skull. The physical models included layers of circulating tissue-mimicking liquids controlled at different temperatures to characterize our ability to quantify small changes in target temperature at depth under normothermic surface tissues. Results: We report SAR patterns that characterize the sense region of a 2.6cm diameter receive antenna, and radiometric power measurements as a function of deep tissue temperature that quantify radiometer sensitivity. The data demonstrate: i) our ability to accurately track temperature rise in realistic tissue targets such as urine refluxed from prewarmed bladder into kidney, and 10°C drop in brain temperature underlying normothermic scalp and skull, and ii) long term accuracy and stability of +0.4°C over 4.5 hours as needed for monitoring core body temperature over extended surgery or monitoring effects of brown fat metabolism over an extended sleep/wake cycle. Conclusions: A non-invasive sensor consisting of 2.6cm diameter receive antenna and integral 1.35GHz total power radiometer has demonstrated sufficient sensitivity to track clinically significant changes in temperature of deep tissue targets underlying normothermic surface tissues for clinical applications like the detection of vesicoureteral reflux, and long term monitoring of brown fat metabolism or brain core temperature during extended surgery.

Oligonucleotide Adsorption Affects Phase Transition but Not Interdigitation of diC14-Amidine Bilayers

In this work, we investigate the effect of a small single-stranded oligonucleotide (ODN) on the colloid stability and structure of cationic diC14-amidine liposomes. Dynamic light scattering (DLS) shows that small, stable, anionic assemblies are formed in presence of excess ODN negative charge. This charge overcompensation condition was further characterized. A less cooperative bilayer phase transition is observed by differential scanning calorimetry (DSC). Electron spin resonance (ESR) spectra of probes at different bilayer depths show that ODN electrostatic adsorption increases the rigidity of both interdigitated gel and lamellar fluid phases. The increase in gel phase rigidity could be explained by the transformation of an adjacent to an interpenetrated interdigitation. Interdigitated fusogenic bilayers may find interesting applications in delivery of therapeutic oligonucleotides.

Preclinical Dosimetry of Magnetic Fluid Hyperthermia for Bladder Cancer

Background Despite positive efficacy, thermotherapy is not widely used in clinical oncology. Difficulties associated with field penetration and controlling power deposition patterns in heterogeneous tissue have limited its use for heating deep in the body. Heat generation using iron-oxide super-paramagnetic nanoparticles excited with magnetic fields has been demonstrated to overcome some of these limitations. The objective of this preclinical study is to investigate the feasibility of treating bladder cancer with magnetic fluid hyperthermia (MFH) by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model. Methods The bladders of 25 female rats were injected with 0.4 ml of Actium Biosystems magnetite-based nanoparticles (Actium Biosystems, Boulder CO) via catheters inserted in the urethra. To assess the distribution of nanoparticles in the rat after injection we used the 7 T small animal MRI system (Bruker ClinScan, Bruker BioSpin MRI GmbH, Ettlingen, Germany). Heat treatments were performed with a small animal magnetic field applicator (Actium Biosystems, Boulder CO) with a goal of raising bladder temperature to 42°C in <10min and maintaining for 60min. Temperatures were measured throughout the rat with seven fiberoptic temperature probes (OpSens Technologies, Quebec Canada) to characterize our ability to localize heat within the bladder target. Results The MRI study confirms the effectiveness of the catheterization procedure to homogenously distribute nanoparticles throughout the bladder. Thermal dosimetry data demonstrate our ability to controllably raise temperature of rat bladder >1°C/min to a steady-state of 42°C. Conclusion Our data demonstrate that a MFH system provides well-localized heating of rat bladder with effective control of temperature in the bladder and minimal heating of surrounding tissues.

Magnetohyperthermia for treatment of gliomas: experimental and clinical studies.

Gliomas comprise a group of heterogeneous primary tumors of the central nervous system that originate from glial cells. Malignant gliomas account for the majority of primary malignant CNS tumors and are associated with high morbidity and mortality. Glioblastoma is the most frequent malignant glioma, and despite recent advances in diagnosis and new treatment options, its prognosis remains dismal. New opportunities for the development of effective therapies for malignant gliomas are urgently needed. Magnetohyperthermia consists of heat generation in the region of the tumor through the application of magnetic nanoparticles subjected to an alternating magnetic field and has shown positive results in both preclinical and clinical assays. The aim of this review was to assess the relevance of hyperthermia induced by magnetic nanoparticles in treating gliomas and to describe possible variations of the technique and its implication in the effectiveness of treatment. An electronic search in the literature of articles published from January 1990 to November 2009 was performed, in databases ISI Web of Science and PubMed, and after screening according to the inclusion criteria, 11 articles were selected. Animal models showed that magnetohyperthermia was effective in promoting tumor cell death and reducing tumor mass or increasing survival of the animals. One clinical study demonstrated that magnetohyperthermia could be applied safely and with few adverse effects. Some studies suggested that mechanisms of cell death, such as apoptosis, necrosis, and antitumor immune response were triggered by magnetohyperthermia. Based on these data, it was concluded that the technique proved to be effective in most experiments, and improvement of the nanocomposites, as well as of the alternating magnetic field equipment, can contribute towards establishing magnetohyperthermia as a promising tool to treat malignant gliomas.