Anilchandra Attaluri

Nanoparticle distribution and temperature elevations in prostatic tumours in mice during magnetic nanoparticle hyperthermia

Among a variety of hyperthermia methods, magnetic nanoparticle hyperthermia is a highly promising approach for its confined heating within the tumour. In this study we perform in vivo animal experiments on implanted prostatic tumours in mice to measure temperature distribution in the tumour during magnetic nanoparticle hyperthermia. Temperature elevations are induced by a commercially available ferrofluid injected via a single injection to the centre of the tumour, when the tumour is subject to an alternating magnetic field. Temperature mapping in the tumours during magnetic nanoparticle hyperthermia has demonstrated the feasibility of elevating tumour temperatures higher than 50°C using only 0.1 cm3 ferrofluid injected in the tumour under a relatively low magnetic field (3 kA/m). Detailed 3-D nanoparticle concentration distribution is quantified using a high-resolution microCT imaging system. The calculated nanoparticle distribution volume based on the microCT scans is useful to analyse nanoparticle deposition in the tumours. Slower ferrofluid infusion rates result in smaller nanoparticle distribution volumes in the tumours. Nanoparticles are more confined in the vicinity of the injection site with slower infusion rates, causing higher temperature elevations in the tumours. The increase in the nanoparticle distribution volume in the tumour group after the heating from that in the tumour group without heating suggests possible nanoparticle re-distribution in the tumours during the heating.

Magnetic resonance imaging contrast of iron oxide nanoparticles developed for hyperthermia is dominated by iron content

Abstract Purpose: Magnetic iron oxide nanoparticles (MNPs) are used as contrast agents for magnetic resonance imaging (MRI) and hyperthermia for cancer treatment. The relationship between MRI signal intensity and cellular iron concentration for many new formulations, particularly MNPs having magnetic properties designed for heating in hyperthermia, is lacking. In this study, we examine the correlation between MRI T2 relaxation time and iron content in cancer cells loaded with various MNP formulations. Materials and methods: Human prostate carcinoma DU-145 cells were loaded with starch-coated bionised nanoferrite (BNF), iron oxide (Nanomag® D-SPIO), Feridex™, and dextran-coated Johns Hopkins University (JHU) particles at a target concentration of 50 pg Fe/cell using poly-D-lysine transfection reagent. T2-weighted MRI of serial dilutions of these labelled cells was performed at 9.4 T and iron content quantification was performed using inductively coupled plasma mass spectrometry (ICP-MS). Clonogenic assay was used to characterise cytotoxicity. Results: No cytotoxicity was observed at twice the target intracellular iron concentration (∼100 pg Fe/cell). ICP-MS revealed highest iron uptake efficiency with BNF and JHU particles, followed by Feridex and Nanomag-D-SPIO, respectively. Imaging data showed a linear correlation between increased intracellular iron concentration and decreased T2 times, with no apparent correlation among MNP magnetic properties. Conclusions: This study demonstrates that for the range of nanoparticle concentrations internalised by cancer cells the signal intensity of T2-weighted MRI correlates closely with absolute iron concentration associated with the cells. This correlation may benefit applications for cell-based cancer imaging and therapy including nanoparticle-mediated drug delivery and hyperthermia.

Magnetic nanoparticle hyperthermia enhances radiation therapy: A study in mouse models of human prostate cancer

Abstract Purpose: We aimed to characterise magnetic nanoparticle hyperthermia (mNPH) with radiation therapy (RT) for prostate cancer. Methods: Human prostate cancer subcutaneous tumours, PC3 and LAPC-4, were grown in nude male mice. When tumours measured 150 mm3 magnetic iron oxide nanoparticles (MIONPs) were injected into tumours to a target dose of 5.5 mg Fe/cm3 tumour, and treated 24 h later by exposure to alternating magnetic field (AMF). Mice were randomly assigned to one of four cohorts to characterise (1) intratumour MIONP distribution, (2) effects of variable thermal dose mNPH (fixed AMF peak amplitude 24 kA/m at 160 ± 5 kHz) with/without RT (5 Gy), (3) effects of RT (RT5: 5 Gy; RT8: 8 Gy), and (4) fixed thermal dose mNPH (43 °C for 20 min) with/without RT (5 Gy). MIONP concentration and distribution were assessed following sacrifice and tissue harvest using inductively coupled plasma mass spectrometry (ICP-MS) and Prussian blue staining, respectively. Tumour growth was monitored and compared among treated groups. Results: LAPC-4 tumours retained higher MIONP concentration and more uniform distribution than did PC3 tumours. AMF power modulation provided similar thermal dose for mNPH and combination therapy groups (CEM43: LAPC-4: 33.6 ± 3.4 versus 25.9 ± 0.8, and PC3: 27.19 ± 0.7 versus 27.50 ± 0.6), thereby overcoming limitations of MIONP distribution and yielding statistically significant tumour growth delay. Conclusion: PC3 and LAPC-4 tumours represent two biological models that demonstrate different patterns of nanoparticle retention and distribution, offering a model to make comparisons of these effects for mNPH. Modulating power for mNPH offers potential to overcome limitations of MIONP distribution to enhance mNPH.

Evaluation of Nano-porous Alumina Membranes for Hemodialysis Application

Globally, kidney failure has consistently been a major health problem. The number of patients suffering from kidney failure is radically increasing. Some studies forecast an exponential growth in the number of kidney failure patients during the coming years. This emphasizes the importance of hemodialysis (HD) membranes. Current dialysis membranes (cellulose based and synthetic polymer membranes) have irregular pore shapes and sizes, nonuniform pore distribution and limited reusable capability, which leads to low efficiency of toxin removal. New alumina membranes with uniform, controllable and well-structured nanoscale pores, channeled pores aligned perpendicular to the membrane plane, high porosity, high thermal and chemical resistance, and better mechanical properties are certainly preferable to currently used membranes. Determination of transport properties of alumina membranes will assist in the development of the alumina membranes for enhancing hemodialysis. Experiments were performed to evaluate hydraulic permeability, solute diffusive permeability, sieving coefficient, and clearance of four solutes (urea, creatinine, Vancomycin, and inulin) for alumina membrane. Based on comparison of these values against those of polyethersulfone (PES) membranes, transport performance of alumina membrane was determined. Hydraulic conductivity of the alumina membrane was approximately twice that of the PES membrane and inulin sieving coefficient for alumina membrane is approximately 21% higher than that for PES membrane. Alumina membrane has higher solute clearances and no albumin leakage, which makes it an effective replacement for current dialysis membranes.

Using MicroCT Imaging Technique to Quantify Heat Generation Distribution Induced by Magnetic Nanoparticles for Cancer Treatments

Magnetic nanoparticles have been used in clinical and animal studies to generate localized heating for tumor treatments when the particles are subject to an external alternating magnetic field. Currently since most tissue is opaque, the detailed information of the nanoparticle spreading in the tissue after injections cannot be visualized directly and is often quantified by indirect methods, such as temperature measurements, to inversely determine the particle distribution. In this study, we use a high resolution microcomputed tomography (microCT) imaging system to investigate nanoparticle concentration distribution in a tissue-equivalent agarose gel. The local density variations induced by the nanoparticles in the vicinity of the injection site can be detected and analyzed by the microCT system. Heating experiments are performed to measure the initial temperature rise rate to determine the nanoparticle-induced volumetric heat generation rates (or specific absorption rate (SAR Wlm 3 )) at various gel locations. A linear relationship between the measured SARs and their corresponding microCT pixel index numbers is established. The results suggest that the microCT pixel index number can be used to represent the nanoparticle concentration in the media since the SAR is proportional to the local nanoparticle concentration. Experiments are also performed to study how the injection amount, gel concentration, and nanoparticle concentration in the nanofluid affect the nanoparticle spreading in the gel. The nanoparticle transport pattern in gels suggests that convection and diffusion are important mechanisms in particle transport in the gel. Although the particle spreading patterns in the gel may not be directly applied to real tissue, we believe that the current study lays the foundation to use microCT imaging systems to guantitatively study nanoparticle distribution in opaque tumor.

MicroCT image-generated tumour geometry and SAR distribution for tumour temperature elevation simulations in magnetic nanoparticle hyperthermia.

Abstract Objectives: The objective of this study was to develop and test computer algorithms to export micro computed tomography (microCT) images and to generate tumour geometry and specific absorption rate (SAR) distribution for heat transfer simulation in magnetic nanoparticle hyperthermia. Methods: Computer algorithms were written to analyse and export microCT images of 3D tumours containing magnetic nanoparticles. MATLAB® and ProE® programs were used to generate a prototype of the tumour geometry. The enhancements in the microCT pixel index number due to presence of nanoparticles in the tumours were first converted into corresponding SAR values. The SAR data were then averaged over three-dimensional clusters of pixels using the SAS® program. This greatly decreased the size of the SAR file, while in the meantime it ensured that the amount of total energy deposited in the tumour was conserved. Both the tumour geometry and the SAR file were then imported into the COMSOL® software package to simulate temperature elevations in the tumour and their surrounding tissue region during magnetic nanoparticle hyperthermia. Results: A linear relationship was obtained to relate individual pixel index numbers in the microCT images to the SAR values under a specific magnetic field. The generated prototype of the tumour geometry based on only 30 slices of microCT images resembled the original tumour shape and size. The tumour geometry and the simplified SAR data set were successfully accepted by the COMSOL software for heat transfer simulation. Up to 20 °C temperature elevations from its baseline temperature were found inside the tumours, implying possible thermal damage to the tumour during magnetic nanoparticle hyperthermia.

New iron-oxide particles for magnetic nanoparticle hyperthermia: an in-vitro and in-vivo pilot study

Magnetic nanoparticle hyperthermia (mNHP) is regarded as a promising minimally invasive procedure. These nanoparticles generate heat when exposed to alternating magnetic fields (AMFs) and thus have shown a potential for selective delivery of heat to a target such as a cancer cell. Despite the great promise however, successful clinical translation has been limited in part by technical challenges of selectively delivering heat only to the target tissue. Interaction of AMF with tissues also deposits heat through Joule heating via eddy currents. Considerations of patient safety thus constrain the choice of AMF power and frequency to values that are insufficient to produce desirable heating from available nanoparticle formulations. Therefore, considerable effort must be directed to the design of particles and the AMF device to maximize the specific delivery of heat to the intended target while minimizing the unintended and non-specific heating. We have recently developed new iron-oxide nanoparticles (IONPs) having much higher heating capability at the clinically relevant amplitudes and frequencies than other formulations. Here, we utilize a new rectangular coil designed for treating multi well tissue culture plate and show that these particles are superior to two commercially available IONPs for hyperthermia of DU145 prostate cancer cells in culture. We report results of pilot in-vivo experiments using the DU145 human prostate xenograft model in nude male mouse. AMF treatment yielded an intratumor temperature rise > 10 °C in <10 min heating (AMF amplitude 29 kA/m @160 kHz) with ~4 mg nanoparticle /g tumor while maintaining rectal (core) temperature well within physiological range.

Method to reduce non-specific tissue heating of small animals in solenoid coils

Purpose: Solenoid coils that generate time-varying or alternating magnetic fields (AMFs) are used in biomedical devices for research, imaging and therapy. Interactions of AMF and tissue produce eddy currents that deposit power within tissue, thus limiting effectiveness and safety. We aim to develop methods that minimise excess heating of mice exposed to AMFs for cancer therapy experiments. Materials and methods: Numerical and experimental data were obtained to characterise thermal management properties of water using a continuous, custom water jacket in a four-turn simple solenoid. Theoretical data were obtained with method-of-moments (MoM) numerical field calculations and finite element method (FEM) thermal simulations. Experimental data were obtained from gel phantoms and mice exposed to AMFs having amplitude >50 kA/m and frequency of 160 kHz. Results: Water has a high specific heat and thermal conductivity, is diamagnetic, polar, and nearly transparent to magnetic fields. We report at least a two-fold reduction of temperature increase from gel phantom and animal models when a continuous layer of circulating water was placed between the sample and solenoid, compared with no water. Thermal simulations indicate the superior efficiency in thermal management by the developed continuous single chamber cooling system over a double chamber non-continuous system. Further reductions of heating were obtained by regulating water temperature and flow for active cooling. Conclusions: These results demonstrate the potential value of a contiguous layer of circulating water to permit sustained exposure to high intensity alternating magnetic fields at this frequency for research using small animal models exposed to AMFs.

Image-guided thermal therapy with a dual-contrast magnetic nanoparticle formulation: A feasibility study

Abstract Purpose/objective: The aim of this study was to develop and investigate the properties of a magnetic iron oxide nanoparticle–ethiodised oil formulation for image-guided thermal therapy of liver cancer. Materials and methods: The formulation comprises bionised nano-ferrite (BNF) nanoparticles suspended in ethiodised oil, emulsified with polysorbate 20 (BNF-lip). Nanoparticle size was measured via photon correlation spectroscopy and transmission electron microscopy. In vivo thermal therapy capability was tested in two groups of male Foxn1nu mice bearing subcutaneous HepG2 xenograft tumours. Group I (n = 12) was used to screen conditions for group II (n = 48). In group II, mice received one of BNF-lip (n = 18), BNF alone (n = 16), or PBS (n = 14), followed by alternating magnetic field (AMF) hyperthermia, with either varied duration (15 or 20 min) or amplitude (0, 16, 20, or 24 kA/m). Image-guided fluoroscopic intra-arterial injection of BNF-lip was tested in New Zealand white rabbits (n = 10), bearing liver VX2 tumours. The animals were subsequently imaged with CT and 3 T MRI, up to 7 days post-injection. The tumours were histopathologically evaluated for distribution of BNF-lip. Results: The BNF showed larger aggregate diameters when suspended in BNF-lip, compared to clear solution. The BNF-lip formulation produced maximum tumour temperatures with AMF >20 kA/m and showed positive X-ray visibility and substantial shortening of T1 and T2 relaxation time, with sustained intratumoural retention up to 7 days post-injection. On pathology, intratumoural BNF-lip distribution correlated well with CT imaging of intratumoural BNF-lip distribution. Conclusion: The BNF-lip formulation has favourable thermal and dual imaging capabilities for image-guided thermal therapy of liver cancer, suggesting further exploration for clinical applications.

Calibration of a Quasi-Adiabatic Magneto-Thermal Calorimeter Used to Characterize Magnetic Nanoparticle Heating

To assess and validate temperature measurement and data analysis techniques for a quasi-adiabatic calorimeter used to measure amplitude-dependent loss power of magnetic nanoparticles exposed to an alternating magnetic field (AMF) at radiofrequencies (160 65 kHz). The data collected and methods developed were used to measure the specific loss power (SLP) for two magnetic iron oxide nanoparticles (IONPs) suspensions, developed for magnetic nanoparticle hyperthermia. Calibration was performed by comparing measured against calculated values of specific absorption rate (SAR) of a copper wire subjected to AMF. Rate of temperature rise from induced eddy currents was measured (n ¼4) for a copper wire of radius 0.99mm and length of 3.38mm in an AMF at amplitudes (H) of 16, 20, 24, and 28kA/m. The AMF was generated by applying an alternating current using an 80-kW induction power supply to a capacitance network containing a 13.5-cm vertical solenoid that held the calorimeter. Samples were taped to an optical fiber temperature probe and inserted into a standard (polystyrene, 5ml) test tube which was suspended in the calorimeter. The sample was subjected to the AMF for 30s or until the temperature of the sample, increased by 30 � C, recorded at 0.3-s intervals. The SAR of the sample was normalized by H 2 f 1/2 , averaged, and compared to theoretical values. Iron (Fe) normalized SLPs of two IONPs (JHU-MION and bionized-nanoferrite (BNF) particles (Micromod Partikeltechnologie, GmbH)) in aqueous suspension were measured in the same setup. We report experimental SAR values for the copper of 2.4 60.1, 4.3 60.2, 6.2 60.1, and 8.5 60.1W/g compared to theoretical values 3.1 60.1, 4.5 60.2, 6.5 60.1, and 9.2 60.2W/g at AMF amplitudes of 16 60.1, 20 60.2, 24 60.1, and 28 60.1kA/m, respectively. Normalized experimental data followed a linear trend approximately parallel to theoretical values with an R 2 -value of 0.99. The measured SLPs of the JHU particles are higher than BNF particles within the tested AMF amplitude range of 15kA/m to 45kA/m. We demonstrated that copper can be used to calibrate magneto-thermal calorimetric systems used for SLP measurements of magnetic nanoparticles for a field range of 15‐28kA/m at 160 65kHz. We also note that the electrical conductivity, diameter of copper sample and accuracy, and response time of thermometry constrain calibration to lower amplitudes, highlighting the need for development of standard reference materials for such applications. [DOI: 10.1115/1.4024273]