Carlos Rinaldi

EGFR-Targeted Magnetic Nanoparticle Heaters Kill Cancer Cells without a Perceptible Temperature Rise

It is currently believed that magnetic nanoparticle heaters (MNHs) can kill cancer cells only when the temperature is raised above 43 °C due to energy dissipation in an alternating magnetic field. On the other hand, simple heat conduction arguments indicate that in small tumors or single cells the relative rates of energy dissipation and heat conduction result in a negligible temperature rise, thus limiting the potential of MNHs in treating small tumors and metastatic cancer. Here we demonstrate that internalized MNHs conjugated to epidermal growth factor (EGF) and which target the epidermal growth factor receptor (EGFR) do result in a significant (up to 99.9%) reduction in cell viability and clonogenic survival in a thermal heat dose dependent manner, without the need for a perceptible temperature rise. The effect appears to be cell type specific and indicates that magnetic nanoparticles in alternating magnetic fields may effectively kill cancer cells under conditions previously considered as not possible.

Effect of Mn substitution on electrical and magnetic properties of Bi0.9La0.1FeO3

Polycrystalline samples of Bi0.90La0.10(Fe1−xMnx)O3 (x=0, 0.05, 0.10, 0.15, and 0.20) were prepared using a novel mechanical activation followed by a conventional solid-state reaction technique. The formation of the desired materials was confirmed using x-ray diffraction. The electrical and magnetic properties of the materials were investigated at different Mn concentrations as a function of temperature. Both dielectric constant and loss tangent increased with the increase in Mn content in the system. The grain and grain boundary contributions have been estimated using impedance spectroscopy analysis. Both grain and grain boundary conductivity increased with a rise in temperature for all Mn concentrations. The value of activation energy for both grain and grain boundary is nearly the same, and decreased with an increase in Mn concentration. There is a systematic increase in the value of magnetization on increasing Mn concentration.

Colloidal dispersions of monodisperse magnetite nanoparticles modified with poly(ethylene glycol).

Monodisperse magnetite nanoparticles modified with poly(ethylene glycol) (PEG) were synthesized using a silane functionalized PEG obtained by reacting 3-aminopropyl triethoxysilane with carboxylic acid-methoxy PEG (mPEG-COOH) using amide reactions. Transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential measurements show the particles are monodisperse (sigma(gv) approximately 0.2) and stable in water for pH of 3-9 and ionic strengths, up to 0.3 M NaCl. Thermogravimetric analysis coupled with TEM and DLS indicates formation of a dense graft layer on the particle surface. An analysis of the interparticle interaction energy indicates that the particles are stabilized by strong steric repulsions between PEG chains on their surface.

Lysosomal Membrane Permeabilization by Targeted Magnetic Nanoparticles in Alternating Magnetic Fields

Lysosomal death pathways are being explored as alternatives of overcoming cancer tumor resistance to traditional forms of treatment. Nanotechnologies that can selectively target and induce permeabilization of lysosomal compartments in cells could become powerful medical tools. Here we demonstrate that iron oxide magnetic nanoparticles (MNPs) targeted to the epidermal growth factor receptor (EGFR) can selectively induce lysosomal membrane permeabilization (LMP) in cancer cells overexpressing the EGFR under the action of an alternating magnetic field (AMF). LMP was observed to correlate with the production of reactive oxygen species (ROS) and a decrease in tumor cell viability. Confocal microscopy images showed an increase in the cytosolic activity of the lysosomal protease cathepsin B. These observations suggest the possibility of remotely triggering lysosomal death pathways in cancer cells through the administration of MNPs which target lysosomal internalization pathways and the application of AMFs.

Magnetic fluid hyperthermia: Advances, challenges, and opportunity

Abstract Though the concepts of magnetic fluid hyperthermia (MFH) were originally proposed over 50 years ago, the technique has yet to be successfully translated into routine clinical application. Significant challenges must be addressed if the field is to progress and realise its potential as an option for treatment of diseases such as cancer. These challenges include determining the optimum fields and frequencies that maximise the effectiveness of MFH without significant detrimental off-target effects on healthy tissue, achieving sufficient concentrations of magnetic nanoparticles (MNPs) within the target tumour, and developing a better mechanistic understanding of MNP-mediated energy deposition and its effects on cells and tissue. On the other hand, emerging experimental evidence indicates that local thermal effects indeed occur in the vicinity of energy-dissipating MNPs. These findings point to the opportunity of engineering MNPs for the selective destruction of cells and/or intracellular structures without the need for a macroscopic tissue temperature rise, in what we here call magnetically mediated energy delivery (MagMED).

Enhanced reduction in cell viability by hyperthermia induced by magnetic nanoparticles.

Colloidal suspensions of iron oxide magnetic nanoparticles are known to dissipate energy when exposed to an oscillating magnetic field. Such energy dissipation can be employed to locally raise temperature inside a tumor between 41°C and 45°C (hyperthermia) to promote cell death, a treatment known as magnetic fluid hyperthermia (MFH). This work seeks to quantify differences between MFH and hot-water hyperthermia (HWH) in terms of reduction in cell viability using two cancer cell culture models, Caco-2 (human epithelial colorectal adenocarcinoma) and MCF-7 (human breast cancer). Magnetite nanoparticles were synthesized via the co-precipitation method and functionalized with adsorbed carboxymethyl dextran. Cytotoxicity studies indicated that in the absence of an oscillating magnetic field, cell viability was not affected at concentrations of up to 0.6 mg iron oxide/mL. MFH resulted in a significant decrease in cell viability when exposed to a magnetic field for 120 minutes and allowed to rest for 48 hours, compared with similar field applications, but with shorter resting time. The results presented here suggest that MFH most likely induces apoptosis in both cell types. When compared with HWH, MFH produced a significant reduction in cell viability, and these effects appear to be cell-type related.

Water dispersible iron oxide nanoparticles coated with covalently linked chitosan

Magnetic nanoparticles consisting of iron oxide cores modified with covalently linked chitosan oligosaccharide (CSO) that are colloidally stable in water and buffers were obtained. Primary oleic acid coated nanoparticles were synthesized through the thermal decomposition method and the surface ligand exchanged to a carboxylic acid silane. Amide linkage between the chitosan and magnetic nanoparticles was obtained through carbodiimide activation, under conditions which promoted particle stability and chitosan solubility. Magnetic measurements indicate that the particles are superparamagnetic. Measurements of hydrodynamic diameter and zeta potential, coupled with TEM measurements, indicated that CSO coated nanoparticles consist of single primary particles coated with a chitosan corona. These nanoparticles are stable in water for a wide range of pH, and in commonly used biological buffers, such as phosphate buffered saline (PBS), Hanks balanced salt solution (HBSS), and Dulbeccos modified eagles medium (DMEM) with fetal bovine serum (FBS).

Effect of Molecular Weight, Temperature, and Additives on the Moisture Sorption Properties of Polyethylene Glycol

Polyethylene glycol (PEG) is a hygroscopic polymer that undergoes the phenomenon of deliquescence once a critical relative humidity (RH(0)) is reached. The purpose of this study was to test the hypothesis that the deliquescence behavior of PEG will be affected by the polymer molecular weight, temperature, and the presence of additives. The deliquescence relative humidity for single component (RH(0)) and binary mixtures (RH(0,mix)) were measured using an automated gravimetric moisture analyzer at 25 and 40 degrees C. Changes in PEG crystallinity after exposure to moisture were qualitatively assessed using powder X-ray diffraction (PXRD). Optical microscopy was used to visually observe the deliquescence phenomenon. For single component systems, decreasing PEG MW and elevating the temperature resulted in a decrease in the observed RH(0). Physical mixtures of acetaminophen and anhydrous citric acid with both PEG 3350 and PEG 100,000 exhibited deliquescence (RH(0,mix)) at a relative humidity below that of either individual component. Qualitative changes in crystallinity were observed from the X-ray diffractograms for each PEG MW grade at high relative humidities, indicating that phase transformation (deliquescence) of the samples had occurred. In conclusion, it was found that the deliquescence behavior of PEG was affected by the polymer MW, temperature, and the presence of additives. This phenomenon may have important implications for the stability of PEG containing formulations.

Thermal potentiation of chemotherapy by magnetic nanoparticles

Clinical studies have demonstrated the effectiveness of hyperthermia as an adjuvant for chemotherapy and radiotherapy. However, significant clinical challenges have been encountered, such as a broader spectrum of toxicity, lack of patient tolerance, temperature control and significant invasiveness. Hyperthermia induced by magnetic nanoparticles in high-frequency oscillating magnetic fields, commonly termed magnetic fluid hyperthermia, is a promising form of heat delivery in which thermal energy is supplied at the nanoscale to the tumor. This review discusses the mechanisms of heat dissipation of iron oxide-based magnetic nanoparticles, current methods and challenges to deliver heat in the clinic, and the current work related to the use of magnetic nanoparticles for the thermal-chemopotentiation of therapeutic drugs.

Synthesis and functionalization of magnetite nanoparticles with aminopropylsilane and carboxymethyldextran

Magnetite nanoparticles were functionalized with carboxymethyldextran (CMDx) covalently attached to the particles to prevent polymer desorption in biomedical applications. Carbodiimide chemistry was used to react carboxylic groups (–COOH) present in the CMDx molecule with amine end groups (NH2) previously grafted onto the nanoparticle surface by condensation of aminopropylsilane (APS) molecules. This method produces highly stable suspensions of magnetite nanoparticles with electrostatic and steric repulsion and no particle precipitation in the presence of electrolytes.