Magnetic nanoparticles and nanocomposites for remote controlled therapies.

This review highlights the state-of-the-art in the application of magnetic nanoparticles (MNPs) and their composites for remote controlled therapies. Novel macro- to nano-scale systems that utilize remote controlled drug release due to actuation of MNPs by static or alternating magnetic fields and magnetic field guidance of MNPs for drug delivery applications are summarized. Recent advances in controlled energy release for thermal therapy and nanoscale energy therapy are addressed as well. Additionally, studies that utilize MNP-based thermal therapy in combination with other treatments such as chemotherapy or radiation to enhance the efficacy of the conventional treatment are discussed.

The role of ROS generation from magnetic nanoparticles in an alternating magnetic field on cytotoxicity.

Monosaccharide coated iron oxide nanoparticles were developed to selectively target colon cancer cell lines for magnetically mediated energy delivery therapy. The nanoparticles were prepared using a coupling reaction to attach the glucose functional group to the iron oxide core, and functionality was confirmed with physicochemical characterization techniques. The targeted nanoparticles were internalized into CT26 cells at a greater extent than non-targeted nanoparticles, and the nanoparticles were shown to be localized within lysosomes. Cells with internalized nanoparticles were exposed to an AMF to determine the potential to delivery therapy. Cellular ROS generation and apoptotic cell death was enhanced with field exposure. The nanoparticle coatings inhibit the Fenton-like surface generation of ROS suggesting a thermal or mechanical effect is more likely the source of the intracellular effect, unless the nanoparticle coating is unstable in the cellular environment. STATEMENT OF SIGNIFICANCE: This is the first study to assess glucose coated MNPs for the delivery of MagMED therapy. With exposure of an AMF, the glucose-coated nanoparticles displayed a significant increase in cellular ROS and apoptotic cell death with no measurable increase in media temperature. To determine the mechanism of toxicity, we investigated the surface generation of ROS through Fenton-like chemistry. The coated systems displayed negligible ROS generation compared to uncoated nanoparticles. These observations suggest the cellular ROS measured is attributed to a thermal or mechanical effect of the internalized nanoparticles. In summary, this manuscript reports on some new insights as to the mechanism of MagMED therapies, which are of high interest to the biomaterials and cancer nanomedicine fields.

Accelerated generation of free radicals by iron oxide nanoparticles in the presence of an alternating magnetic field.

The surfaces of iron oxide nanoparticles are capable of catalytically generating reactive oxygen species (ROS) through the Fenton and Haber-Weiss reactions. Fenton chemistry has been shown to be temperature dependent with an increase in activity up to 40 °C and then a decrease above this temperature as the hydrogen peroxide degrades into oxygen and water which limits the reaction. When exposed to an alternating magnetic field (AMF), iron oxide nanoparticles absorb the energy from the magnetic field and convert it into heat. In this study, we observed an increase in the degradation of methylene blue when a suspension of magnetite nanoparticles (Fe3O4) was exposed to an AMF indicating there was an increase in the ROS generation in response to the AMF. The increase in ROS generation compared to the Arrhenius prediction was both time and concentration dependent; in which we observed a decrease in ROS enhancement with increased time of exposure and concentration. We postulate that the decrease is due to agglomeration in the presence of the field. As the nanoparticles agglomerate, there is a decrease in surface area per mass limiting the reaction rate.

Synthesis and characterization of PEG-iron oxide core-shell composite nanoparticles for thermal therapy.

In this study, core-shell nanoparticles were developed to achieve thermal therapy that can ablate cancer cells in a remotely controlled manner. The core-shell nanoparticles were prepared using atomic transfer radical polymerization (ATRP) to coat iron oxide (Fe3O4) nanoparticles with a poly(ethylene glycol) (PEG) based polymer shell. The iron oxide core allows for the remote heating of the particles in an alternating magnetic field (AMF). The coating of iron oxide with PEG was verified through Fourier transform infrared spectroscopy and thermal gravimetric analysis. A thermoablation (55°C) study was performed on A549 lung carcinoma cells exposed to nanoparticles and over a 10 min AMF exposure. The successful thermoablation of A549 demonstrates the potential use of polymer coated particles for thermal therapy.

Binary blend of glyceryl monooleate and glyceryl monostearate for magnetically induced thermo-responsive local drug delivery system.

PURPOSE: To develop a novel monoglycerides-based thermal-sensitive drug delivery system, specifically for local intracavitary chemotherapy. METHODS: Lipid matrices containing mixtures of glyceryl monooleate (GMO) and glyceryl monostearate (GMS) were evaluated for their potential application as magnetically induced thermo-responsive local drug delivery systems using a poorly water-soluble model drug, nifedipine (NF). Oleic acid-modified iron oxide (OA-Fe3O4) nanoparticles were embedded into the GMO-GMS matrix for remote activation of the drug release using an alternating magnetic field (AMF). RESULTS: The crystallization behavior of binary blends of GMO and GMS as characterized by DSC did show temperature dependent phase transition. GMO-GMS (75:25 wt%) blend showed a melting (T m ) and crystallization (T c ) points at 42°C and 37°C, respectively indicating the potential of the matrix to act as an 'on-demand' drug release. The matrix released only 35% of the loaded drug slowly in 10 days at 37°C whereas 96% release was obtained at 42°C. A concentration of 0.5% OA-Fe3O4 heated the matrix to 42.3 and 45.5°C within 5 min and 10 min of AMF exposure, respectively. CONCLUSIONS: The in vitro NF release profiles form the monoglycerides matrix containing 0.5% OA-Fe3O4 nanoparticles after AMF activation confirmed the thermo-responsive nature of the matrix that could provide pulsatile drug release 'on-demand'.

Block copolymer cross-linked nanoassemblies improve particle stability and biocompatibility of superparamagnetic iron oxide nanoparticles.

PURPOSE: To develop cross-linked nanoassemblies (CNAs) as carriers for superparamagnetic iron oxide nanoparticles (IONPs). METHODS: Ferric and ferrous ions were co-precipitated inside core-shell type nanoparticles prepared by cross-linking poly(ethylene glycol)-poly(aspartate) block copolymers to prepare CNAs entrapping Fe(3)O(4) IONPs (CNA-IONPs). Particle stability and biocompatibility of CNA-IONPs were characterized in comparison to citrate-coated Fe(3)O(4) IONPs (Citrate-IONPs). RESULTS: CNA-IONPs, approximately 30 nm in diameter, showed no precipitation in water, PBS, or a cell culture medium after 3 or 30 h, at 22, 37, and 43°C, and 1, 2.5, and 5 mg/mL, whereas Citrate-IONPs agglomerated rapidly (> 400 nm) in all aqueous media tested. No cytotoxicity was observed in a mouse brain endothelial-derived cell line (bEnd.3) exposed to CNA-IONPs up to 10 mg/mL for 30 h. Citrate-IONPs (> 0.05 mg/mL) reduced cell viability after 3 h. CNA-IONPs retained the superparamagnetic properties of entrapped IONPs, enhancing T2-weighted magnetic resonance images (MRI) at 0.02 mg/mL, and generating heat at a mild hyperthermic level (40 ~ 42°C) with an alternating magnetic field (AMF). CONCLUSION: Compared to citric acid coating, CNAs with a cross-linked anionic core improved particle stability and biocompatibility of IONPs, which would be beneficial for future MRI and AMF-induced remote hyperthermia applications.