Impact of magnetic field parameters and iron oxide nanoparticle properties on heat generation for use in magnetic hyperthermia.

Heating of nanoparticles (NPs) using an AC magnetic field depends on several factors, and optimization of these parameters can improve the efficiency of heat generation for effective cancer therapy while administering a low NP treatment dose. This study investigated magnetic field strength and frequency, NP size, NP concentration, and solution viscosity as important parameters that impact the heating efficiency of iron oxide NPs with magnetite (Fe3O4) and maghemite (γ-Fe2O3) crystal structures. Heating efficiencies were determined for each experimental setting, with specific absorption rates (SARs) ranging from 3.7 to 325.9 W/g Fe. Magnetic heating was conducted on iron oxide NPs synthesized in our laboratories (with average core sizes of 8, 11, 13, and 18 nm), as well as commercially-available iron oxides (with average core sizes of 8, 9, and 16 nm). The experimental magnetic coil system made it possible to isolate the effect of magnetic field parameters and independently study the effect on heat generation. The highest SAR values were found for the 18 nm synthesized particles and the maghemite nanopowder. Magnetic field strengths were applied in the range of 15.1 to 47.7 kA/m, with field frequencies ranging from 123 to 430 kHz. The best heating was observed for the highest field strengths and frequencies tested, with results following trends predicted by the Rosensweig equation. An increase in solution viscosity led to lower heating rates in nanoparticle solutions, which can have significant implications for the application of magnetic fluid hyperthermia in vivo.

Magnetic Heating of Iron Oxide Nanoparticles and Magnetic Micelles for Cancer Therapy.

The inclusion of magnetic nanoparticles into block copolymer micelles was studied towards the development of a targeted, magnetically triggered drug delivery system for cancer therapy. Herein, we report the synthesis of magnetic nanoparticles and poly(ethylene glycol-b-caprolactone) block copolymers, and experimental verification of magnetic heating of the nanoparticles, self-assembly of the block copolymers to form magnetic micelles, and thermally-enhanced drug release. The semicrystalline core of the micelles melted at temperatures just above physiological conditions, indicating that they could be used to release a chemotherapy agent from a thermo-responsive polymer system. The magnetic nanoparticles were shown to heat effectively in high frequency magnetic fields ranging from 30-70 kA/m. Magnetic micelles also showed heating properties, that when combined with a chemotherapeutic agent and a targeting ligand could be developed for localized, triggered drug delivery. During the magnetic heating experiments, a time lag was observed in the temperature profile for magnetic micelles, likely due to the heat of fusion of melting of polycaprolactone micelle cores before bulk solution temperatures increased. Doxorubicin, incorporated into the micelles, released faster when the micelles were heated above the core melting point.

Polymer micelles with crystalline cores for thermally triggered release.

Interest in the use of poly(ethylene glycol)-b-polycaprolactone diblock copolymers in a targeted, magnetically triggered drug delivery system has led to this study of the phase behavior of the polycaprolactone core. Four different diblock copolymers were prepared by the ring-opening polymerization of caprolactone from the alcohol terminus of poly(ethylene glycol) monomethylether, M(n) ≈ 2000. The critical micelle concentration depended on the degree of polymerization for the polycaprolactone block and was in the range of 2.9 to 41 mg/L. Differential scanning calorimetry curves for polymer solutions with a concentration above the critical micelle concentration showed a melting endotherm in the range of 40 to 45 °C, indicating the polycaprolactone core was semicrystalline. Pyrene was entrapped in the micelle core without interfering with the ability of the polycaprolactone to crystallize. When the polymer solution was heated above the melting point of the micelle core, the pyrene was free to leave the core. Temperature-dependent measurements of the critical micelle concentration and temperature-dependent dynamic light scattering showed that the micelles remain intact at temperatures above the melting point of the polycaprolactone core.

Surface crosslinking for delayed release of proxyphylline from PHEMA hydrogels.

Delayed release systems find applications in chronotherapeutics and colon-specific delivery. They have also been considered suitable carriers for the oral delivery of peptides and proteins. In prior work, our research group has reported surface crosslinking as an effective technique to modify drug release profiles for poly(vinyl alcohol) (PVA) hydrogels, reducing the early burst effect in particular. Here, we demonstrate the feasibility of delayed release of proxyphylline from poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels via surface crosslinking. Studies on in vitro drug release and the morphology changes of PHEMA hydrogels during swelling and drug release showed that the highly surface crosslinked layers and the ruptures occurring in these layers during swelling were likely responsible for the delayed release. In addition, the initial burst was significantly reduced or even eliminated from the drug release profile for PHEMA to achieve near zero-order release by judicious selection of two surface crosslinking parameters: crosslinking reagent concentration and exposure time used for the surface crosslinking treatment.

Modifying the release of proxyphylline from PVA hydrogels using surface crosslinking.

Drug release profiles were altered to prevent the initial burst effect or introduce a lag phase by creating surface crosslinked layers in poly(vinyl alcohol) (PVA) hydrogels. Confocal laser scanning microscopy (CLSM) confirmed the successful introduction of these surface crosslinked layers. The thickness and crosslinking density of the surface crosslinked layer were highly dependent on the surface crosslinking conditions (i.e., exposure time and glutaraldehyde (GTA) concentration used). By judicious selection of these parameters, the initial burst release could be eliminated and a reproducible delayed release could be achieved. Highly surface crosslinked layers had a tendency to rupture during the swelling process of PVA hydrogels; these raptures were found to coincide with delayed release of proxyphylline from surface crosslinked PVA hydrogels.

Developmental toxicity assessment of thermoresponsive poly(N-isopropylacrylamide-co-acrylamide) oligomers in CD-1 mice.

BACKGROUND: Although polymers and hydrogels are used successfully in biomedical applications, including implants and drug delivery devices, smaller molecular weight oligomers, such as those investigated here, have not been extensively studied in vivo. Poly(N-isopropylacrylamide-co-acrylamide), or P(NIPAAm-co-AAm), has a unique thermoresponsive behavior and is under investigation as a novel drug delivery system for metastatic cancer treatment. To date, no studies have been published regarding the safety of P(NIPAAm-co-AAm) to the conceptus. METHODS: From gestation days (GD) 6-16, pregnant CD-1 mice were dosed via i.p. injection with aqueous solutions containing 500, 750, or 1,000 mg/kg/d P(NIPAAm-co-AAm). Dams were sacrificed on GD 17 and their litters were examined for abnormalities. RESULTS: P(NIPAAm-co-AAm) caused no statistically significant difference in maternal weight gain or percent resorbed or dead fetuses compared to control values, but fetal weight was significantly decreased in the two highest dosage groups. CONCLUSIONS: At the highest dosages employed, maternal exposure to P(NIPAAm-co-AAm) was associated with decreased fetal weight. However, as the estimated human exposure levels for persons using this system would be some 1,500-fold lower than the lowest dosage administered in this study, the authors feel that this oligomer was not shown to pose a biologically significant risk at relevant human dosages.

Synthesis and characterization of grafted thermosensitive hydrogels for heating activated controlled release.

Poly(N-isopropylacrylamide), PNIPAAm, hydrogels are negatively thermosensitive which means that they have an expanded hydrogel structure at low temperatures and a shrunken structure at high temperatures. Based on this negative thermosensitivity of PNIPAAm, a drug delivery system with PNIPAAm oligomers grafted onto poly(hydroxyethyl methacrylate) PHEMA, a thermally nonresponsive polymer was designed. Poly(hydroxyethyl methacrylate-g-N-isopropylacrylamide), P(HEMA-g-NIPAAm) hydrogels were synthesized to control the release of an imbedded drug. This new grafted system exhibited high diffusivity at temperatures greater than the lower critical solution temperature (LCST) of the PNIPAAm oligomers. Utilizing PNIPAAm's LCST of approximately 34 degrees C, the release rate was controlled by the temperature of the release medium. The LCST of PNIPAAm was tuned by making copolymers with hydrophobic butyl methacrylate (BMA). Theophylline and inulin release profiles were studied using PHEMA, PNIPAAm and P(HEMA-g-NIPAAm) at three temperatures with drug diffusion coefficients determined as a function of temperature and drug type. The molecular weights between crosslinks and mesh sizes of PHEMA hydrogels were calculated using Flory-Rehner and rubber-elasticity theories.

Combination of viral biology and nanotechnology: new applications in nanomedicine.

Viruses are well known for their ability to cause disease, but their beneficial usefulness as vectors for gene therapy have been noted as well. As an extension of their use in a gene therapy context, their combination with nanotechnology is starting to benefit many areas of science and medicine. These include nanofabrication and medical diagnostics, to name a few, as well as viro-nanotherapy, here defined as the combination of viral biology with nanotechnology to create new therapeutic avenues to treat disease. This review provides examples of areas wherein viruses in combination with nanotechnology are being used to either advance scientific knowledge or accelerate the development of new diagnostics and therapeutics for human pathological conditions.

Evaluating the toxicity of bDtBPP on CHO-K1 cells for testing of single-use bioprocessing systems considering media selection, cell culture volume, mixing, and exposure duration.

Single-use bioprocessing bags are gaining popularity due to ease of use, lower risk of contamination, and ease of process scale-up. Bis(2,4-di-tert-butylphenyl)phosphate (bDtBPP), a degradant of tris(2,4-di-tert-butylphenyl)phosphite, marketed as Irgafos 168®, which is an antioxidant stabilizer added to resins, has been identified as a potentially toxic leachate which may impact the performance of single-use, multilayer bioprocessing bags. In this study, the toxicity of bDtBPP was tested on CHO-K1 cells grown as adherent or suspended cells. The EC50 (effective concentration to cause 50% cell death) for adherent cells was found to be one order of magnitude higher than that for suspended CHO-K1 cells. While CHO-K1 cells had good cell viability when exposed to moderate concentrations of bDtBPP, the degradant was shown to impact the viable cell density (VCD) at much lower concentrations. Hence, in developing an industry-standard assay for testing the cytotoxicity of leachates, suspended cells (as commonly used in the bioprocessing industry) would likely be most sensitive, particularly when reporting EC50 values based on VCD. The effects of mixing, cell culture volume, and exposure duration were also evaluated for suspended CHO-K1 cells. It was found that the sensitivity of cell culture to leachates from single-use plastic bags was enhanced for suspended cells cultured for longer exposure times and when the cells were subjected to continuous agitation, both of which are important considerations in the production of biopharmaceuticals. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1318-1323, 2016.

Determining iron oxide nanoparticle heating efficiency and elucidating local nanoparticle temperature for application in agarose gel-based tumor model.

Magnetic iron oxide nanoparticles (MNPs) have been developed for magnetic fluid hyperthermia (MFH) cancer therapy, where cancer cells are treated through the heat generated by application of a high frequency magnetic field. This heat has also been proposed as a mechanism to trigger release of chemotherapy agents. In each of these cases, MNPs with optimal heating performance can be used to maximize therapeutic effect while minimizing the required dosage of MNPs. In this study, the heating efficiencies (or specific absorption rate, SAR) of two types of MNPs were evaluated experimentally and then predicted from their magnetic properties. MNPs were also incorporated in the core of poly(ethylene glycol-b-caprolactone) micelles, co-localized with rhodamine B fluorescent dye attached to polycaprolactone to monitor local, nanoscale temperatures during magnetic heating. Despite a relatively high SAR produced by these MNPs, no significant temperature rise beyond that observed in the bulk solution was measured by fluorescence in the core of the magnetic micelles. MNPs were also incorporated into a macro-scale agarose gel system that mimicked a tumor targeted by MNPs and surrounded by healthy tissues. The agarose-based tumor models showed that targeted MNPs can reach hyperthermia temperatures inside a tumor with a sufficient MNP concentration, while causing minimal temperature rise in the healthy tissue surrounding the tumor.

Conventional free radical polymerization in room temperature ionic liquids: a green approach to commodity polymers with practical advantages.

Free-radical polymerization of methyl methacrylate and styrene using conventional organic initiators in the room temperature ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate ([C4mim][PF6]) is rapid and produces polymers with molecular weights up to 10x higher than from benzene; both polymerization and isolation of products were achieved without using VOCs, offering economic as well as environmental advantages.

Application of ionic liquids as plasticizers for poly(methyl methacrylate).

The room temperature ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate, [C4mim][PF6] was found to be an efficient plasticizer for poly(methyl methacrylate), prepared by in situ radical polymerization in the ionic liquid medium; the polymers have physical characteristics comparable with those containing traditional plasticizers and retain greater thermal stability.

Minimization of initial burst in poly(vinyl alcohol) hydrogels by surface extraction and surface-preferential crosslinking.

Surface extraction and surface-preferential crosslinking were investigated as effective methods to reduce the burst effect for proxyphylline release from poly(vinyl alcohol) hydrogels. Both these techniques involved changing the surface characteristics to reduce drug diffusion during the early stages of release, with the goal of subtracting the burst effect from the release profile without altering the long-term release rate. The extraction process was carried out on both relaxed and dry gels. Proxyphylline was extracted from both freshly made and dried hydrogel samples, with the extraction from dried samples providing better control of the burst effect with smaller amounts of drug removed from the gels. The success of extracting from the dried samples was attributed to the lack of drug diffusivity and redistribution after extraction when the majority of the device remained dry. Surface-preferential crosslinking, by dipping preformed proxyphylline-loaded samples in a concentrated crosslinking solution, effectively diminished the burst effect by slowing macromolecular relaxation near the surface. Notably, this technique maintained the same long-term drug release rate as the untreated gels and less than 0.2% of the loaded proxyphylline was removed during the crosslinking step.

Interactions of iron oxide nanoparticles with the immune system: challenges and opportunities for their use in nano-oncology.

Iron oxide (IO) nanoparticles hold great promise as diagnostic and therapeutic agents in oncology. Their intrinsic physical properties make IO nanoparticles particularly interesting for simultaneous drug delivery, molecular imaging, and applications such as localized hyperthermia. Multiple non-targeted IO nanoparticle preparations have entered clinical trials, but more exciting, new tumortargeted IO nanoparticle preparations are currently being tested in preclinical settings. This paper will analyze the challenges faced by this new theranostic modality, with a specific focus on the interactions of IO nanoparticles with the innate and adaptive immune systems, and their effect on nanoparticle biodistribution and tumor targeting. Next, we will review the critical need for innovative surface chemistry solutions and strategies to overcome the immune interactions that prevent existing tumor-targeted IO preparations from entering clinical trials. Finally, we will provide an outlook for the future role of IO nanoparticles in oncology, which have the promise of becoming significant contributors to improved diagnosis and treatment of cancer patients.

Synthesis and Characterization of Multifunctional Chitosan- MnFe2O4 Nanoparticles for Magnetic Hyperthermia and Drug Delivery.

Multifunctional nanoparticles composed of MnFe2O4 were encapsulated in chitosan for investigation of system to combine magnetically-triggered drug delivery and localized hyperthermia for cancer treatment with the previously published capacity of MnFe2O4 to be used as an efficient MRI contrast agent for cancer diagnosis. This paper focuses on the synthesis and characterization of magnetic MnFe2O4 nanoparticles, their dispersion in water and their incorporation in chitosan, which serves as a drug carrier. The surface of the MnFe2O4 nanoparticles was modified with meso-2,3-di-mercaptosuccinic acid (DMSA) to develop stable aqueous dispersions. The nanoparticles were coated with chitosan, and the magnetic properties, heat generation and hydrodynamic size of chitosan-coated MnFe2O4 were evaluated for various linker concentrations and in a range of pH conditions.

Magnetothermally-responsive nanomaterials: combining magnetic nanostructures and thermally-sensitive polymers for triggered drug release.

This paper reviews the design and development of magnetothermally-triggered drug delivery systems, whereby magnetic nanoparticles are combined with thermally-activated materials. By combining superparamagnetic nanoparticles with lower critical solution temperature (LCST) polymers, an alternating current (AC) magnetic field can be used to trigger localized heating in vivo, which in turn causes a phase change in the host polymer to allow diffusion and release of drugs. The use of magnetic nanoparticles for biomedical applications is reviewed, as well as the design of thermally-activated polymeric systems. Current research on externally-triggered delivery is highlighted, with a focus on the design and challenges in developing magnetothermally-activated systems.

Numerical study on the multi-region bio-heat equation to model magnetic fluid hyperthermia (MFH) using low Curie temperature nanoparticles.

This study develops and solves two-dimensional convective-conductive coupled partial differential equations based on Pennes' bio-heat transfer model using low Curie temperature nanoparticles (LCTNPs) to illustrate thermal behavior quantitatively within tumor-normal composite tissue by establishing a multi-region finite difference algorithm. The model combines NEel relaxation and temperature-variant saturation magnetization derived from Brillouin Equation and Curie-Weiss Law. The numerical results indicate that different deposition patterns of LCTNP and boundary conditions directly effect the steady state temperature distribution. Compared with high Curie temperature nanoparticles (HCTNPs), optimized distributions of LCTNPs within tumorous tissue can be used to control the temperature increase in tumors for hyperthermia treatment using an external magnetic field while healthy tissue surrounding a tumor can be kept closer to normal body tissue, reducing the side effects observed in whole body and regional hyperthermia therapy.