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.

Hippocampal proton MR spectroscopy in early Alzheimer's disease and mild cognitive impairment.

Proton magnetic resonance spectroscopy ((1)H-MRS) studies have previously reported reduced brain N-acetyl aspartate (NAA) and increased myo-inositol (mI) in people with established Alzheimer's disease (AD). The earliest structure affected by AD is the hippocampus but relatively few studies have examined its neuronal integrity by MRS in AD and fewer still in people with amnestic mild cognitive impairment (MCI). We measured the hippocampal concentration of NAA, mI, choline (Cho) and creatine + phosphocreatine (Cr + PCr) in 39 patients with AD, 21 subjects with MCI and 38 age matched healthy elderly controls. Patients with AD had a significantly lower hippocampal [NAA] than controls, with subjects with MCI intermediate between the other two groups. [NAA] was positively correlated with memory in the impaired groups. Using mean hippocampal [NAA] and [Cr + PCr] we correctly classified 72% of people with AD, and 75% of controls. Reductions in [NAA] can be detected in the hippocampi of subjects with MCI and hippocampal [NAA] and [Cr + PCr] can distinguish between mild AD and normal elderly controls.

Synthesis and structure activity relationship studies of novel Staphylococcus aureus Sortase A inhibitors.

Synthetic methods have been developed for lead Sortase A inhibitors identified from previous studies. Several derivatives of the lead inhibitor were synthesized to derive preliminary structure activity relationships (SAR). Different regions of the lead inhibitor that are critical for the enzyme activity have been determined by systematic SAR studies. The E stereochemistry of the lead compound was found to be critical for its activity. Replacement of the E double bond with Z double bond or a rigid triple bond reduced the enzyme inhibitory activity in most cases. Reduction of the double bond to a C-C single bond resulted in complete loss of activity. Amide carbonyl and NH groups were also found to be crucial for the activity of this class of inhibitors, as well. The morpholine ring oxygen atom was also found to be an important factor for the activity of the lead inhibitor. Preliminary SAR studies led to the identification of compounds with improved enzyme inhibition. The most active compound was found to have an IC(50) value of 58 microM against the enzyme.

Proteome-based identification of plasma proteins associated with hippocampal metabolism in early Alzheimer's disease.

BACKGROUND AND METHODS: There is an urgent need for peripheral surrogates of Alzheimer's disease (AD) that accurately reflect disease state and severity as well as correlate with key features of its neuropathology. The aim of this study was to identify plasma proteins associated with known in vivo markers of disease activity. In an earlier proteomic study of plasma, we discovered a panel of 15 proteins that were differentially expressed in AD and further validated complement factor-H (CFH) and alpha-2-macroglobulin (A2M) as AD-specific plasma biomarkers. In the present study, we extended these findings by testing the associations of these plasma proteins with neuro-imaging measures of disease progression in AD. We combined (1)H-magnetic resonance spectroscopy of the hippocampus and MRI-based hippocampal volumetry with proteomic analysis of plasma in early AD and mild cognitive impairment (MCI) to achieve this goal. Using (1)H-magnetic resonance spectroscopy, we derived estimates of the hippocampal metabolite ratio N-acetylaspartate/myo-inositol (NAA/mI), a biochemical measure that is associated with cognitive decline in early AD. We also undertook a proteomic analysis of plasma in these individuals using two-dimensional gel electrophoresis (2DGE). RESULTS: We observed that two plasma proteins previously shown to be differentially expressed in AD, complement factor-H (CFH) and alpha-2-macroglobulin (A2M) showed significant positive correlations with hippocampal NAA/mI ratio in AD. CONCLUSIONS: The association of plasma CFH and A2M with hippocampal NAA/mI in this cohort of AD subjects suggests that these proteins may reflect disease progression in early AD. These findings warrant validation in large population-based datasets.