Nipon Pothayee

Magnetic Nanoclusters with Hydrophilic Spacing for Dual Drug Delivery and Sensitive Magnetic Resonance Imaging

Magnetic Block Ionomer Clusters (MBIClusters) with hydrophilic ionic cores and nonionic coronas have been prepared that have ultrahigh transverse NMR relaxivities together with capacities for incorporating high concentrations of polar antibiotic payloads. Magnetite-polymer nanoparticles were assembled by adsorbing the polyacrylate block of an aminofunctional poly(ethylene oxide-b-acrylate) (H2N-PEO-b-PAA) copolymer onto magnetite nanoparticles. The PEO blocks extended into aqueous media to keep the nanoparticles dispersed. Amines at the tips of the H2N-PEO corona were then linked through reaction with a PEO diacrylate oligomer to yield MBIClusters where the metal oxide in the precursor nanoparticles were distinctly separated by the hydrophilic polymer. The intensity average spacing between the magnetite nanoparticles within the clusters was estimated to be ~50 nm. These MBIClusters with hydrophilic intra-cluster space had transverse relaxivities (r2s) that increased from 190 to 604 s-1 mM Fe-1 measured at 1.4 T and 37 °C as their average sizes increased. The clusters were loaded with up to ~38 wt% of the multi-cationic drug gentamicin. MRI scans focused on the livers of mice demonstrated that these MBIClusters are sensitive contrast agents.

Changing the Enzyme Reaction Rate in Magnetic Nanosuspensions by a Non‐Heating Magnetic Field

Weak magnetic fields (< 1 T) are known to change the paths and kinetics of some radical chemical reactions at room temperature through spin conversion of short-lived radical pairs. [1] Magnetic fields were also used to tune enzyme activity (oxidation of glucose). Specifically, exposure of magnetic nanoparticles functionalized with enzymes to magnetic field allowed the movement of particles in proximity to electrode, thus activating the enzyme. [2] Moreover, radio-frequency (RF) alternating current (AC) magnetic fields can induce the heating of single-domain magnetic nanoparticles (MNPs), and this can be used in magnetic hyperthermia to kill tumors. [3] Herein we describe a distinct effect of non-heating superlow-frequency magnetic fields as well as more conventional RF magnetic fields on the kinetics of chemical reactions catalyzed by the enzymes a-chymotrypsin (ChT) or bgalactosidase (b-GaL) immobilized on nanoscale MNP aggregates. Magnetite MNPs (7 to 12 nm diameter) were synthesized by reducing tris(acetylacetonato)iron(III), then they were coated with anionic poly(ethylene glycol)-bpolyacrylate (PEG-PAA), or poly(ethylene glycol)-b-polymethacrylate (PEG-PMA) copolymers. The polymers were bound to the magnetite surfaces by the carboxylate groups. [4] According to thermogravimetric analysis, the content of Fe3O4 in both coated MNP materials was about 35 wt %, and this was in excellent agreement with that measured by inductively coupled plasma-mass spectrometry. Upon dispersion in water (pH 6.5), they formed nanoscale, negatively charged aggregates (hydrodynamic intensity average diameters and zeta potentials of 194 nm, 70 mV and 39 nm, 49 mV for PEG-PAA/MNP and PEG-PMA/MNP, respectively, as determined by dynamic light scattering). Based on TEM, they contained clusters of 7 to 20 MNP grains. Enzymes were conjugated to these aggregates using 1-ethyl-3-(3dimethylaminopropyl)-carbodiimide and N-hydroxysulfosuccinimide to couple amines on the protein to carboxylic acids on the copolymer (Scheme 1).

Efficacy of Amphiphilic Core-Shell Nanostructures Encapsulating Gentamicin in an In Vitro Salmonella and Listeria Intracellular Infection Model

ABSTRACT Core-shell nanostructures with nonionic amphiphilic shells and ionic cores encapsulating gentamicin were designed for therapy against intracellular pathogens, including Salmonella and Listeria. Flow cytometry and confocal microscopy showed that their uptake into J774A.1 macrophages proceeded mainly by fluid-phase endocytosis and clathrin-mediated pathways. The nanostructures were nontoxic in vitro at doses of 50 to 250 μg/ml, and they significantly reduced the amounts of intracellular Salmonella (0.53 log) and Listeria (3.16 log), thereby suggesting effective transport into the cells.

Remote Actuation of Magnetic Nanoparticles For Cancer Cell Selective Treatment Through Cytoskeletal Disruption

Motion of micron and sub-micron size magnetic particles in alternating magnetic fields can activate mechanosensitive cellular functions or physically destruct cancer cells. However, such effects are usually observed with relatively large magnetic particles (>250 nm) that would be difficult if at all possible to deliver to remote sites in the body to treat disease. Here we show a completely new mechanism of selective toxicity of superparamagnetic nanoparticles (SMNP) of 7 to 8 nm in diameter to cancer cells. These particles are coated by block copolymers, which facilitates their entry into the cells and clustering in the lysosomes, where they are then magneto-mechanically actuated by remotely applied alternating current (AC) magnetic fields of very low frequency (50 Hz). Such fields and treatments are safe for surrounding tissues but produce cytoskeletal disruption and subsequent death of cancer cells while leaving healthy cells intact.

Manganese graft ionomer complexes (MaGICs) for dual imaging and chemotherapy

Novel manganese graft ionomer complexes (MaGICs) that contain Mn ions complexed with a polyaminobisphosphonate-g-poly(ethylene oxide) (PEO) copolymer were developed for use as T1-weighted contrast agents for MRI. The complexes exhibited good colloidal stability without release of free manganese and did not result in any in vitro toxicity against mouse hepatocytes. T1 relaxivities of the MaGICs at physiological pH were 2-10 times higher than that of a commercial manganese-based positive contrast agent. Anticancer drugs including doxorubicin, cisplatin and carboplatin were successfully encapsulated into the MaGICs with high efficiency. Drug release behavior was sustained and depended on pH (faster in acidic environments), drug structures and drug concentration (faster with high concentration). The anticancer drug-loaded manganese nanocarriers exhibited excellent anticancer activity against MCF-7 breast cancer cells together with high relaxivity. Thus, these drug-loaded MaGICs could potentially be utilized for simultaneous diagnosis and treatment of cancer.

Ammonium Bisphosphonate Polymeric Magnetic Nanocomplexes for Platinum Anticancer Drug Delivery and Imaging with Potential Hyperthermia and Temperature-Dependent Drug Release

Novel magnetite-ammonium bisphosphonate graft ionic copolymer nanocomplexes (MGICs) have been developed for potential drug delivery, magnetic resonance imaging, and hyperthermia applications. The complexes displayed relatively uniform sizes with narrow size distributions upon self-assembly in aqueous media, and their sizes were stable under simulated physiological conditions for at least 7 days. The anticancer drugs, cisplatin and carboplatin, were loaded into the complexes, and sustained release of both drugs was observed. The transverse NMR relaxivities ( s) of the complexes were 244 s−1 (mM Fe)−1 which is fast compared to either the commercial T2-weighted MRI agent Feridex IV® or our previously reported magnetite-block ionomer complexes. Phantom MRI images of the complexes demonstrated excellent negative contrast effects of such complexes. Thus, the bisphosphonate-bearing MGICs could be promising candidates for dual drug delivery and magnetic resonance imaging. Moreover, the bisphosphonate MGICs generate heat under an alternating magnetic field of 30 kA·m−1 at 206 kHz. The temperature of the MGIC dispersion in deionized water increased from 37 to 41°C after exposure to the magnetic field for 10 minutes, corresponding to a specific absorption rate of 77.0 W·g−1. This suggests their potential as hyperthermia treatment agents as well as the possibility of temperature-dependent drug release, making MGICs more versatile in potential drug delivery applications.