An implantable smart magnetic nanofiber device for endoscopic hyperthermia treatment and tumor-triggered controlled drug release.

The study describes the design and synthesis of an implantable smart magnetic nanofiber device for endoscopic hyperthermia treatment and tumor-triggered controlled drug release. This device is achieved using a two-component smart nanofiber matrix from monodisperse iron oxide nanoparticles (IONPs) as well as bortezomib (BTZ), a chemotherapeutic drug. The IONP-incorporated nanofiber matrix was developed by electrospinning a biocompatible and bioresorbable polymer, poly (d,l-lactide-co-glycolide) (PLGA), and tumor-triggered anticancer drug delivery is realized by exploiting mussel-inspired surface functionalization using 2-(3,4-dihydroxyphenyl)ethylamine (dopamine) to conjugate the borate-containing BTZ anticancer drug through a catechol metal binding in a pH-sensitive manner. Thus, an implantable smart magnetic nanofiber device can be exploited to both apply hyperthermia with an alternating magnetic field (AMF) and to achieve cancer cell-specific drug release to enable synergistic cancer therapy. These results confirm that the BTZ-loaded mussel-inspired magnetic nanofiber matrix (BTZ-MMNF) is highly beneficial not only due to the higher therapeutic efficacy and low toxicity towards normal cells but also, as a result of the availability of magnetic nanoparticles for repeated hyperthermia application and tumor-triggered controlled drug release. STATEMENT OF SIGNIFICANCE: The current work report on the design and development of a smart nanoplatform responsive to a magnetic field to administer both hyperthermia and pH-dependent anticancer drug release for the synergistic anticancer treatment. The iron oxide nanoparticles (IONPs) incorporated nanofiber matrix was developed by electrospinning a biocompatible polymer, poly (d,l-lactide-co-glycolide) (PLGA), and tumor-triggered anticancer drug delivery is realized by surface functionalization using 2-(3,4-dihydroxyphenyl)ethylamine (dopamine) to conjugate the boratecontaining anticancer drug bortezomib through a catechol metal binding in a pH-sensitive manner. This implantable magnetic nanofiber device can be exploited to apply hyperthermia with an alternating magnetic field and to achieve cancer cell-specific drug release to enable synergistic cancer therapy, which results in an improvement in both quality of life and patient compliance.

Selective inhibition of KCa3.1 channels mediates adenosine regulation of the motility of human T cells.

Adenosine, a purine nucleoside, is present at high concentrations in tumors, where it contributes to the failure of immune cells to eliminate cancer cells. The mechanisms responsible for the immunosuppressive properties of adenosine are not fully understood. We tested the hypothesis that adenosine's immunosuppressive functions in human T lymphocytes are in part mediated via modulation of ion channels. The activity of T lymphocytes relies on ion channels. KCa3.1 and Kv1.3 channels control cytokine release and, together with TRPM7, regulate T cell motility. Adenosine selectively inhibited KCa3.1, but not Kv1.3 and TRPM7, in activated human T cells. This effect of adenosine was mainly mediated by A2A receptors, as KCa3.1 inhibition was reversed by SCH58261 (selective A2A receptor antagonist), but not by MRS1754 (A2B receptor antagonist), and it was mimicked by the A2A receptor agonist CGS21680. Furthermore, it was mediated by the cAMP/protein kinase A isoform (PKAI) signaling pathway, as adenylyl-cyclase and PKAI inhibition prevented adenosine effect on KCa3.1. The functional implication of the effect of adenosine on KCa3.1 was determined by measuring T cell motility on ICAM-1 surfaces. Adenosine and CGS21680 inhibited T cell migration. Comparable effects were obtained by KCa3.1 blockade with TRAM-34. Furthermore, the effect of adenosine on cell migration was abolished by pre-exposure to TRAM-34. Additionally, adenosine suppresses IL-2 secretion via KCa3.1 inhibition. Our data indicate that adenosine inhibits KCa3.1 in human T cells via A2A receptor and PKAI, thereby resulting in decreased T cell motility and cytokine release. This mechanism is likely to contribute to decreased immune surveillance in solid tumors.

Surface modification of a biodegradable magnesium alloy with phosphorylcholine (PC) and sulfobetaine (SB) functional macromolecules for reduced thrombogenicity and acute corrosion resistance.

Siloxane functionalized phosphorylcholine (PC) or sulfobetaine (SB) macromolecules (PCSSi or SBSSi) were synthesized to act as surface modifying agents for degradable metallic surfaces to improve acute blood compatibility and slow initial corrosion rates. The macromolecules were synthesized using a thiol-ene radical photopolymerization technique and then utilized to modify magnesium (Mg) alloy (AZ31) surfaces via an anhydrous phase deposition of the silane functional groups. X-ray photoelectron spectroscopy surface analysis results indicated successful surface modification based on increased nitrogen and phosphorus or sulfur composition on the modified surfaces relative to unmodified AZ31. In vitro acute thrombogenicity assessment after ovine blood contact with the PCSSi and SBSSi modified surfaces showed a significant decrease in platelet deposition and bulk phase platelet activation compared with the control alloy surfaces. Potentiodynamic polarization and electrochemical impedance spectroscopy data obtained from electrochemical corrosion testing demonstrated increased corrosion resistance for PCSSi- and SBSSi-modified AZ31 versus unmodified surfaces. The developed coating technique using PCSSi or SBSSi showed promise in acutely reducing both the corrosion and thrombotic processes, which would be attractive for application to blood contacting devices, such as vascular stents, made from degradable Mg alloys.

KCa3.1 and TRPM7 channels at the uropod regulate migration of activated human T cells.

The migration of T lymphocytes is an essential part of the adaptive immune response as T cells circulate around the body to carry out immune surveillance. During the migration process T cells polarize, forming a leading edge at the cell front and a uropod at the cell rear. Our interest was in studying the involvement of ion channels in the migration of activated human T lymphocytes as they modulate intracellular Ca(2+) levels. Ca(2+) is a key regulator of cellular motility. To this purpose, we created protein surfaces made of the bio-polymer PNMP and coated with ICAM-1, ligand of LFA-1. The LFA-1 and ICAM-1 interaction facilitates T cell movement from blood into tissues and it is critical in immune surveillance and inflammation. Activated human T lymphocytes polarized and migrated on ICAM-1 surfaces by random walk with a mean velocity of ∼6 µm/min. Confocal microscopy indicated that Kv1.3, CRAC, and TRPM4 channels positioned in the leading-edge, whereas KCa3.1 and TRPM7 channels accumulated in the uropod. The localization of KCa3.1 and TRPM7 at the uropod was associated with oscillations in intracellular Ca(2+) levels that we measured in this cell compartment. Further studies with blockers against Kv1.3 (ShK), KCa3.1 (TRAM-34), CRAC (SKF-96365), TRPM7 (2-APB), and TRPM4 (glibenclamide) indicated that blockade of KCa3.1 and TRPM7, and not Kv1.3, CRAC or TRPM4, inhibits the T cell migration. The involvement of TRPM7 in cell migration was confirmed with siRNAs against TRPM7. Downregulation of TRPM7 significantly reduced the number of migrating T cells and the mean velocity of the migrating T cells. These results indicate that KCa3.1 and TRPM7 selectively localize at the uropod of migrating T lymphocytes and are key components of the T cell migration machinery.

Corrosion behavior and cytotoxicity of Mg-35Zn-3Ca alloy for surface modified biodegradable implant material.

This study was conducted to investigate the biocompatibility of Mg-Zn-Ca ternary alloy as a biodegradable material. The casting alloy underwent anodization in an alkaline electrolyte at current density 300 mA/cm(2) and frequency 50 Hz to obtain porous oxide layer. Plasma anodization film using pulse was shown to form irregular porous oxide film. As a result of corrosion test, the corrosion current was shown to decrease and the corrosion voltage was shown to increase in the anodized group, which showed the improvement of corrosion resistance after surface treatment. Sodium silicate (0.1 M) was directly oxidized due to high charges caused by spark and then formed SiO(2), and the compounds produced inside the film were shown MgO, Mg(2) SiO(4), and SiO(2.) In the histological examination in rats, all samples of the untreated group were shown to be absorbed 3 weeks later into the body. After the magnesium alloy was implanted, blood vessel expansion and tissue change were shown in the adjacent tissues. However, the changed tissues were shown to return to normal muscle tissues 4 weeks later when the alloy was completely absorbed. These results suggest that anodized Mg-35Zn-3Ca alloy has good biocompatibility in vivo and controls the absorption rate of biomaterials.

Self-aligned nanogaps on multilayer electrodes for fluidic and magnetic assembly of carbon nanotubes.

A self-aligned nanogap between multiple metal layers has been developed using a new controlled undercut and metallization technique (CUMT), and practically applied for self-assembly of individual carbon nanotubes (CNTs) over the developed nanogap. This new method allows conventional optical lithography to fabricate nanogap electrodes and self-aligned patterns with nanoscale precision. The self-aligned nickel (Ni) pattern on the nanogap electrode works as an assembly spot where the residual iron (Fe) catalyst at the end of the CNT is magnetically captured. The captured CNT is forced to be aligned parallel to the flow direction by fluidic shear force. The combined forces of magnetic attraction and fluidic alignment provide massive self-assembly of CNTs at target positions. Both multiwalled nanotubes (MWNTs) and single walled nanotubes (SWNTs) were successfully assembled over the nanogap electrodes, and their electrical characteristics were fully characterized. The CNTs self-assembled on the developed electrodes with a nanogap and showed a very reliable and reproducible current-voltage (I-V) characteristic. The method developed in this work can envisage the mass fabrication of individual CNT-assembled devices which can be applied to nanoelectronic devices or nanobiosensors.

The precise self-assembly of individual carbon nanotubes using magnetic capturing and fluidic alignment.

A new method for the self-assembly of a carbon nanotube (CNT) using magnetic capturing and fluidic alignment has been developed and characterized in this work. In this new method, the residual iron (Fe) catalyst positioned at one end of the CNT was utilized as a self-assembly driver to attract and position the CNT, while the assembled CNT was aligned by the shear force induced from the fluid flow through the assembly channel. The self-assembly procedures were successfully developed and the electrical properties of the assembled multi-walled carbon nanotube (MWNT) and single-walled carbon nanotube (SWNT) were fully characterized. The new assembly method developed in this work shows its feasibility for the precise self-assembly of parallel CNTs for electronic devices and nanobiosensors.

Tiny medicine: nanomaterial-based biosensors.

Tiny medicine refers to the development of small easy to use devices that can help in the early diagnosis and treatment of disease. Early diagnosis is the key to successfully treating many diseases. Nanomaterial-based biosensors utilize the unique properties of biological and physical nanomaterials to recognize a target molecule and effect transduction of an electronic signal. In general, the advantages of nanomaterial-based biosensors are fast response, small size, high sensitivity, and portability compared to existing large electrodes and sensors. Systems integration is the core technology that enables tiny medicine. Integration of nanomaterials, microfluidics, automatic samplers, and transduction devices on a single chip provides many advantages for point of care devices such as biosensors. Biosensors are also being used as new analytical tools to study medicine. Thus this paper reviews how nanomaterials can be used to build biosensors and how these biosensors can help now and in the future to detect disease and monitor therapies.

A label-free electronic biosensor for detection of bone turnover markers.

This paper describes the development of a biosensor based on label-free immunosensing for the detection of the C-terminal telopeptide bone turnover marker from type-1 collagen. A self-assembled monolayer (SAM) of dithiodipropionic acid was deposited on a gold electrode. Then streptavidin and biotinylated anti-human C-terminal telopeptide antibody were successively conjugated on the self-assembled monolayer. Electrochemical impedance measurements were made to characterize each step of the SAM/streptavidin/biotinylated antibody binding. Subsequently, electrochemical impedance was measured with different concentrations of C-teminal telopeptide. A detection limit of 50 ng/mL and a dynamic range up to 3 µg/mL were achieved. To our knowledge, this is the first attempt to develop a label-free immunosensor based on electrochemical impedance with DC bias for detection of bone-related degradation and rebuilding products. The electronic biosensor might eventually be used for quantitative point-of-care screening of bone health. It is hoped that analysis of bone turnover markers can indicate the beginning of bone diseases such as osteoarthritis and osteoporosis so that treatment might start early when it is most effective.