Masaki Sekino

Visible Drug Delivery by Supramolecular Nanocarriers Directing to Single-Platformed Diagnosis and Therapy of Pancreatic Tumor Model

Nanoparticle therapeutics are promising platforms for cancer therapy. However, it remains a formidable challenge to assess their distribution and clinical efficacy for therapeutic applications. Here, by using multifunctional polymeric micellar nanocarriers incorporating clinically approved gadolinium (Gd)-based magnetic resonance imaging contrast agents and platinum (Pt) anticancer drugs through reversible metal chelation of Pt, simultaneous imaging and therapy of an orthotopic animal model of intractable human pancreatic tumor was successfully performed without any serious toxicity. The strong tumor contrast enhancement achieved by the micelles correlated with the 24 times increase of r(1) of the Gd chelates, the highest for the formulations using clinically approved Gd chelates reported to date. From the micro-synchrotron radiation X-ray fluorescence spectrometry scanning of the lesions, we confirmed that both the Gd chelates and Pt drugs delivered by the micelles selectively colocalized in the tumor interior. Our study provides new insights for the design of theranostic micelles with high contrast enhancement and site-specific clinical potential.

Ultraflexible, large-area, physiological temperature sensors for multipoint measurements

Significance We have successfully fabricated very unique ultraflexible temperature sensors that exhibit changes in resistivity by six orders of magnitude or more for a change in temperature of only 5 °C or less. Our approach offers an ideal solution to measure temperature over a large area with high spatial resolution, high sensitivity of 0.1 °C or less, and fast response time of 100 ms. Indeed, such a large change of resistivity for our sensors can significantly simplify the readout circuitry, which was the key to demonstrate, to our knowledge, the world’s first successful measurement of dynamic change of temperature in the lung during very fast artificial respiration. Furthermore, we have demonstrated real-time multipoint thermal sensing using organic transistor active-matrix circuits. We report a fabrication method for flexible and printable thermal sensors based on composites of semicrystalline acrylate polymers and graphite with a high sensitivity of 20 mK and a high-speed response time of less than 100 ms. These devices exhibit large resistance changes near body temperature under physiological conditions with high repeatability (1,800 times). Device performance is largely unaffected by bending to radii below 700 µm, which allows for conformal application to the surface of living tissue. The sensing temperature can be tuned between 25 °C and 50 °C, which covers all relevant physiological temperatures. Furthermore, we demonstrate flexible active-matrix thermal sensors which can resolve spatial temperature gradients over a large area. With this flexible ultrasensitive temperature sensor we succeeded in the in vivo measurement of cyclic temperatures changes of 0.1 °C in a rat lung during breathing, without interference from constant tissue motion. This result conclusively shows that the lung of a warm-blooded animal maintains surprising temperature stability despite the large difference between core temperature and inhaled air temperature.

Mechanically Adaptive Organic Transistors for Implantable Electronics

A unique form of adaptive electronics is demonstrated, which change their mechanical properties from rigid and planar to soft and compliant, in order to enable soft and conformal wrapping around 3D objects, including biological tissue. These devices feature excellent mechanical robustness and maintain initial electrical properties even after changing shape and stiffness.

Asymmetries of prefrontal cortex in human episodic memory: effects of transcranial magnetic stimulation on learning abstract patterns.

Functional neuroimaging suggests asymmetries of memory encoding and retrieval in the prefrontal lobes, but different hypotheses have been presented concerning the nature of prefrontal hemispheric specialization. We studied an associative memory task involving pairs of Kanji (Chinese) pictographs and unfamiliar abstract patterns. Subjects were ten Japanese adults fluent in Kanji, so only the abstract patterns represented novel material. During encoding, transcranial magnetic stimulation (TMS) was applied over the left and right dorsolateral prefrontal cortex (DLPFC). A significant (P<0.05) reduction in subsequent recall of new associations was seen only with TMS over the right DLPFC. This result suggests that the right DLPFC contributes to encoding of visual-object associations, and is consistent with a material-specific rather than a process-specific model of mnemonic function in DLPFC.

Enhanced in vivo Magnetic Resonance Imaging of Tumors by PEGylated Iron-Oxide-Gold Core-Shell Nanoparticles with Prolonged Blood Circulation Properties

High-density poly(ethylene glycol) (PEG)-coated iron-oxide-gold core-shell nanoparticles (AuIONs) were developed as T(2) -weighted magnetic resonance imaging (MRI) contrast agents for cancer imaging. The PEG-coated iron-oxide-gold core-shell nanoparticles (PEG-AuIONs) were approximately 25 nm in diameter with a narrow distribution. Biodistribution experiments in mice bearing a subcutaneous colon cancer model prepared with C26 murine colon adenocarcinoma cells showed high accumulation of the PEG-AuIONs within the tumor mass and low nonspecific accumulation in the liver and spleen, resulting in high specificity to solid tumors. T(2) -weighted MR images following intravenous injection of PEG-AuIONs showed selective negative enhancement of tumor tissue in an orthotopic pancreatic cancer model prepared with MiaPaCa-2 human pancreatic adenocarcinoma cells. These results indicate that PEG-AuIONs are a promising MRI contrast agent for diagnosis of malignant tumors, including pancreatic cancer.

Comparison of current distributions in electroconvulsive therapy and transcranial magnetic stimulation

We compared current density distributions in electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) by numerical calculations. The model consisted of an air region and three types of tissues with different conductivities representing the brain, the skull, and the scalp. In the ECT model, electric currents were applied through electrodes with a voltage of 100 V. In the TMS model, a figure-eight coil (6 cm diameter per coil) was placed on the vertex of the head model. An alternating current with a peak intensity of 3.0 kA and a frequency of 4.2 kHz was applied to the coil. The maximum current densities inside the brain in ECT (bilateral electrode position) and TMS were 234 and 322 A/m2, respectively. The results indicate that magnetic stimulators can generate comparable current densities to ECT. While the skull significantly affected current distributions in ECT, TMS efficiently induced eddy currents in the brain. In addition, TMS is more beneficial than ECT because the localized curren...

FEM-based determination of optimum current distribution in transcranial magnetic stimulation as an alternative to electroconvulsive therapy

In this study, we investigated dependences of the current distribution in transcranial magnetic stimulation (TMS) on coil current intensity, coil diameter, and coil position, and compared the current distribution with that of electroconvulsive therapy (ECT). The head model consisted of 4-mm finite elements. In the ECT model, a voltage of 100 V was applied between a pair of electrodes place on the tempora. In the TMS model, eddy current distributions were obtained for figure-eight coils with diameters of 50, 75, and 100 mm, and coil positions varied from the vertex to the forehead. The difference in current distributions in ECT and TMS decreased with the coil position approaching to the forehead. The coil of 100-mm diameter gave the minimum difference at a coil current of 87 kA. The difference decreased with an increase in the coil diameter.

A strain-absorbing design for tissue–machine interfaces using a tunable adhesive gel

To measure electrophysiological signals from the human body, it is essential to establish stable, gentle and nonallergic contacts between the targeted biological tissue and the electrical probes. However, it is difficult to form a stable interface between the two for long periods, especially when the surface of the biological tissue is wet and/or the tissue exhibits motion. Here we resolve this difficulty by designing and fabricating smart, stress-absorbing electronic devices that can adhere to wet and complex tissue surfaces and allow for reliable, long-term measurements of vital signals. We demonstrate a multielectrode array, which can be attached to the surface of a rat heart, resulting in good conformal contact for more than 3 h. Furthermore, we demonstrate arrays of highly sensitive, stretchable strain sensors using a similar design. Ultra-flexible electronics with enhanced adhesion to tissue could enable future applications in chronic in vivo monitoring of biological signals.

Inflammation-free, gas-permeable, lightweight, stretchable on-skin electronics with nanomeshes

Thin-film electronic devices can be integrated with skin for health monitoring and/or for interfacing with machines. Minimal invasiveness is highly desirable when applying wearable electronics directly onto human skin. However, manufacturing such on-skin electronics on planar substrates results in limited gas permeability. Therefore, it is necessary to systematically investigate their long-term physiological and psychological effects. As a demonstration of substrate-free electronics, here we show the successful fabrication of inflammation-free, highly gas-permeable, ultrathin, lightweight and stretchable sensors that can be directly laminated onto human skin for long periods of time, realized with a conductive nanomesh structure. A one-week skin patch test revealed that the risk of inflammation caused by on-skin sensors can be significantly suppressed by using the nanomesh sensors. Furthermore, a wireless system that can detect touch, temperature and pressure is successfully demonstrated using a nanomesh with excellent mechanical durability. In addition, electromyogram recordings were successfully taken with minimal discomfort to the user.

Enhanced magnetic resonance imaging of experimental pancreatic tumor in vivo by block copolymer-coated magnetite nanoparticles with TGF-β inhibitor

Early detection of solid tumors, particularly pancreatic cancer, is of substantial importance in clinics. Enhanced magnetic resonance imaging (MRI) with iron oxide nanoparticles is an available way to detect the cancer. The effective and selective accumulation of these nanoparticles in the tumor tissue is needed for improved imaging, and in this regard, their longevity in the blood circulation time is crucial. We developed here block copolymer-coated magnetite nanoparticles for pancreatic cancer imaging, by means of a chelation between the carboxylic acid groups in poly(ethylene glycol)-poly(aspartic acid) block copolymer (PEG-PAsp) and Fe on the surface of the iron oxide nanoparticles. These nanoparticles had considerably narrow distribution, even upon increased ionic strength or in the presence of fetal bovine serum. The PEG-PAsp-coated nanoparticles were further shown to be potent as a contrast agent for enhanced MRI for an experimental pancreatic cancer, xenografts of the human-derived BxPC3 cell line in BALB/c nude mice, with combined administration of TGF-beta inhibitor. Iron staining of tumor tissue confirmed the accumulation of the nanoparticles in tumor tissue. Use of the PEG-PAsp-coated magnetite nanoparticles, combined with the TGF-beta inhibitor, is of promising clinical importance for the detection of intractable solid cancers, including pancreatic cancer.