ITC-6102RO, a novel B7-H3 antibody-drug conjugate, exhibits potent therapeutic effects against B7-H3 expressing solid tumors.

BACKGROUND: The B7-H3 protein, encoded by the CD276 gene, is a member of the B7 family of proteins and a transmembrane glycoprotein. It is highly expressed in various solid tumors, such as lung and breast cancer, and has been associated with limited expression in normal tissues and poor clinical outcomes across different malignancies. Additionally, B7-H3 plays a crucial role in anticancer immune responses. Antibody-drug conjugates (ADCs) are a promising therapeutic modality, utilizing antibodies targeting tumor antigens to selectively and effectively deliver potent cytotoxic agents to tumors. METHODS: In this study, we demonstrate the potential of a novel B7-H3-targeting ADC, ITC-6102RO, for B7-H3-targeted therapy. ITC-6102RO was developed and conjugated with dHBD, a soluble derivative of pyrrolobenzodiazepine (PBD), using Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linkers with high biostability. We assessed the cytotoxicity and internalization of ITC-6102RO in B7-H3 overexpressing cell lines in vitro and evaluated its anticancer efficacy and mode of action in B7-H3 overexpressing cell-derived and patient-derived xenograft models in vivo. RESULTS: ITC-6102RO inhibited cell viability in B7-H3-positive lung and breast cancer cell lines, inducing cell cycle arrest in the S phase, DNA damage, and apoptosis in vitro. The binding activity and selectivity of ITC-6102RO with B7-H3 were comparable to those of the unconjugated anti-B7-H3 antibody. Furthermore, ITC-6102RO proved effective in B7-H3-positive JIMT-1 subcutaneously xenografted mice and exhibited a potent antitumor effect on B7-H3-positive lung cancer patient-derived xenograft (PDX) models. The mode of action, including S phase arrest and DNA damage induced by dHBD, was confirmed in JIMT-1 tumor tissues. CONCLUSIONS: Our preclinical data indicate that ITC-6102RO is a promising therapeutic agent for B7-H3-targeted therapy. Moreover, we anticipate that OHPAS linkers will serve as a valuable platform for developing novel ADCs targeting a wide range of targets.

Sulfonate Version of OHPAS Linker Has Two Distinct Pathways of Breakdown: Elimination Route Allows Para-Hydroxy-Protected Benzylsulfonate (PHP-BS) to Serve as an Alternative Self-Immolative Group.

Recently we have reported that the ortho-hydroxy-protected aryl sulfate (OHPAS) system can be exploited as a new self-immolative group (SIG) for phenolic payloads. We extended the system to nonphenolic payloads by simply introducing a para-hydroxy benzyl (PHB) spacer. As an additional variation of the system, we explored a benzylsulfonate version of the OHPAS system and found that it has two distinct breakdown pathways, cyclization and 1,4-elimination, the latter of which implies that para-hydroxy-protected (PHP) benzylsulfonate (BS) can also be used as an alternative SIG. The PHP-BS system was found to be stable chemically and in mouse and human plasma, having payload release rates comparable to those of the original OHPAS conjugates.

Aryl Sulfate is a Useful Motif for Conjugating and Releasing Phenolic Molecules: Sulfur Fluorine Exchange Click Chemistry Enables Discovery of Ortho-Hydroxy-Protected Aryl Sulfate Linker.

A new self-immolative linker motif, Ortho Hydroxy-Protected Aryl Sulfate (OHPAS), was devised, and OHPAS-containing antibody drug conjugates (ADC) were tested in vitro and in vivo. Conveniently synthesized using Sulfur Fluorine Exchange (SuFEx) chemistry, it is based structurally on diaryl sulfate, with one aryl acting as a payload and the other as a self-immolative sulfate unit having a latent phenol function at the ortho position. The chemically stable OHPAS linker was stable in plasma samples from 5 different species, yet it can release the payload molecule smoothly upon chemical or biological triggering. The payload release proceeds via intramolecular cyclization, producing a cyclic sulfate coproduct that eventually hydrolyzes to a catechol monosulfate. A set of OHPAS-containing ADCs based on Trastuzumab were prepared with a drug to antibody ratio of ∼2, and were shown to be cytotoxic in 5 different cancer cell lines in vitro and dose-dependently inhibited tumor growth in a NCI-N87 mouse xenograft model. We conclude that OHPAS conjugates will be of considerable use for delivering phenol-containing payloads to tissues targeted for medical intervention.

Introduction of Para-Hydroxy Benzyl Spacer Greatly Expands the Utility of Ortho-Hydroxy-Protected Aryl Sulfate System: Application to Nonphenolic Payloads.

The ortho-hydroxy-protected aryl sulfate (OHPAS) linker is composed of a diaryl sulfate backbone equipped with a latent phenol moiety at the ortho position of one of the aryl units. The Ar-OH released when the ortho phenol undergoes intramolecular cyclization and displaces the second aryl unit can be viewed as a payload. We have shown in the preceding paper that the OHPAS linkers are highly stable chemically and in various plasmas, yet release payloads when exposed to suitable triggering conditions. As an extension of the OHPAS system, we employed a para-hydroxy benzyl (PHB) spacer for coupling to nonphenolic payloads; this tactic again provided a highly stable system capable of smooth release of appended payloads. The PHB modification works beautifully for tertiary amine and N-heterocycle payloads.

A Multi-Functional CMOS Biosensor Array With On-Chip DEP-Assisted Sensing for Rapid Low-Concentration Analyte Detection and Close-Loop Particle Manipulation With No External Electrodes.

This article presents a fully-integrated dielectrophoresis (DEP)-assisted multi-functional CMOS biosensor array chip with 4096 working electrodes (WEs), 12288 photodiodes (PDs), reference electrodes (REs), and counter electrodes (CEs), while each WE and photodiode can be reconfigured to support on-chip DEP actuation, electrochemical potentiostat, optical shadow imaging, and complex impedance sensing. The proposed CMOS biosensor is an example of an actuation-assisted label-free biosensor for the rapid sensing of low-concentration analytes. The DEP actuator of the proposed CMOS biosensor does not require any external electrode. Instead, on-chip WE pairs can be re-used for DEP actuation to simplify the sensor array design. The CMOS biosensor is implemented in a standard 130-nm BiCMOS process. Theoretical analyses and finite element method (FEM) simulations of the on-chip DEP operations are conducted as proof of concept. Biological assay measurements (DEP actuation/electrochemical potentiostat/impedance sensing) with E.coli bacteria and microbeads (optical shadow imaging) demonstrate rapid detection of low-concentration analytes and simultaneous manipulation and detection of large particles. The on-chip DEP operations draw the analytes closer to the sensor electrode surface, which overcomes the diffusion limit and accelerates low-concentration analyte sensing. Moreover, the DEP-based movement of large particles can be readily detected by on-chip photodiode arrays to achieve close-loop manipulation and sensing of particles and droplets. These show the unique advantages of the DEP-assisted multi-functional biosensor.

Electrocatalytic effects of carbon dissolution in Pd nanoparticles.

Highly dispersed Pd nanoparticles were prepared by borohydride reduction of Pd(acac)(2) in 1,2-propanediol at an elevated temperature. They were uniformly dispersed on carbon black without significant aggregation. X-ray diffraction showed that carbons from the Pd precursor dissolved in Pd, increasing its lattice parameter. A modified reduction process was tested to remove the carbon impurities. Carbon removal greatly enhanced catalytic activity toward the oxygen reduction reaction. It also generated an inconsistency between the electronic modifications obtained from X-ray photoelectron spectroscopy and the electrochemical method. CO displacement measurements showed that the formation of Pd-C bonds decreased the work function of the surface Pd atoms.

Effect of ß-resin of binderless coke on mechanical properties of high-density carbon blocks at high molding pressure.

High-density carbon blocks have excellent mechanical, thermal, and electrical properties. In particular, these blocks are applied in various fields while maintaining excellent physical properties even in harsh environments. In this study, binderless coke manufactured under certain conditions was used to form green bodies (GBs) under various pressure conditions of 50 to 250 MPa, and the bodies were carbonized to form a high-density carbon block (CB). Then, the effect of the ß-resin and oxygen functional groups of binderless coke on the mechanical properties of the high-density carbon block according to molding pressure was considered. When molding at a pressure of under 200 MPa, the ratio of O and C (O/C) has a greater effect, and the larger the O/C, the higher the mechanical properties. On the other hand, when molding at a high pressure of 250 MPa, the ß-resin content has a greater effect and steadily increases when the ß-resin content is low and when the mechanical properties are sufficiently reduced. In particular, in the case of CB-N7A3-250, which has the highest ß-resin content of 3.7 wt%, the density was 1.79 g/cm3, the flexural strength was 106 MPa, and the shore hardness was 99 HSD.

A Multimodal and Multifunctional CMOS Cellular Interfacing Array for Digital Physiology and Pathology Featuring an Ultra Dense Pixel Array and Reconfigurable Sampling Rate.

The article presents a fully integrated multimodal and multifunctional CMOS biosensing/actuating array chip and system for multi-dimensional cellular/tissue characterization. The CMOS chip supports up to 1,568 simultaneous parallel readout channels across 21,952 individually addressable multimodal pixels with 13 µm × 13 µm 2-D pixel pitch along with 1,568 Pt reference electrodes. These features allow the CMOS array chip to perform multimodal physiological measurements on living cell/tissue samples with both high throughput and single-cell resolution. Each pixel supports three sensing and one actuating modalities, each reconfigurable for different functionalities, in the form of full array (FA) or fast scan (FS) voltage recording schemes, bright/dim optical detection, 2-/4-point impedance sensing (ZS), and biphasic current stimulation (BCS) with adjustable stimulation area for single-cell or tissue-level stimulation. Each multi-modal pixel contains an 8.84 µm × 11 µm Pt electrode, 4.16 µm × 7.2 µm photodiode (PD), and in-pixel circuits for PD measurements and pixel selection. The chip is fabricated in a standard 130nm BiCMOS process as a proof of concept. The on-chip electrodes are constructed by unique design and in-house post-CMOS fabrication processes, including a critical Al shorting of all pixels during fabrication and Al etching after fabrication that ensures a high-yield planar electrode array on CMOS with high biocompatibility and long-term measurement reliability. For demonstration, extensive biological testing is performed with human and mouse progenitor cells, in which multidimensional biophysiological data are acquired for comprehensive cellular characterization.

Preparation of mesoporous carbon-carbon nanotube composites using the template method.

Reported herein is a simple template method for preparing mesoporous carbons (MPCs) from a mesophase pitch, using homemade nano-sized MgOs and MgO-carbon nanotube (CNT) composites as templates. Nano-sized MgO particles containing iron-molybdenum were synthesized through the heat treatment of the precursor ash, and the MgO-CNT composites were prepared via catalytic chemical vapor deposition of CH4 over the MgO-based particles. MPCs with a high surface area of 443-578 m2/g were obtained through the heat treatment of well-mixed mesophase pitch-MgO (or MgO-CNT), followed by mild-acid treatment to remove the MgO and other catalyst components. All the materials (the precursors, nano-particles, and MPCs) were analyzed via powder X-ray diffraction, N2 adsorption-desorption isotherms, scanning electron microscopy, and high resolution transmission electron microscopy. The formation of the pore structure in the MPCs is discussed, and the potential application of the MPC-CNT composite is demonstrated through cyclic voltammetry.

Characteristics of porous carbon nano-fibers synthesized by selective catalytic gasification.

Carbon nanofibers (CNFs) with uniquely oriented channels were prepared via selective catalytic gasification in air at 450 and 500 degrees C, using Pt or Ru nano particles as catalysts. Catalytic gasification was chosen because it can selectively generate channels in the vicinity of the catalyst particles at relatively low temperatures, where thermal oxidation does not intensively occur. The structures and surface properties of the CNFs were examined via X-ray diffraction, analysis of the nitrogen adsorption-desorption isotherms, and high-resolution transmission electron microscopy. The effects of the catalyst species and loading amount on the formation of pores (channels) were investigated. The gasification mechanism, especially the channeling direction, throught the selection of the gasification catalysts, is discussed based on the results. This process can be effectively utilized for preparation of porous carbons, which have a well-aligned graphitic structure, and also channel-type pores can be designed by selection of gasification catalysts and conditions. The present porous CNF can be applied for catalyst support in fuel cells, without further treatment (e.g., acid treatment for the removal of metallic components).

Study on the water flooding in the cathode of direct methanol fuel cells.

Water flooding phenomena in the cathode of direct methanol fuel cells were analyzed by using electrochemical impedance spectroscopy. Two kinds of commercial gas diffusion layers with different PTFE contents of 5 wt% (GDL A5) and 20 wt% (GDL B20) were used to investigate the water flooding under various operating conditions. Water flooding was divided into two types: catalyst flooding and backing flooding. The cathode impedance spectra of each gas diffusion layer was obtained and compared under the same conditions. The diameter of the capacitive semicircle became larger with increasing current density for both, and this increase was greater for GDL B20 than GDL A5. Catalyst flooding is dominant and backing flooding is negligible when the air flow rate is high and current density is low. An equivalent model was suggested and fitted to the experimental data. Parameters for catalyst flooding and backing flooding were individually obtained. The capacitance of the catalyst layer decreases as the air flow rate decreases when the catalyst flooding is dominant.

Electrochemical catalytic activity for oxygen reduction reaction of nitrogen-doped carbon nanofibers.

The electrocatalytic activity of nitrogen-doped carbon nanofibers (N-CNFs), which are synthesized directly from vaporized acetonitrile over nickel-iron based catalysts, for oxygen reduction reaction (ORR), was investigated. The nitrogen content and specific surface area of N-CNFs can be controlled through the synthesis temperature (300-680 degrees C). The graphitization degree of N-CNFs also are significantly affected by the temperature, whereas the chemical compositions of nitrogen species are similar irrespective of the synthesis conditions. From measurement of the electrochemical double layer capacitance, the surface of N-CNFs is found to have stronger interaction with ions than undoped-carbon surfaces. Although N-CNFs show higher over-potential than Pt catalysts do, N-CNFs were observed to have a noticeable ORR activity, as opposed to the carbon samples without nitrogen doping. The activity dependency of N-CNFs on the content of the nitrogen with which they were doped is discussed, based on the experiment results. The single cell of the direct methanol fuel cell (DMFC) was tested to investigate the performance of a membrane-electrode assembly that includes N-CNFs as the cathode catalyst layer.

Surface oxidation of petroleum pitch to improve mesopore ratio and specific surface area of activated carbon.

In this study, surface oxidation of petroleum pitch was performed to enhance the thermal stability, specific surface area, and mesopore ratio of activated carbon. The oxygen uptake of the pitch by surface oxidation has a strong influence on the formation of the specific surface area and pore size of activated carbon. It was confirmed that the oxygen uptake from the surface to the inner side of the surface oxidized pitch was the highest at the temperature of 330 °C (IP330-AC), with a mesopore ratio of 63.35% and specific surface area of 1811 m2 g-1. The oxygen content of the surface oxidized pitch increased proportionately with the mesopore ratio in activated carbon. The specific surface area and mesopore ratio of IP330-AC were respectively 163% and 487% higher than those of petroleum-based commercial activated carbon (A-BAC), and 102% and 491% higher than those of coconut-based commercial activated carbon (P60).

Preparation of Isotropic Carbon Fibers from Kerosene-Purified Coal Tar Pitch by Co-Carbonization with Pyrolysis Fuel Oil.

An inexpensive and general-purpose carbon fiber was prepared using coal tar pitch. In contrast to the solvent extraction process employing expensive solvents, a low-cost centrifugal separation method facilitated the reduction of loss due to the pitch purification and an overall yield increase. The coal tar pitch purified by centrifugation and subsequently co-carbonized with pyrolysis fuel oil improved in spinnability. Moreover, the resulting spinnable pitch had a softening point of 250 °C. The obtained carbon fibers were heat-treated at 1000 °C for 5 min, resulting in a tensile strength of approximately 1000 MPa and an average diameter of 9 µm. In this study, we present an effective method for obtaining low-cost general-purpose isotropic carbon fibers.

The Effect of Oxygen Content in Binderless Cokes for High-Density Carbon Blocks from Coal Tar Pitch.

High-density carbon blocks are much lighter than metals and have excellent mechanical properties and are one of the materials garnering attention to replace existing metal parts. In this study, a binderless coke was produced by changing the flow rates of nitrogen and air as a carrier gas during heat treatment of coal tar pitch and using this, a green body was formed at 150 MPa and carbonized to produce a high-density carbon block. We express the binderless coke produced in this way by N10A0, N7A3, N5A5, N3A7, N0A10 according to the ratio of nitrogen and air, and in the case of carbon block, we have added CB in front of it. We then considered the effect of oxygen content in the binderless cokes on the optical, chemical, and mechanical properties. It was observed that the produced binderless cokes develop into a dense mosaic structure with a small particle size as the air flow rate increased. To survey the change in oxygen content of the produced binderless coke, O1s and C1s regions were measured using X-ray photoelectric spectroscopy (XPS), and O1s/C1s was calculated. The O1s/C1s ratio steadily increased as the air flow rate increased, and in the case of N0A10, it increased about twice as much as that of N10A0 to 11.20%. ß-resin has a very large effect on the mechanical strength of the carbon block in addition to air in the pitch. And in the case of CB-N0A10, it shows the best mechanical strength with a density of 1.72 g/cm3, bending strength of 87 MPa, and shore hardness of 93 HSD.

A CMOS Multi-Modal Electrochemical and Impedance Cellular Sensing Array for Massively Paralleled Exoelectrogen Screening.

The paper presents a 256-pixel CMOS sensor array with in-pixel dual electrochemical and impedance detection modalities for rapid, multi-dimensional characterization of exoelectrogens. The CMOS IC has 16 parallel readout channels, allowing it to perform multiple measurements with a high throughput and enable the chip to handle different samples simultaneously. The chip contains a total of 2 × 256 working electrodes of size 44 µm × 52 µm, along with 16 reference electrodes of dimensions 56 µm × 399 µm and 32 counter electrodes of dimensions 399 µm × 106 µm, which together facilitate the high resolution screening of the test samples. The chip was fabricated in a standard 130nm BiCMOS process. The on-chip electrodes are subjected to additional fabrication processes, including a critical Al-etch step that ensures the excellent biocompatibility and long-term reliability of the CMOS sensor array in bio-environment. The electrochemical sensing modality is verified by detecting the electroactive analyte NaFeEDTA and the exoelectrogenic Shewanella oneidensis MR-1 bacteria, illustrating the chip's ability to quantify the generated electrochemical current and distinguish between different analyte concentrations. The impedance measurements with the HEK-293 cancer cells cultured on-chip successfully capture the cell-to-surface adhesion information between the electrodes and the cancer cells. The reported CMOS sensor array outperforms the conventional discrete setups for exoelectrogen characterization in terms of spatial resolution and speed, which demonstrates the chip's potential to radically accelerate synthetic biology engineering.

Ionic-liquid-assisted sonochemical synthesis of carbon-nanotube-based nanohybrids: control in the structures and interfacial characteristics.

A versatile, facile, and rapid synthetic method of advanced carbon nanotube (CNT)-based nanohybrid fabrication, or the so-called ionic-liquid-assisted sonochemical method (ILASM), which combines the supramolecular chemistry between ionic liquids (ILs) and CNTs with sonochemistry for the control in the size and amount of uniformly decorated nanoparticles (NPs) and interfacial engineering, is reported. The excellence in electrocatalysis of hybrid materials with well-designed nanostructures and favorable interfaces is demonstrated by applying them to electrochemical catalysis. The synthetic method discussed in this report has an important and immediate impact not only on the design and synthesis of functional hybrid nanomaterials by supramolecular chemistry and sonochemistry but also on applications of the same into electrochemical devices such as sensors, fuel cells, solar cells, actuators, batteries, and capacitors.

Electrode-Electrolyte Interface Impedance Characterization of Ultra-Miniaturized Microelectrode Arrays Over Materials and Geometries for Sub-Cellular and Cellular Sensing and Stimulation.

Electrochemical interfaces with low-impedance, high biocompatibility, and long-term stability are of paramount importance for microelectrode arrays (MEAs), that are widely used in numerous cellular sensing/stimulation applications, e.g., brain interface, electroceuticals, neuroprosthetics, drug discovery, chemical screening, and fundamental biological research. It is becoming increasingly critical since sensing/actuations at sub-cellular resolution necessitate ultra-miniaturized electrodes, which exhibit exacerbated electrochemical interfaces, especially on interfacial impedance. This paper reports the first comprehensive characterization and interfacial electrochemical impedance spectroscopy (EIS) of the ultra-miniaturized electrodes for different electrode sizes ( 8×8 µm2 , 16×16 µm2 , and 32×32 µm2 ) and a wide material collection (Au, Pt, TiN, and ITO). Equivalent electrochemical interfacial circuit models with interface capacitance, charge transfer resistance, and solution resistance are obtained for all the electrode designs based on their EIS measurements. The results can potentially guide the designs of ultra-miniaturized MEAs for future bioelectronics systems.

Manufacture of high density carbon blocks by self-sintering coke produced via a two-stage heat treatment of coal tar.

High-strength and high-density carbonized carbon blocks from self-sintering coke were manufactured using coal tar and two-stage heat treatments (1st and 2nd stage treatments). First, the molecular weight distribution of the refined coal tar was controlled through a pressured heat treatment (1st stage treatment). Second, the 1st stage heat-treated coal tar (1S-CT) was treated using a delayed coking system (2nd stage treatment) to become the self-sintering coke. Finally, carbon blocks were molded from 2nd stage heat-treated coke (2S-C) and carbonized at 1200 °C for 1 h. Through rapid decomposition of the high molecular weight components in the coal tar at 360 °C in the 1st stage treatment, the molecular weight distribution of coal tar was confirmed to be controllable by the 1st stage treatment. Swelling during carbonization was observed in carbon blocks manufactured from 2S-C containing more than 15 wt% of volatile matter from 150-450 °C. The optimum conditions of the two-stage heat treatments were confirmed to be 300 °C for 3 h and 500 °C for 1 h. The highest density and flexural strength of the carbonized carbon blocks manufactured from 2S-C were 1.46 g/cm3 and 69.2 MPa, respectively.

Mechanical and electrical properties of MCMB/Chopped carbon fiber composite with different bead size.

The carbonization and graphitization of carbon/carbon (C/C) composites prepared from mesocarbon microbeads (MCMB) and chopped carbon fiber (CCF) have been studied with a wide range of temperatures, CCF contents and MCMB sizes. Three different sizes of MCMB were prepared with coal tar pitch at three temperatures, 420, 430 and 440 °C, and identified as about 12.8, 16.0 and 20.1 µm, respectively. Each size of MCMB was mixed with CCFs at ratios of 2, 4, 6 and 8 wt. % and formed into block shape. After carbonization at 1200 °C, carbonized C/C blocks (CCBs) were graphitized at 2000, 2400 and 2800 °C. The CCB prepared with CCF content of 2 wt. % and an MCMB size of 16.0 µm exhibited the highest flexural strength of about 151 MPa. The graphitized C/C block (GCB) with CCF content of 2 wt. %, which was graphitized at 2000 °C showed the highest flexural strength of about 159 MPa.