Measuring Human Auditory Evoked Fields with a Flexible Multi-Channel OPM-Based MEG System.

BACKGROUND: Magnetoencephalography (MEG) is a non-invasive imaging technique for directly measuring the external magnetic field generated from synchronously activated pyramidal neurons in the brain. The optically pumped magnetometer (OPM) is known for its less expensive, non-cryogenic, movable and user-friendly custom-design provides the potential for a change in functional neuroimaging based on MEG. METHODS: An array of OPMs covering the opposite sides of a subject's head is placed inside a magnetically shielded room (MSR) and responses evoked from the auditory cortices are measured. RESULTS: High signal-to-noise ratio auditory evoked response fields (AEFs) were detected by a wearable OPM-MEG system in a MSR, for which a flexible helmet was specially designed to minimize the sensor-to-head distance, along with a set of bi-planar coils developed for background field and gradient nulling. Neuronal current sources activated in AEF experiments were localized and the auditory cortices showed the highest activities. Performance of the hybrid optically pumped magnetometer-magnetoencephalography/electroencephalography (OPM-MEG/EEG) system was also assessed. CONCLUSIONS: The multi-channel OPM-MEG system performs well in a custom built MSR equipped with bi-planar coils and detects human AEFs with a flexible helmet. Moreover, the similarities and differences of auditory evoked potentials (AEPs) and AEFs are discussed, while the operation of OPM-MEG sensors in conjunction with EEG electrodes provides an encouraging combination for the exploration of hybrid OPM-MEG/EEG systems.

Identification and characterization of endogenous biomarkers for hepatic vectorial transport (OATP1B3-P-gp) function using metabolomics with serum pharmacology.

The organic anion-transporting polypeptide 1B3 and P-glycoprotein (P-gp) provide efficient directional transport (OATP1B3-P-gp) from the blood to the bile that serves as a key determinant of hepatic disposition of the drug. Unfortunately, there is still a lack of effective means to evaluate the disposal ability mediated by transporters. The present study was designed to identify a suitable endogenous biomarker for the assessment of OATP1B3-P-gp function in the liver. We established stably transfected HEK293T-OATP1B3 and HEK293T-P-gp cell lines. Results showed that azelaic acid (AzA) was an endogenous substrate for OATP1B3 and P-gp using serum pharmacology combined with metabolomics. There is a good correlation between the serum concentration of AzA and probe drugs of rOATP1B3 and rP-gp when rats were treated with their inhibitors. Importantly, after 5-fluorouracil-induced rat liver injury, the relative mRNA level and expression of rOATP1B3 and rP-gp were markedly down-regulated in the liver, and the serum concentration of AzA was significantly increased. These observations suggest that AzA is an endogenous substrate of both OATP1B3 and P-gp, and may serve as a potential endogenous biomarker for the assessment of the function of OATP1B3-P-gp for the prediction of changes in the pharmacokinetics of drugs transported by OATP1B3-P-gp in liver disease states.

Detection and analysis of MEG signals in occipital region with double-channel OPM sensors.

BACKGROUND: Magnetoencephalography (MEG) has high temporal and spatial resolution and good spatial accuracy in determining the locations of source activity among most non-invasive imaging. The recently developed technology of optically-pumped magnetometer (OPM) has sensitivity comparable to that of the superconducting quantum interference device (SQUID) used in commercial MEG system. NEW METHOD: Double-channel OPM-MEG system detects human photic blocking of alpha rhythm at the occipital region of skull in the magnetically shielded environment via a wearable whole-cortex 3D-printed helmet. RESULTS: The alpha rhythm can be detected by the OPM-MEG system, the MEG signals are undoubtedly caused by photic blocking and similar with the results measured by SQUID magnetometer. COMPARISON WITH EXISTING METHODS: Due to the dependency of current commercial whole-cortex SQUID-MEG system on the liquid helium, the separation from the liquid helium space to the human head is usually at least a few centimeters. The wearable OPM-MEG system, however, can significantly improve the detection efficiency since its sensors can be mounted close to scalp, normally less than 1 cm. CONCLUSIONS: OPM-MEG system successfully detects alpha rhythm blocked by light stimulation and works well in the home-made magnetically shielded environment. OPM-MEG system shows a substitute for the traditional MEG system.

pH-sensitive MOF integrated with glucose oxidase for glucose-responsive insulin delivery.

Glucose-responsive insulin delivery system mimicking the function of pancreatic ß-cells to maintain blood glucose homeostasis would effectively alleviate diabetes. Here, a new glucose-responsive delivery (ZIF@Ins&GOx) for self-regulated insulin release was constructed by encapsulating insulin and glucose oxidase (GOx) into pH-sensitive zeolitic imidazole framework-8 (ZIF-8) nanocrystals. After entering the cavities of ZIF-8, glucose can be oxidized into gluconic acid by GOx, causing a decrease in local pH. Then, ZIF-8 nanocrystals would be degraded under the acidic microenvironment that in turn triggers the release of insulin in a glucose responsive fashion. In vitro studies indicated that the biological activity of insulin could be protected by the rigid structure of ZIF-8 and the release of insulin could be modulated in response to glucose concentrations. In vivo experiments demonstrated that a single subcutaneous injection of the ZIF@Ins&GOx would facilitate the stabilization of blood glucose level of normoglycemic state for up to 72 h in type 1 diabetes (T1D). The multifunctional insulin delivery system shows a new proof-of-concept for T1D treatment by using ZIF-8 nanocrystals loaded with insulin and enzyme.

Cytomembrane-Mediated Transport of Metal Ions with Biological Specificity.

Metal ions are of significant importance in biomedical science. This study reports a new concept of cytomembrane-mediated biospecific transport of metal ions without using any other materials. For the first time, cytomembranes are exploited for two-step conjugation with metal ions to provide hybrid nanomaterials. The innate biofunction of cell membranes renders the hybrids with superior advantages over common vehicles for metal ions, including excellent biocompatibility, low immunogenic risk, and particularly specific biotargeting functionality. As a proof-of-concept demonstration, cancer cell membranes are used for in vivo delivery of various metal ions, including ruthenium, europium, iron, and manganese, providing a series of tumor-targeted nanohybrids capable of photothermal therapy/imaging, magnetic resonance imaging, photoacoustic imaging, and fluorescence imaging with improved performances. In addition, the special structure of the cell membrane allows easy accommodation of small-molecular agents within the nanohybrids for effective chemotherapy. This study provides a new class of metal-ion-included nanomaterials with versatile biofunctions and offers a novel solution to address the important challenge in the field of in vivo targeted delivery of metal ions.

Artificially Reprogrammed Macrophages as Tumor-Tropic Immunosuppression-Resistant Biologics to Realize Therapeutics Production and Immune Activation.

To engineer patient-derived cells into therapy-purposed biologics is a promising solution to realize personalized treatments. Without using gene-editing technology, a live cell-typed therapeutic is engineered for tumor treatment by artificially reprogramming macrophages with hyaluronic acid-decorated superparamagnetic iron oxide nanoparticles (HIONs). This nanoparticle-assisted cell-reprogramming strategy demonstrates profound advantages, due to the combined contributions from the biological regulation of HIONs and the intrinsic nature of macrophages. Firstly, the reprogrammed macrophages present a substantial improvement in their innate capabilities, such as more effective tumor targeting and more efficient generation of bioactive components (e.g., reactive oxygen species, bioactive cytokines) to suppress tumor growth. Furthermore, this cell therapeutic exhibits cytostatic/proapoptotic effects specific to cancer cells. Secondly, HIONs enable macrophages more resistant to the intratumoral immunosuppressive environment. Thirdly, the macrophages are endowed with a strong ability to prime in situ protumoral M2 macrophages into antitumor M1 phenotype in a paracrine-like manner. Consequently, a synergistic tumor-inhibition effect is achieved. This study shows that engineering nanomaterial-reprogrammed live cells as therapeutic biologics may be a more preferable option to the commonly used approaches where nanomaterials are administrated to induce bioresponse of certain cells in vivo.

A self-delivery system based on an amphiphilic proapoptotic peptide for tumor targeting therapy.

In recent decades, drug self-delivery systems (DSDSs) have appeared with extraordinary superiority for cancer therapy while realizing intracellular delivery without supererogatory drug carriers. Here, we have designed and programmed a novel self-delivery system to realize tumor targeting therapy. The amphiphilic proapoptotic peptide KLAKLAKKLAKLAKGCK(Fmoc)2 (KLA) was used to form a self-assembled structure (KD) by encapsulating the hydrophobic anticarcinogen doxorubicin (DOX). Then, tumor recognizing hyaluronic acid (HA) was coated on the surface of KD to obtain a tumor targeting self-delivery system (KDH). The protective layer of HA could protect the therapeutic agents from being inactivated during blood circulation, and further specifically recognize tumor cells by the CD44 receptor after KDH had located the tumor regions. Additionally, hyaluronidase (HAase) overexpressed in the endosome of tumor cells could degrade the protective layer of HA and accelerate the liberation of KLA and DOX. The proapoptotic peptide KLA had the ability to locate mitochondria and induce mitochondrial dysfunction; meanwhile the anticarcinogen DOX diffused to the nuclei to inhibit the growth of tumor cells. Both in vitro and in vivo studies identified that our self-delivery system KDH possessed precise tumor targeting, and exhibited fantastic antitumor efficacy as well as negligible side effects.

Tumor Starvation Induced Spatiotemporal Control over Chemotherapy for Synergistic Therapy.

By integrating the characteristics of each therapy modality and material chemistry, a multitherapy modality is put forward: tumor starvation triggered synergism with sensitized chemotherapy. Following starvation-induced amplification of pathological abnormalities in tumors, chemotherapy is arranged to be locally activated and accurately reinforced to perfect multitherapy synergism from spatial and temporal perspectives. To this end, glucose oxidase (GOD) and a hypoxic prodrug of tirapazamine (TPZ) are loaded in acidity-decomposable calcium carbonate (CaCO3 ) nanoparticles concurrently tethered by hyaluronic acid. This hybrid nanotherapeutic shows a strong tendency to accumulate in tumors postinjection due to the cooperation between passive and active targeting mechanisms. The GOD-driven oxidation reaction deprives tumors of glucose for starvation therapy and concomitantly induces tumorous abnormality amplifications including elevated acidity and exacerbated hypoxia. Programmatically, the acidity amplification causes CaCO3 decomposition, offering not only spatial control over the liberation of embedded TPZ just within tumors but also the temporal control over timely chemotherapy initiation to match the occurrence of hypoxia amplification and thus benefiting perfect synergism between starvation therapy and chemotherapy.

Aggressive Man-Made Red Blood Cells for Hypoxia-Resistant Photodynamic Therapy.

Extreme hypoxia of tumors represents the most notable barrier against the advance of tumor treatments. Inspired by the biological nature of red blood cells (RBCs) as the primary oxygen supplier in mammals, an aggressive man-made RBC (AmmRBC) is created to combat the hypoxia-mediated resistance of tumors to photodynamic therapy (PDT). Specifically, the complex formed between hemoglobin and enzyme-mimicking polydopamine, and polydopamine-carried photosensitizer is encapsulated inside the biovesicle that is engineered from the recombined RBC membranes. The mean corpuscular hemoglobin of AmmRBCs reaches about tenfold as high as that of natural RBCs. Owing to the same origin of outer membranes, AmmRBCs share excellent biocompatibility with parent RBCs. The introduced polydopamine plays the role of the antioxidative enzymes existing inside RBCs to effectively prevent the oxygen-carrying hemoglobin from the oxidation damage during the circulation. This biomimetic engineering can accumulate in tumors, permit in situ efficient oxygen supply, and impose strong PDT efficacy toward the extremely hypoxic tumor with complete tumor elimination. The man-made pseudo-RBC shows potentials as a universal oxygen-self-supplied platform to sensitize hypoxia-limited tumor treatment means, including but not limited to PDT. Meanwhile, this study offers ideas to the production of artificial substitutes of packed RBCs for clinical blood transfusion.

Virus-Inspired Nanogenes Free from Man-Made Materials for Host-Specific Transfection and Bio-Aided MR Imaging.

Many viruses have a lipid envelope derived from the host cell membrane that contributes much to the host specificity and the cellular invasion. This study puts forward a virus-inspired technology that allows targeted genetic delivery free from man-made materials. Genetic therapeutics, metal ions, and biologically derived cell membranes are nanointegrated. Vulnerable genetic therapeutics contained in the formed "nanogene" can be well protected from unwanted attacks by blood components and enzymes. The surface envelope composed of cancer cell membrane fragments enables host-specific targeting of the nanogene to the source cancer cells and homologous tumors while effectively inhibiting recognition by macrophages. High transfection efficiency highlights the potential of this technology for practical applications. Another unique merit of this technology arises from the facile combination of special biofunction of metal ions with genetic therapy. Typically, Gd(III)-involved nanogene generates a much higher T1 relaxation rate than the clinically used Gd magnetic resonance imaging agent and harvests the enhanced MRI contrast at tumors. This virus-inspired technology points out a distinctive new avenue for the disease-specific transport of genetic therapeutics and other biomacromolecules.

Double-Targeting Explosible Nanofirework for Tumor Ignition to Guide Tumor-Depth Photothermal Therapy.

This study reports a double-targeting "nanofirework" for tumor-ignited imaging to guide effective tumor-depth photothermal therapy (PTT). Typically, ≈30 nm upconversion nanoparticles (UCNP) are enveloped with a hybrid corona composed of ≈4 nm CuS tethered hyaluronic acid (CuS-HA). The HA corona provides active tumor-targeted functionality together with excellent stability and improved biocompatibility. The dimension of UCNP@CuS-HA is specifically set within the optimal size window for passive tumor-targeting effect, demonstrating significant contributions to both the in vivo prolonged circulation duration and the enhanced size-dependent tumor accumulation compared with ultrasmall CuS nanoparticles. The tumors featuring hyaluronidase (HAase) overexpression could induce the escape of CuS away from UCNP@CuS-HA due to HAase-catalyzed HA degradation, in turn activating the recovery of initially CuS-quenched luminescence of UCNP and also driving the tumor-depth infiltration of ultrasmall CuS for effective PTT. This in vivo transition has proven to be highly dependent on tumor occurrence like a tumor-ignited explosible firework. Together with the double-targeting functionality, the pathology-selective tumor ignition permits precise tumor detection and imaging-guided spatiotemporal control over PTT operation, leading to complete tumor ablation under near infrared (NIR) irradiation. This study offers a new paradigm of utilizing pathological characteristics to design nanotheranostics for precise detection and personalized therapy of tumors.

A self-delivery membrane system for enhanced anti-tumor therapy.

Nowadays, cell membrane targeting therapy has drawn much attention for its high anti-tumor effect by avoiding the cellular barriers. In this study, therapeutic agent conjugated chimeric peptide (Cp) was anchored in cracked cancer cell membranes (CCCM) to construct a self-delivery membrane system (M-Cp), which could relize precise cell membrane targeting therapy. It was found that compared with Cp, M-Cp could target to the cancer cell membrane with longer retention time, which is very crucial for in vivo applications. And the superior cell membrane targeting ability was attributed to the specific proteins (focal adhesion proteins, focal adhesion kinase, RHO family proteins, and integrin) on the CCCM surface. Importantly, the M-Cp could promote tumor-specific immune response, which further enhanced anti-tumor effect when combined with therapeutic agents in M-Cp. What's more, this self-delivery membrane system could be used as a template for cell membrane targeting therapy by changing the therapeutic agents as well as the CCCM, and this strategy would open a new window for various cell membrane targeting therapy.

A biomimetic theranostic O2-meter for cancer targeted photodynamic therapy and phosphorescence imaging.

In this report, a biomimetic theranostic oxygen (O2)-meter (cancer cell membrane@Pt(II) porphyrinic-metal organic framework, designated as mPPt) was constructed for cancer targeted and phosphorescence image-guided photodynamic therapy (PDT). mPPt presents high photosensitizers (PSs) loading and evitable self-quenching behaviors for favorable biological O2 sensing and PDT. Besides, endowed by the surface functionalization of cancer cell membrane, the homotypic targeting and immune escape abilities of mPPt could dramatically enhance its cancer targeting ability. Importantly, the O2-dependent phosphorescence responsibility of mPPt could be employed to pre-evaluate the real time O2 level in situ and guide the PDT under light irradiation. A significant anticancer effect is observed after intravenous injection of mPPt and subsequent treatment with PDT with no obvious side effects. As a versatile platform for cell imaging, O2 fluctuation monitoring as well as PDT, this biomimetic O2-meter exhibits great potential for biological analysis and personalized cancer theranostics.

Universal Porphyrinic Metal-Organic Framework Coating to Various Nanostructures for Functional Integration.

A universal strategy was reported that enables functional group-capped nanostructures with various morphologies and compositions to be coated by porphyrin metal-organic framework (MOF). Based on the nanostructure-induced heterogeneous nucleation, the controlled growth of MOF shell on the surface of nanostructures can be realized. It was demonstrated that this modification strategy can realize controlled growth of porphyrin MOF on a series of organic and inorganic nanostructures, such as polydopamine (PDA) nanoparticles, PDA@Pt nanoparticles, graphene oxide sheets, and Au nanorods. The as-prepared composites exhibit excellent catalytic and optical properties that originate from the nanostructure as well as the coated porphyrin MOF. We further explored the potential applications of PDA@MOF and PDA@Pt@MOF in nanomedicine and photocatalysis.

Preferential Cancer Cell Self-Recognition and Tumor Self-Targeting by Coating Nanoparticles with Homotypic Cancer Cell Membranes.

The ultimate goal in cancer therapy and diagnosis is to achieve highly specific targeting to cancer cells. Coated with the source cancer cell membrane specifically derived from the homologous tumors, the nanoparticles are identified with the self-recognition internalization by the source cancer cell lines in vitro and the highly tumor-selective targeting "homing" to the homologous tumor in vivo even in the competition of another heterologous tumor. As the result, MNP@DOX@CCCM nanovehicle showed strong potency for tumor treatment in vivo and the MR imaging. This bioinspired strategy shows great potential for precise therapy/diagnosis of various tumors merely by adjusting the cell membrane source accordingly on the nanoparticle surface.