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Introduction Nasopharyngeal carcinoma (NPC) is a common cancer in southern China and Taiwan, and radiation therapy combined with or without chemotherapy is its mainstay treatment. Although it is highly sensitive to radiotherapy, local recurrence and distant metastasis remain difficult unsolved problems. In recent years, graphene oxide (GO) has been found to be a promising novel anticancer drug carrier. Here, we present our designed functionalized GO, polyethylene glycol-coated GO (GO-PEG), as a drug carrier, which was loaded with erlotinib and showed promising anticancer effects on NPC cells. Methods The effects of GO-PEG-erlotinib on the proliferation, migration, and invasion of NPC cells were investigated by WST-8 assay, wound healing assay, and invasion assay, respectively. RNA sequencing was conducted and analyzed to determine the molecular mechanisms by which GO-PEG-erlotinib affects NPC cells. Results Our results showed that GO-PEG-erlotinib reduced NPC cell viability in a dose-dependent manner and also inhibited the migration and invasion of NPC cells. The RNA sequencing revealed several related molecular mechanisms. Conclusion GO-PEG-erlotinib effectively suppressed NPC cell proliferation, migration, and invasion, likely by several mechanisms. GO-PEG-erlotinib may be a potential therapeutic agent for treating NPC in the future.

Background This report presents the third case of trochlear schwannoma arising from the pineal region and the first case to be resected using a paramedian infratentorial supracerebellar approach. Schwannomas of cranial nerves have traditionally been thought to arise from the transitional point where the axonal envelopment switches from glial cells to Schwann cells; however, recent temporal bone histopathologic evidence from vestibular schwannomas challenges this view. Of the 38 cases of pathology-confirmed trochlear schwannoma in the literature, there are only 2 cases arising from the pineal region, where the nerve sheath transition zone is located. Here, we discuss an unusual case of trochlear schwannoma arising from this transition zone. Case Description A 65-year-old man was admitted to our institute after a traffic accident. He complained of headache and dizziness, and a computed tomography scan revealed an isodense mass in the pineal region with obstructive hydrocephalus. Magnetic resonance imaging with contrast showed an enhancing mass in the pineal region. The tumor was subtotally resected using a paramedian infratentorial supracerebellar approach, and pathology confirmed the diagnosis of trochlear schwannoma. Conclusions Trochlear schwannoma should be considered when a mass is identified in the pineal region. This diagnosis should still be entertained for mass lesions along the free tentorial edge because the tumor may arise distant from the glial-Schwann transition zone located by the dorsal midbrain. We propose a treatment algorithm for this rare tumor that seeks to maximize functional outcome.

Conventional treatment for treating primary central nervous system lymphoma (PCNSL) has consisted of either whole-brain radiotherapy (WBRT) or methotrexate (MTX)-based combined modality therapy. However, delayed cognitive sequelae have emerged as a significant debilitating complication in PCNSL patients. A prospective observational case-series study with prospective assessments of neurocognitive functions (NCFs), neuroimaging, and activities of daily living in newly-diagnosed PCNSL patients was undertaken. A battery of neuropsychological measures, used to evaluate NCFs, is composed of ten standardized NCF tests, representing four domains sensitive to disease and treatment effects (executive function, attention, verbal memory, psychomotor speed), and activities of daily living. A total of 15 patients with newly-diagnosed PCNSL were consecutively enrolled in this study. Comparing the NCF scores between the baseline (before WBRT) and post-treatment (after combined chemoradiation therapy) intervals (Mean = 122.33 days, SD = 34.49, range = 77-196), neurobehavioral outcomes consistently remained improving or stable in almost each domain of NCF. Specifically, the scores on Paced Auditory Serial Addition Test-Revised (PASAT-R) were significantly improved between the baseline and post-chemoradiation assessment. Under the multidisciplinary treatment guidelines for treating patients with newly-diagnosed PCNSL, multi-domain NCF become stabilized and even improved after the course of conformal WBRT combined with or without MTX-based chemotherapy.

Magnetic nanoparticles (MNPs) are useful for magnetic targeted drug delivery while ligand-mediated active targeting is another common delivery strategy for cancer therapy. In this work, we intend to prepare magnetic graphene oxide (mGO) by chemical co-precipitation of MNPs on the GO surface, followed by conjugation of the gastrin releasing peptide (GRP) as a targeting ligand, for dual targeted drug/gene delivery in invasive brain glioma treatment. mGO was grafted with chitosan, complexed with shRNA plasmid DNA for stomatin-like protein 2 (SLP2) gene silencing, modified with urocanic acid for plasmid DNA endosomal escape, PEGylated for GRP conjugation, and loaded with the chemotherapeutic drug irinotecan (CPT-11) by π-π interaction for pH-responsive drug release (mGOCUG/CPT-11/shRNA). In addition to the in depth characterization of the physico-chemical and biological properties during each preparation step, we also study the loading/pH-responsive release behavior of CPT-11 and the shRNA plasmid loading/cell transfection efficiency. The targeting and antitumor efficacies of the nanocomposite were studied with U87 human glioblastoma cells

T lymphocyte infiltration with immunotherapy potentially suppresses most devastating brain tumors. However, local immune privilege and tumor heterogeneity usually limit the penetration of immune cells and therapeutic agents into brain tumors, leading to tumor recurrence after treatment. Here, a rabies virus glycoprotein (RVG)-camouflaged gold yarnball (RVG@GY) that can boost the targeting efficiency at a brain tumor

We used reduced graphene oxide (rGO), which has two times higher photothermal conversion efficiency than graphene oxide (GO), as a photothermal agent for cancer photothermal therapy (PTT). By conjugating a photosensitizer IR780 to rGO, the IR780-rGO could be endowed with reactive oxygen species (ROSs) generation ability for concurrent photodynamic therapy (PDT). The IR780-rGO was coated with hyaluronic acid (HA) by electrostatic interaction to facilitate its intracellular uptake by U87 glioblastoma cells. The IR780-rGO/HA was loaded with doxorubicin (DOX) for chemotherapy (CT), to develop a pH-responsive drug delivery nano-platform for targeted multimodal cancer CT/PTT/PDT. We fully characterized the properties of all nanocomposites during the synthesis steps. The high loading efficiency of DOX on IR780-rGO-HA provides 3 mg/mg drug loading, while IR780-rGO-HA/DOX shows 3 times higher drug release at endosomal pH value (pH 5) than at pH 7.4. The mechanism for PTT/PDT was confirmed from the ability of IR780-rGO-HA to induce time-dependent temperature rise, synthesis of heat shock protein 70 (HSP70) and generation of intracellular ROSs, after exposure to 808 nm near infrared (NIR) laser light. The nano-vehicle IR780-rGO-HA shows high biocompatibility toward 3T3 fibroblast and U87 cancer cell lines, as well as enhanced intracellular uptake by U87 through active targeting. This translates into increased cytotoxicity of IR780-rGO-HA/DOX, by lowering the drug half-maximal inhibitory concentration (IC

The nonspecific distribution and non-targeted heating of chemotherapeutic agents in the human body commonly produce adverse side effects during brain cancer management. Even though an external magnetic field can partially gather extracellular magnetic drug carriers near brain tumor, magnetic guidance alone still cannot precisely identify and target either tumors or healthy tissues due to a lack of selectivity. In this study, we successfully developed thermal and magnetic dual-responsive thermosensitive magnetic liposomes (TML), which co-encapsulates Camptosar (CPT-11) and citric acid-coated magnetic Fe3O4 nanoparticles within the aqueous core and surface-conjugated with Cetuximab (CET) for recognizing over-expressed epidermal growth factor receptors on cancer cell surface. This drug carrier system can control the release of encapsulated drug when exposed to a high-frequency alternating magnetic field (AMF) that elevates the temperature of the liposomal membrane and triggers drug release from TML after their selective endocytosis by cancer cells. By detailed characterizing the physico-chemical and biological properties of liposomes, we demonstrated the liposomal formulation is with high biocompatibility and showed no hemolysis in vitro. Enhanced intracellular uptake of TML-CPT-11-CET by human primary glioblastoma cells (U87) also supported targeted delivery through CET-mediated endocytosis. The treatment of TML-CPT-11-CET solutions by AMF in vitro showed rise in solution temperature and enhanced drug release, which enhanced cytotoxicity of CPT-11 toward U87 though cell apoptosis as revealed from flow cytometry analysis of apoptotic cells and Western blot studies of marker proteins. Finally, the in vivo therapeutic efficacy was demonstrated in mice orthotopic xenograft brain tumor model from IVIS and PET/MRI studies.

The combination of liposomes and magnetic nanoparticles (MNPs) is a promising approach for cancer therapy due to its capability for magnetic field-directed targeted drug delivery at the diseased area. Contemporaneously, bubble-generating liposomes are of great interest in the field of cancer therapy, due to its triggered drug release properties and its ability to rupture cancer cells through cavitation induction. Therefore, the objective of the current study is to develop a bubble-generating magnetic liposomal (BMLs) drug delivery system with triggered drug release properties for targeted delivery of doxorubicin (DOX) in cancer therapy. Citric acid-coated iron oxide MNPs was co-entrapped with ammonium bicarbonate to produce BMLs by lipid film hydration method. BMLs were further modified by coating hyaluronic acid-polyethylene glycol (HA-PEG) on liposome surface to produce HA-PEG-BMLs for ligand-mediated active targeting of tumor cells. The resultant liposomes were found to be spherical in shape with an average particle size ranging from 100 to 170 nm. The physico-chemical properties and bubble-generating properties of liposomes were studied. In vitro drug release studies showed enhanced drug release under hyperthermia condition (43 °C) from BMLs/DOX and HA-PEG-BMLs/DOX due to more intense CO2 bubbles generation with faster decomposition rates of co-entrapped ammonium bicarbonate. In vitro cell culture studies using human glioblastoma cells (U87) were performed to evaluate the targeting efficiencies and anti-tumor efficacy of DOX-loaded liposomes. Magnetic targeted delivery of DOX was also demonstrated from LIVE/DEAD cell viability assays. The confocal microscopy and flow cytometry analysis confirmed enhanced intracellular uptake of HA-PEG-BMLs by U87 though binding of HA to overexpressed CD44 receptors on cell surface, which facilitated internalization of HA-PEG-BMLs/DOX through endocytosis and resulted in elevated DOX concentration in cancer cells. The combination of elevated intracellular DOX concentration and triggered DOX release at 43 °C led to enhanced cytotoxicity toward U87 cells in vitro. Thus, HA-PEG-BMLs will be useful for hyperthermia-induced targeted delivery of DOX for cancer therapy.

A series of metal decorated hydrogenated TiO2 nanofibers (metal-H:TiO2 NFs) are synthesized successfully in this study. It is synthesized by the hydrothermal approach and combined with wet impregnation method in thermal hydrogen reduction. Nine types of metal nanoparticles, Ag, Co, Cr, Cu, Fe, Ni, Pd, Pt and Y, were used to decorate on the surface of H:TiO2 to enhance the photocatalytic activity. The photocatalytic performance of various metal-H:TiO2 NFs was estimated by the photodegradation of organic dyes. Ag-H:TiO2 NFs gives the fastest decoloration rate of brilliant green among others. Moreover, the evolution rate of H2 over Pd-H:TiO2 NFs under UV-A and UV-B illumination is 17,000 μmol/g·h and 25,600 μmol/g·h, respectively, which corresponding to photoefficiency values of ∼7.54% and ∼11.35%. The metal-H:TiO2 NFs developed in this study can be a facile and environmentally friendly way for searching the high-performance photocatalysts in the field of environmental and energy issue.

The low vessel density and oxygen concentration in hypoxia are the main causes of reduced efficiency of anticancer therapeutics and can stimulate the tumor's relapse. Research showed that macrophages could cross the blood-vessel barriers and reach the hypoxic regions of tumors. Using macrophages in a drug delivery system has been a promising method for tumor targeting in recent years. In this work, we successfully modified monocyte chemoattractant protein-1 (MCP-1) and iron-based metal-organic framework (MIL-100(Fe)) on the photothermal agent, gold nanorods (GNRs) (i.e., MCP-1/GNR@MIL-100(Fe)), to increase cellular uptake and biocompatibility. The results of TEM, UV-vis, and FTIR all confirmed that we'd synthesized MCP-1/GNR@MIL-100(Fe) successfully, and the MCP-1/GNR@MIL-100(Fe) also showed good biocompatibility. A transwell migration assay illustrated that our material attracted macrophages, and the material uptake amount was increased by 1.5 times after MCP-1 functionalization. It also indicated that the macrophages have a tumor-targeting ability. In the in vivo experiment, we subcutaneously implanted U251 MG cells in nude mice as a xenograft model to demonstrate the photothermal activity of MCP-1/GNR@MIL-100(Fe). With successive NIR treatment, the tumor growth could be controlled, and the tumor volume still remained below 100 mm3 after laser treatment. MCP-1/GNR@MIL-100(Fe) combined with the laser treatment showed an excellent antitumor efficacy from the histology of tumor tissues, survival rates, and bioluminescence imaging.

A 2D monocular endoscope has been used in transcanal transpromontory vestibular schwannoma surgery instead of craniotomy. However, the absence of depth perception is the limitation of this approach. With the loss of depth perception, the surgeon will be not able to perform delicate and particularly complicated surgery. A binocular endoscope has been developed to provide stereoscopic vision with better depth perception for complicated anatomic structures and has been applied in some endoscopic surgeries. However, the diameter of the endoscope is a limitation in the performance of transcanal otologic surgeries. A small diameter endoscope facilitates easier surgery in a restricted space. A computer-based 3D imaging system can obtain 3D images in real-time using a small monocular endoscope. In this study, to evaluate the feasibility of a computer-based 3D imaging system for endoscopic lateral skull base surgery, we applied this 3D imaging system in a transcanal transpromontorial approach in two patients with vestibular schwannomas. The surgical procedure was completed without complication in these two cases. There was no mortality, perioperative complications, nor notable postoperative complications. Using this computer-based 3D imaging system, a better depth perception and stereoscopic vision was observed compared to a conventional 2D endoscope. The improvement in depth perception offers superior management of the complicated surgical anatomy.

Simple Summary To improve the use of hydrophobic photosensitizer IR-780 in photothermal/photodynamic therapy (PTT/PDT), we entrap IR-780 within the lipid bilayer of liposomes (ILs). Compared to free IR-780, ILs showed well-preserved photothermal response by maintaining the photostability of IR-780 from repeated near infrared (NIR) laser exposure both in vitro and in vivo. Combined with fast endocytosis by human glioblastoma cells, ILs demonstrated enhanced cytotoxicity and induced higher cell apoptosis rate toward human glioblastoma cells over free IR-780, due to PTT with overexpression of heat shock protein and PDT with generation of intracellular reactive oxygen species. To overcome the blood–brain barrier, we used convection enhanced delivery (CED) for specific delivery of ILs to brain tumors in intracranial glioma xenograft. Upon three successive NIR laser irradiations, the liposomal IR-780 could significantly improve the anti-cancer efficacy in glioma treatment, leading to diminished intracranial tumor size and prolonged animal survival time. Abstract As a hydrophobic photosensitizer, IR-780 suffers from poor water solubility and low photostability under near infrared (NIR) light, which severely limits its use during successive NIR laser-assisted photothermal/photodynamic therapy (PTT/PDT). To solve this problem, we fabricate cationic IR-780-loaded liposomes (ILs) by entrapping IR-780 within the lipid bilayer of liposomes. We demonstrate enhanced photostability of IR-780 in ILs with well-preserved photothermal response after three repeated NIR laser exposures, in contrast to the rapid decomposition of free IR-780. The cationic nature of ILs promotes fast endocytosis of liposomal IR-780 by U87MG human glioblastoma cells within 30 min. For PTT/PDT in vitro, ILs treatment plus NIR laser irradiation leads to overexpression of heat shock protein 70 and generation of intracellular reactive oxygen species by U87MG cells, resulting in enhanced cytotoxicity and higher cell apoptosis rate. Using intracranial glioma xenograft in nude mice and administration of ILs by convection enhanced delivery (CED) to overcome blood-brain barrier, liposomal IR-780 could be specifically delivered to the brain tumor, as demonstrated from fluorescence imaging. By providing a highly stable liposomal IR-780, ILs significantly improved anti-cancer efficacy in glioma treatment, as revealed from various diagnostic imaging tools and histological examination. Overall, CED of ILs plus successive laser-assisted PTT/PDT may be an alternative approach for treating brain tumor, which can retard glioma growth and prolong animal survival times from orthotopic brain tumor models.

A high-frequency magnetic field (MF) generates an electric current by charging conductors that enable the induction of various biological processes, including changes in cell fate and programming. In this study, we show that electromagnetized carbon porous nanocookies (NCs) under MF treatment facilitate magnetoelectric conversion for growth factor release and cell stimulation to induce neuron cell differentiation and proliferation in vitro and in vivo. Integrating four-dimensional printing technology, the NCs are exposed on the surface, which enhances the cell adhesion and allows direct manipulation of electromagnetic stimulation of the cells. Remarkably, large amounts of growth factor encapsulated in NC@conduit resulted in excellent permeability and on-demand release, improving the in vivo layers of myelin sheaths and directing the axon orientation at 1 month postimplantation. This study offers proof of principle for MF-guided in vivo neuron regeneration as a potentially viable tissue regeneration approach for neuronal diseases. Researchers in Taiwan have developed a printable biomaterial that has potential for neuron regeneration and treating neural diseases. Four-dimensional printed materials are objects created using 3D printing technology but whose properties can be altered in time, by electrical pulses for example. A team led by San-Yuan Chen from National Chiao Tung University and Shang-Hsiu Hu from National Tsing Hua University, both in Hsinchu, made biomedical four-dimensional printed material by combining stretchable and biocompatible graphene oxide nanosheets with so-called nanocookies: porous carbon with silica embedded into its surface. The pores in the carbon act as a scaffold on which neurons can grow, and an electric current induced in the silica by a high-frequency magnetic field stimulated this growth. The team observed this stimulation in both cell cultures and rat models. 4D Printing Conduits: Electromagnitized carbon porous nanoccookies (NCs) under MF facilitate magneto-electrical conversion for growth factor release and cell simulation. Integrating four-dimensional (4D) printed technology, exposed NCs are able to enhances the cell adhesion and manifest directly electromagnetic stimulation to cells.

Understanding the molecular mechanisms of graphene oxide (GO)-based biomaterials is important for logical biomedical applications. Previous studies have revealed biointeractions between GO and immune effector cells, but the effects on neutrophils, crucial cells in the immune system, have not been thoroughly discussed. In this study, GO nanoformulations were synthesized with different functional groups, including GO, GO-carboxylated (GO-COOH), and PEGylated GO (GO-PEG), with different surface features, which were elucidated using imaging methods and surface-sensitive quantitative spectroscopic techniques, including atomic force microscopy (AFM), transmission electron microscopy (TEM), and X-ray photoemission spectroscopy (XPS). The GO-based nanoformulations elicited reactive oxygen species (ROS) generation and neutrophil extracellular trap (NET) formation in human neutrophils. Nanoformulated GO stimulates NET development via the formation of ROS. An endocytosis study revealed that nanoformulated GO facilitated internalization by neutrophils via macropinocytosis and actin-dependent phagocytosis. Importantly, calcium mobilization and phosphorylation proteins such as mitogen-activated protein kinases (extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38) and AKT were involved in the activation of neutrophils. These findings offer the first verification that nanoformulated GO exhibits direct effects on human neutrophils.

In this work, we aimed to develop liposomal nanocomposites containing citric-acid-coated iron oxide magnetic nanoparticles (CMNPs) for dual magneto-photothermal cancer therapy induced by alternating magnetic field (AMF) and near-infrared (NIR) lasers. Toward this end, CMNPs were encapsulated in cationic liposomes to form nano-sized magnetic liposomes (MLs) for simultaneous magnetic hyperthermia (MH) in the presence of AMF and photothermia (PT) induced by NIR laser exposure, which amplified the heating efficiency for dual-mode cancer cell killing and tumor therapy. Since the heating capability is directly related to the amount of entrapped CMNPs in MLs, while the liposome size is important to allow internalization by cancer cells, response surface methodology was utilized to optimize the preparation of MLs by simultaneously maximizing the encapsulation efficiency (EE) of CMNPs in MLs and minimizing the size of MLs. The experimental design was performed based on the central composite rotatable design. The accuracy of the model was verified from the validation experiments, providing a simple and effective method for fabricating the best MLs, with an EE of 87% and liposome size of 121 nm. The CMNPs and the optimized MLs were fully characterized from chemical and physical perspectives. In the presence of dual AMF and NIR laser treatment, a suspension of MLs demonstrated amplified heat generation from dual hyperthermia (MH)&ndash, photothermia (PT) in comparison with single MH or PT. In vitro cell culture experiments confirmed the efficient cellular uptake of the MLs from confocal laser scanning microscopy due to passive accumulation in human glioblastoma U87 cells originated from the cationic nature of MLs. The inducible thermal effects mediated by MLs after endocytosis also led to enhanced cytotoxicity and cumulative cell death of cancer cells in the presence of AMF&ndash, NIR lasers. This functional nanocomposite will be a potential candidate for bimodal MH&ndash, PT dual magneto-photothermal cancer therapy.

Introduction: The purpose of this study is to determine the success and complication rates of linear accelerator (LINAC)-based radiosurgery (X-knife) for indirect carotid-cavernous fistulas (CCFs). Materials and Methods: This retrospective study was performed at the Department of Radiosurgery, Chang Gung Memorial Hospital, Taiwan, and reviewed data from May 2006 to May 2018. Thirteen patients with CCF who were treated with stereotactic radiosurgery were included, and side, volume, pathological type, origin, location, postoperative regression, and recurrence rate were evaluated with postradiotherapy. Patients were either followed up with contrast magnetic resonance imaging or angiography. Radiosurgery was considered successful if the patients' clinical symptoms improved with radiological remission or if there was a reduction in CCF flow in angiography. Results: Of the 11 patients, three (27.3%) received transarterial embolization (TAE) before radiosurgery. Successful radiological outcomes were seen in 10 (90.9%) patients, and the remaining one patient (9.1%) had stationary disease with no reduction in CCF flow. Ten patients (90.9%) had improved clinical symptoms; however, one patient (9.1%) was complicated with iatrogenic blindness after TAE treatment. No acute or subacute transient postradiation changes, optic nerve injuries, or brainstem radionecrosis were noted in any of the patients. Conclusions: In this study, LINAC-based radiosurgery for CCF was found to be an effective, safe, and successful treatment alternative to TAE treatment in patients with indirect CCF. The risk of postradiotherapy complications was low, and obliteration and regression rates were high.

The role of brain FDG-PET in patients with lung cancer and brain metastases remains unclear. Here, we sought to determine the prognostic significance of whole-body PET/CT plus brain PET/MR in predicting the time to neurological progression (nTTP) and overall survival (OS) in this patient group. Of 802 patients with non-small cell lung cancer who underwent primary staging by a single-day protocol of whole-body PET/CT plus brain PET/MR, 72 cases with adenocarcinoma and brain metastases were enrolled for a prognostic analysis of OS. On the basis of the available follow-up brain status, only 52 patients were eligible for prognostic analysis of nTTP. Metastatic brain tumors were identified on post-contrast MR imaging, and the tumor-to-brain ratio (TBR) was measured on PET images. Multivariate analysis revealed that FDG-PET findings and eligibility for initial treatment with targeted therapy were significant independent predictors of nTTP and OS. A new index, termed the molecular imaging prognostic (MIP) score, was proposed to define three disease classes. MIP scores were significant predictors of both nTTP and OS (P

Monitoring of drug efficacy in glioblastoma multiforme (GBM) is a major clinical problem. Glioblastomas shed large quantities of exosomes into the circulation. Although these hold promise as potential biomarkers of therapeutic response, their identification and quantification remain challenging. Recently, we develop a highly sensitive and rapid analytical technique for profiling circulating exosomes directly from serum plasma of patients with glioblastoma. Exosomes are labeled with target-specific metal nanoparticles and detected by a miniaturized integrated magneto-electrochemical sensing system. Compared with current methods, this integrated system has a much higher detection sensitivity and can differentiate GBM exosomes from nontumor host cell–derived exosomes. We also show that circulating GBM exosomes can be used to analyze primary tumor mutations and as a predictive metric of treatment-induced changes. This platform could provide both an early indicator of drug efficacy and a potential molecular stratifier for human clinical trials.

Herein, we design a rGO-based magnetic nanocomposite by decorating rGO with citrate-coated magnetic nanoparticles (CMNP). The magnetic rGO (mrGO) was modified by phospholipid-polyethylene glycol to prepare PEGylated mrGO, for conjugating with gastrin-releasing peptide receptor (GRPR)-binding peptide (mrGOG). The anticancer drug doxorubicin (DOX) was bound to mrGO (mrGOG) by π-π stacking for drug delivery triggered by the low pH value in the endosome. The mrGOG showed enhanced photothermal effect under NIR irradiation, endorsing its role for dual targeted DOX delivery. With efficient DOX release in the endosomal environment and heat generation from light absorption in the NIR range, mrGOG/DOX could be used for combination chemo-photothermal therapy after intracellular uptake by cancer cells. We characterized the physico-chemical as well as biological properties of the synthesized nanocomposites. The mrGOG is stable in biological buffer solution, showing high biocompatibility and minimum hemolytic properties. Using U87 glioblastoma cells, we confirmed the magnetic drug targeting effect in vitro for selective cancer cell killing. The peptide ligand-mediated targeted delivery increases the efficiency of intracellular uptake of both nanocomposite and DOX up to ~3 times due to the over-expressed GRPR on U87 surface, leading to higher cytotoxicity. The increased cytotoxicity using mrGOG over mrGO was shown from a decreased IC50 value (0.70 to 0.48 μg/mL) and an increased cell apoptosis rate (19.8% to 47.1%). The IC50 and apoptosis rate changed further to 0.19 μg/mL and 76.8% in combination with NIR laser irradiation, with the photothermal effect supported from upregulation of heat shock protein HSP70 expression. Using U87 tumor xenograft model created in nude mice, we demonstrated that magnetic guidance after intravenous delivery of mrGOG/DOX could significantly reduce tumor size and prolong animal survival over free DOX and non-magnetic guided groups. Augmented with NIR laser treatment for 5 min, the anti-cancer efficacy significantly improves with elevated cell apoptosis and reduced cell proliferation. Together with safety profiles from hematological as well as major organ histological analysis of treated animals, the mrGOG nanocomposite is an effective nanomaterial for combination chemo-photothermal cancer therapy.

Die Untersuchung von Biomarkern und injizierten theranostischen Nanomaterialien in Geweben und Organen spielt eine zentrale Rolle bei zahlreichen medizinischen Verfahren von der Krebsdiagnose bis hin zur Arzneimittelverabreichung. Zu diesem Zweck kann die elektrochemische Rastersondenmikroskopie hochaufgeloste Abbildungen der raumlichen Verteilung von wichtigen Biomolekulen ohne optische Interferenzen liefern. Wir haben weiche Mikroelektroden zum Abtasten grosflachiger und dicker Gewebeschnitte und Organe, die in eine Elektrolytlosung eingetaucht sind, verwendet. Die Messung amperometrischer Strome wurde durch den lokalen Fluss redoxaktiver Spezies ermoglicht, welche lokal und spezifisch durch Biomarker und Nanomaterialien in den Proben erzeugt wurden. Die biologischen Verteilungen von Graphenoxidnanostreifen in Mauseleber, von prognostischen Proteinbiomarkern in menschlichem Hautkrebsgewebe und von redoxaktiven Proteinen in Mauseherzen wurden separat abgebildet.

A magnetic targeted functionalized graphene oxide (GO) complex is constituted as a nanocarrier for targeted delivery and pH-responsive controlled release of chemotherapy drugs to cancer cells. Magnetic graphene oxide (mGO) was prepared by chemical co-precipitation of Fe3O4 magnetic nanoparticles on GO nano-platelets. The mGO was successively modified by chitosan and mPEG-NHS through covalent bindings to synthesize mGOC-PEG. The polyethylene glycol (PEG) moiety is expected to prolong the circulation time of mGO by reducing the reticuloendothelial system clearance. Irinotecan (CPT-11) or doxorubicin (DOX) was loaded to mGOC-PEG through π-π stacking interactions for magnetic targeted delivery of the cancer chemotherapy drug. The best values of loading efficiency and loading content of CPT-11 were 54% and 2.7% respectively; whereas for DOX, they were 65% and 393% The pH-dependent drug release profile was further experimented at different pHs, in which ~60% of DOX was released at pH 5.4 and ~10% was released at pH 7.4. In contrast, ~90% CPT-11 was released at pH 5.4 and ~70% at pH 7.4. Based on the drug loading and release characteristics, mGOC-PEG/DOX was further chosen for in vitro cytotoxicity tests against U87 human glioblastoma cell line. The IC50 value of mGOC-PEG/DOX was found to be similar to that of free DOX but was reduced dramatically when subject to magnetic targeting. It is concluded that with the high drug loading and pH-dependent drug release properties, mGOC-PEG will be a promising drug carrier for targeted delivery of chemotherapy drugs in cancer therapy.

Compact nanohybrids can potentially unite various therapeutic features and reduce side effects for precise cancer therapy. However, the poor accumulation and limited tumor penetration of drugs at the tumor impede the manifestation of nanomedicine. We developed a rabies virus glycoprotein (RVG)-amplified hierarchical targeted hybrid that acts as a stealthy and magnetolytic carrier that transports dual tumor-penetrating agents incorporating two drugs (boron-doped graphene quantum dots (B-GQDs)/doxorubicin and pH-responsive dendrimers (pH-Den)/palbociclib). The developed RVG-decorated hybrids (RVG-hybrids) enhance the accumulation of drugs at tumor by partially bypassing the BBB via spinal cord transportation and pH-induced aggregation of hierarchical targeting. The penetrated delivery of dual pH-Den and B-GQD drugs to deep tumors is actuated by magnetoelectric effect, which are able to generate electrons to achieve electrostatic repulsion and disassemble the hybrids into components of a few nanometers in size. The synergy of magnetoelectric drug penetration and chemotherapy was achieved by delivery of the B-GQDs and pH-Den to orthotopic tumors, which prolonged the host survival time. This RVG-amplified dual hierarchical delivery integrated with controlled and penetrated release from this hybrid improve the distribution of the therapeutic agents at the brain tumor for synergistic therapy, exhibiting potential for clinic use.

Piezoresistive pressure sensors have garnered significant attention because of their wide applications in automobiles, intelligent buildings, and biomedicine. For in vivo testing, the size of pressure sensors is a vital factor to monitor the pressure of specific portions of a human body. Therefore, the primary focus of this study is to miniaturize piezoresistive pressure sensors with graphene oxide (GO)-incorporated poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) composite films on a flexible substrate for biomedical applications. Prior to the fabrication of pressure sensors, a comprehensive material analysis was applied to identify the horizontal placement of GO flakes within the PEDOT:PSS copolymers, revealing a reduction in variable range hopping distance and an enhancement in carrier mobility. For devices scaled to 0.2 cm, the sensitivity of PEDOT:PSS pressure sensors was conspicuously decreased owing to the late response, which can be effectively solved by GO incorporation. Using technology computer-aided design simulations, the current crowded at the PEDOT:PSS film surface and in the vicinity of an indium-tin-oxide electrode corner was found to be responsible for the changes in piezoresistive behaviors of the scaled devices. The miniaturized flexible piezoresistive pressure sensors with PEDOT:PSS/GO composite films are capable of monitoring the brain pressure of intracranial surgery of a rat and discerning different styles of music for a potential application in hearing aids.

Injectable hydrogels in regeneration medicine can potentially mimic hierarchical natural living tissue and fill complexly shaped defects with minimally invasive implantation procedures. To achieve this goal, however, the versatile hydrogels that usually possess the nonporous structure and uncontrollable spatial agent release must overcome the difficulties in low cell‐penetrative rates of tissue regeneration. In this study, an adaptable microporous hydrogel (AMH) composed of microsized building blocks with opposite charges serves as an injectable matrix with interconnected pores and propagates gradient growth factor for spontaneous assembly into a complex shape in real time. By embedding gradient concentrations of growth factors into the building blocks, the propagated gradient of the nerve growth factor, integrated to the cell‐penetrative connected pores constructed by the building blocks in the nerve conduit, effectively promotes cell migration and induces dramatic bridging effects on peripheral nerve defects, achieving axon outgrowth of up to 4.7 mm and twofold axon fiber intensity in 4 days in vivo. Such AMHs with intrinsic properties of tunable mechanical properties, gradient propagation of biocues and effective induction of cell migration are potentially able to overcome the limitations of hydrogel‐mediated tissue regeneration in general and can possibly be used in clinical applications.

Photothermal therapy is considered to be a promising approach for minimally invasive tumor treatment. Before the clinical trial, the photo-induced heat production efficiency in tumor tissue needs improvement. Herein, we demonstrated a one-pot hydrothermal synthesis followed by calcination to prepare the Ag NPs-precipitated TiO2 photocatalysts. With calcination temperature ascending, anatase TiO2 transformed into rutile TiO2, and self-precipitated Ag NPs vanished. Besides, fibers started to sinter with adjacent fibers, transforming into the bulk form. Due to the rich Ag NPs precipitated on the surface, leading to strong surface plasma resonance, Ag doped anatase TiO2 NFs (STF) presented the superior photocatalytic activity. Under the irradiation, 10,000 ppm of STF showed significant temperature enhancement in the photothermal conversion in vitro and the photothermal therapy in vivo. The body surface temperature can be increased up to 47.96 °C with an irradiation time of 5.0 min. Moreover, the tumor growth was inhibited for up to 24 days, and the survival rate of mice was extended. From the protein identification of HE and Caspase 3 stain, STF proficiently disturbed the tumor expansion and led to tumor cell apoptosis. STF triggered by xenon lamp irradiation contributed to the significant tumor ablation and showed great potential in photothermal therapy.

Ischemic stroke, and the consequent brain cell death, is a common cause of death and disability worldwide. Current treatments that primarily aim to relieve symptoms are relatively inefficient in achieving brain tissue regeneration and functional recovery, and thus novel therapeutic options are urgently needed. Although cell-based therapies have shown promise for treating the infarcted brain, a recurring challenge is the inadequate retention and engraftment of transplanted cells at the target tissue, thereby limiting the ultimate therapeutic efficacy. Here, we show that transplantation of preassembled three-dimensional (3D) spheroids of mesenchymal stem cells (MSCs) and vascular endothelial cells (ECs) results in significantly improved cell retention and survival compared with conventional mixed-cell suspensions. The transplanted 3D spheroids exhibit notable neuroprotective, proneurogenic, proangiogenic and anti-scarring potential as evidenced by clear extracellular matrix structure formation and paracrine factor expression and secretion; this ultimately results in increased structural and motor function recovery in the brain of an ischemic stroke mouse model. Therefore, transplantation of MSCs and ECs using the 3D cell spheroid configuration not only reduces cell loss during cell harvesting/administration but also enhances the resultant therapeutic benefit, thus providing important proof-of-concept for future clinical translation.