Waste-Wood-Isolated Cellulose-Based Activated Carbon Paper Electrodes with Graphene Nanoplatelets for Flexible Supercapacitors.

Waste wood, which has a large amount of cellulose fibers, should be transformed into useful materials for addressing environmental and resource problems. Thus, this study analyzed the application of waste wood as supercapacitor electrode material. First, cellulose fibers were extracted from waste wood and mixed with different contents of graphene nanoplatelets (GnPs) in water. Using a facile filtration method, cellulose papers with GnPs were prepared and converted into carbon papers through carbonization and then to porous activated carbon papers containing GnPs (ACP-GnP) through chemical activation processes. For the morphology of ACP-GnP, activated carbon fibers with abundant pores were formed. The increase in the amount of GnPs attached to the fiber surfaces decreased the number of pores. The Brunauer-Emmett-Teller surface areas and specific capacitance of the ACP-GnP electrodes decreased with an increase in the GnP content. However, the galvanostatic charge-discharge curves of ACPs with higher GnP contents gradually changed into triangular and linear shapes, which are associated with the capacitive performance. For example, ACP with 15 wt% GnP had a low mass transfer resistance and high charge delivery of ions, resulting in the specific capacitance value of 267 Fg-1 owing to micropore and mesopore formation during the activation of carbon paper.

Bevacizumab plus irinotecan with or without gamma knife radiosurgery after failure of concurrent chemo-radiotherapy for high-grade glioma.

INTRODUCTION: Concurrent chemo-radiotherapy (CCRT) with temozolomide (TMZ) is a standard first-line treatment for high-grade glioma. However, if CCRT with TMZ treatment fails, second-line treatment options have limited value. Bevacizumab plus irinotecan is the only available treatment option for such patients. The role of gamma knife radiosurgery (GKS) in patients with high-grade gliomas is not well-established. In this study, we evaluated the efficacy and safety of bevacizumab plus irinotecan with or without GKS in the treatment of high-grade glioma patients who progressed after initially being treated with CCRT with TMZ. METHODS: We collected clinical data of patients with biopsy-proven high-grade glioma (glioblastoma multiforme (GBM) or anaplastic astrocytoma) who were treated at Samsung Medical Center from January 2015 to December 2020, retrospectively. We evaluated the overall survival (OS), progression-free survival (PFS), and safety of bevacizumab plus irinotecan with or without GKS. RESULTS: In total, 203 patients were diagnosed with high-grade glioma, including GBM and anaplastic astrocytoma. The median OS was 8.73 months (95% confidence interval [CI]: 7.27-10.18), and the median PFS was 4.36 months (95% CI: 3.75-4.97). Sixty-eight (33.4%) patients underwent GKS prior to bevacizumab plus irinotecan treatment, which led to a significantly prolonged OS (10.13 months, 95% CI: 8.65-11.60 vs. 8.26 months, 95% CI: 7.01-9.51, p = 0.012). The most common adverse events of any grade were neutropenia (36.9%) and thrombocytopenia (22.6%). However, the incidence of adverse events in patients who underwent GKS prior to bevacizumab plus irinotecan was not different compared with those in patients who did not undergo GKS. CONCLUSIONS: Bevacizumab plus irinotecan was well-tolerated and moderately effective in patients with high-grade gliomas. The addition of GKS prior to bevacizumab plus irinotecan led to a significant OS benefit with a manageable safety profile. GKS prior to bevacizumab plus irinotecan can therefore be considered a potential treatment option for these patients.

High concordance of actionable genomic alterations identified between circulating tumor DNA-based and tissue-based next-generation sequencing testing in advanced non-small cell lung cancer: The Korean Lung Liquid Versus Invasive Biopsy Program.

BACKGROUND: Because of the growing number of actionable biomarkers in non-small cell lung cancer (NSCLC), sufficient tissue availability for testing is becoming a greater challenge. Liquid biopsy offers a potential solution by complementing standard tissue-based methods. In this study, the authors analyzed the concordance of actionable genomic alterations sequenced from circulating tumor DNA (ctDNA; Guardant360) and tissue (Oncomine Focus Assay). METHODS: From September 2015 to May 2018, 421 paired plasma and tissue samples from patients with advanced NSCLC who had previously undergone tissue testing by standard methods were collected. Both types of samples were available for 287 patients (262 in cohort 1 [treatment-naive] and 25 in cohort 2 [treatment failure]), and only 1 sample type was available for 134 patients (50 in cohort 3 [plasma only] and 84 in cohort 4 [tissue only]). RESULTS: In cohort 1, 198 samples (77.6%) showed concordance between tissue and plasma next-generation sequencing (NGS). Among the discordant cases, plasma testing detected additional genomic alterations in 11 patients (4.2%). In 50 patients without tissue-based NGS results (cohort 3), the ctDNA-based test detected genomic alterations in 20 samples (40.0%). The median allele frequency (AF) of mutations identified with ctDNA-based NGS (0.74%) was lower than that identified with the tissue-based NGS test (13.90%). Clinical responses to matched targeted therapy occurred, regardless of the ctDNA AF. Upfront ctDNA-based testing identified 60.4% of patients with genomic alterations. In addition, ctDNA-based testing uncovered 12.0% more actionable alterations when it was performed after tissue-based NGS testing. CONCLUSIONS: The results indicate that a ctDNA-based test identifies additional patients with actionable genomic alterations and could, therefore, be used to complement traditional tissue-based testing for NSCLC. LAY SUMMARY: Circulating tumor DNA (ctDNA)-based next-generation sequencing (NGS) testing is becoming essential as the number of actionable genomic biomarker increases for the treatment selection of non-small cell lung cancer. This study demonstrates the additive value of ctDNA-based testing in addition to tissue-based NGS and standard of care-based biomarker testing for detecting additional patients with actionable genomic alterations. Clinical responses have also been observed in patients with a low allele frequency detected by ctDNA-based NGS testing.

Surgical versus nonsurgical management of lumbar degenerative spondylolisthesis based on spinal canal cross-sectional area.

Disability and pain associated with lumbar degenerative spondylolisthesis (LDS) result in a significant burden on both the healthcare costs and patients' quality of life. Currently, there exists controversy regarding employment of either nonsurgical management (NSM) or surgical management (SM) in a clinical setting. Spinal canal cross-sectional area (SCA) has been an important morphological parameter for the analysis of LDS. However, there is lack of research about the comparative value of NSM and SM according to SCA. Moreover, previous research have not yet evaluated the clinical most suitable cutoff values of SCA. The objective of this research was to evaluate the effective of NSM and SM for LDS using SCA as an objective morphological parameter. The axial T2 magnetic resonance imaging images were obtained from each patient. We collected SCA samples from 149 patients with LDS. 72 patients underwent SM and the rest did NSM. We measured SCA at the L4/5 LDS on magnetic resonance imaging using a picture archiving and communications system. We measured SCA at the intervertebral disk posterior border, turning down to reach the facet joint side on the opposite edge at the L4/5 level. The average SCA value was 114.34 ±â€…48.11 mm2 in the NSM group and 69.88 ±â€…27.87 mm2 in the SM group. Therefore, the SM group had considerably lower SCA (P < .001). In view of the effectiveness of SCA as a prediction factor of surgical option, Receiver Operating Characteristic curve analysis show the optimal cutoff value for SCA as 83.21 mm2, with 70.8% sensitivity, 71.4% specificity, and an area under the curve of 0.80 (95% CI, 0.73-0.87). The narrower the SCA, the higher the probability of SM. Thus, it is proposed that to evaluate surgical decision making, the pain physician should carefully inspect the SCA.

Enhanced transfection by antioxidative polymeric gene carrier that reduces polyplex-mediated cellular oxidative stress.

PURPOSE: To test the hypothesis in which polyplex-induced oxidative stress may affect overall transfection efficiency, an antioxidative transfection system minimizing cellular oxidative stress was designed for enhanced transfection. METHODS: An amphiphilic copolymer (PEI-PLGA) was synthesized and used as a micelle-type gene carrier containing hydrophobic antioxidant, α-tocopherol. Cellular oxidative stress and the change of mitochondrial membrane potential after transfection was measured by using a fluorescent probe (H2DCFDA) and lipophilic cationic probe (JC-1), respectively. Transfection efficiency was determined by measuring a reporter gene (luciferase) expression level. RESULTS: The initial transfection study with conventional PEI/plasmid DNA polyplex showed significant generation of reactive oxygen species (ROS). The PEI-PLGA copolymer successfully carried out the simultaneous delivery of α-tocopherol and plasmid DNA (PEI-PLGA/Toco/pDNA polyplex) into cells, resulting in a significant reduction in cellular ROS generation after transfection and helped to maintain the mitochondrial membrane potential (ΔΨ). In addition, the transfection efficiency was dramatically increased using the antioxidative transfection system. CONCLUSIONS: This work showed that oxidative stress would be one of the important factors that should be considered in designing non-viral gene carriers and suggested a possible way to reduce the carrier-mediated oxidative stress, which consequently leads to enhanced transfection.

Survival Outcomes of Patients with Follicular Lymphoma after Relapse or Progression: A Single-Center Real-World Data Analysis.

Background: Follicular lymphoma (FL) is considered incurable because remission and relapse are common. Although various salvage treatment options have been proposed, there is no consensus on treatment strategy for FL patients who failed primary treatment. Methods: This single-center study analyzed postevent overall survival (OS) among 70 patients who experienced relapse or progression after rituximab-containing immunochemotherapy according to type of salvage treatment and nature of relapse or progression. Results: Of 70 patients, 42 experienced progression of disease within 24 months (POD24), and six showed disease progression during first-line treatment. Large-cell transformation was found in nine patients with POD24. At the median follow-up of 104 months (95% CI: 90-118 months), POD24 patients experienced significantly worse OS than patients without POD24, and postevent OS was not satisfactory after conventional salvage chemotherapy because the majority of patients relapsed or progressed. However, autologous stem cell transplantation (ASCT) after the first relapse resulted in survival prolongation in patients with POD24. Half of the patients (34/67, 51%) participated in at least one clinical trial during treatment after first relapse, and patients participating in at least one clinical trial irrespective of line of treatment tended to experience better survival. Conclusions: Relapsed or refractory FL patients showed various clinical courses and treatment outcomes according to relapse or progression. Consolidation treatment with ASCT and active participation to clinical trials might prolong survival duration, especially in POD24 cases.

Real-World Evidence of Trastuzumab, Pertuzumab, and Docetaxel Combination as a First-Line Treatment for Korean Patients with HER2-Positive Metastatic Breast Cancer.

PURPOSE: Trastuzumab has markedly improved the survival outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and dual blockade of HER2 using trastuzumab and pertuzumab in combination with taxanes (THP) has become a standard of care for HER2-positive metastatic breast cancer (MBC) worldwide since the CLEOPATRA trial. We assessed the outcomes of THP as a first-line treatment for Korean HER2-positive MBC patients in the real-world setting. MATERIALS AND METHODS: Between August 2008 and October 2020, we identified 228 HER2-positive MBC patients who received THP as a first-line palliative chemotherapy. We analyzed survival outcomes, efficacy, and adverse events of THP retrospectively. RESULTS: After a median follow-up duration of 28.7 months, median overall survival and progression-free survival were 58.3 months (95% confidence interval [CI], 36.6 to 80.0) and 19.1 months (95% CI, 16.2 to 21.9), respectively. Better survival outcomes were observed in patient who received docetaxel for more than six cycles. Patients exposed to anti-HER2 directed therapies in a perioperative setting had poor survival outcomes. The overall response rate was 86.8% with a complete response (CR) rate of 17.7%. Among responders, 16.7% of patients sustained THP over 35 months and showed better survivals and higher CR rates. Adverse events were comparable to those reported in previous studies. CONCLUSION: In a real-world context, clinical outcomes of Korean HER2-positive MBC patients treated with THP were similar to those of patients in the CLEOPATRA trial. Much longer follow-up results would be warranted.

Acute to Subacute Spinal Cord Infarction Mimicking Acute Multiple Sclerosis: Usefulness of Diffusion-weighted MRI for Diagnosis.

BACKGROUND: Spinal Cord Infarction (SCI) is difficult to diagnose because of its rarity, unknown etiology, and unestablished diagnostic criteria. Additionally, the timeline of SCI has not been studied in detail, as few studies using Diffusion-Weighted Image (DWI) sequences of the spine of a small target population have been previously conducted. CASE STUDY: A 56-year-old male with underlying arrhythmia suddenly developed visual field defects on the right side, pain in the left upper extremity, and a tingling sensation in the left hand. Brain Magnetic resonance imaging (MRI) revealed acute to subacute stages of multifocal brain infarction. On additional cervical spinal MRI, it showed atypical MRI findings of SCI, considered late acute to early subacute phase, which were similar to those seen in the acute phase of multiple sclerosis (MS). Additional DWI revealed restricted diffusion. From these findings, it could be inferred that the patient's SCI occurred at the same time as the multifocal brain infarctions caused by atrial fibrillation. CONCLUSION: A DWI sequence of spine MRI could be helpful in the diagnosis of acute to subacute phase SCI and in differentiating with acute MS.

Dielectric Behavior near a Spherical Ion.

The dielectric response of a polar solvent to an ion is analyzed in terms of the bound charge, the net charge that accumulates near the ion as a consequence of the inhomogeneous polarization of the surrounding solvent. We demonstrate that the total bound charge arising in a full molecular treatment is identical to the total bound charge from standard continuum theory. In continuum theory, the bound charge resides in an infinitely thin layer, while in a molecular description the bound charge is spread over a region of finite width. Near simple atomic ions, the width of the bound charge distribution is roughly 1.3 nm. By simulating a sequence of ion charges from 0.1 to 2 e, where e is the magnitude of the electron charge, we analyze the applicability of linear response theory, which has been used by several authors. With increasing charge, the nonlinear response extends to an increasing distance from the ion. However, outside the region containing bound charge, the response is linear and in accord with continuum theory. Previous attempts to assign a dielectric constant to a solvent in the interfacial region are analyzed.

Sustained-Release Microspheres of Rivoceranib for the Treatment of Subfoveal Choroidal Neovascularization.

The wet type of age-related macular degeneration (AMD) accompanies the subfoveal choroidal neovascularization (CNV) caused by the abnormal extension or remodeling of blood vessels to the macula and retinal pigment epithelium (RPE). Vascular endothelial growth factor (VEGF) is known to play a crucial role in the pathogenesis of the disease. In this study, we tried to repurpose an investigational anticancer drug, rivoceranib, which is a selective inhibitor of VEGF receptor-2 (VEGFR2), and evaluate the therapeutic potential of the drug for the treatment of wet-type AMD in a laser-induced CNV mouse model using microsphere-based sustained drug release formulations. The PLGA-based rivoceranib microsphere can carry out a sustained delivery of rivoceranib for 50 days. When administered intravitreally, the sustained microsphere formulation of rivoceranib effectively inhibited the formation of subfoveal neovascular lesions in mice.

Hyaluronic Acid Coating on Hydrophobic Tracheal Scaffold Enhances Mesenchymal Stem Cell Adhesion and Tracheal Regeneration.

BACKGROUND: Long segmental tracheal repair is challenging in regenerative medicine due to low adhesion of stem cells to tracheal scaffolds. Optimal transplantation of stem cells for tracheal defects has not been established. We evaluated the role of hyaluronic acid (HA) coating of tracheal scaffolds in mesenchymal stem cell (MSC) adhesion and tracheal regeneration in a rabbit model. METHODS: A three-dimensionally printed tubular tracheal prosthesis was incubated with dopa-HA-fluorescein isothiocyanate in phosphate-buffered saline for 2 days. MSCs were incubated with an HA-coated scaffold, and their adhesion was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. HA coated scaffolds with or without MSC seeding were transplanted at the circumferential tracheal defect in rabbits, and survival, rigid bronchoscopy, radiologic findings, and histologic findings were compared between the two groups. RESULTS: HA-coated scaffolds showed better MSC adhesion than non-coated scaffolds. The HA-coated scaffolds with MSC group showed a wider airway and greater mucosal regeneration compared to the HA-coated scaffolds without MSC group. CONCLUSION: HA coating of scaffolds can promote MSC adhesion and tracheal regeneration.

Health-Related Utility of EQ-5D in Korean Adults With Chronic Urticaria: Mapping From Urticaria Outcome Measures.

PURPOSE: A need for useful measures reflective of the socio-economic burden of chronic urticaria (CU) has arisen. To obtain utility estimates for CU, we investigated EuroQol-5-Dimension (EQ-5D) indices according to urticaria control status and urticaria severity. METHODS: In this prospective observational study, we administered patient-oriented questionnaires on EQ-5D and urticaria outcomes, including Urticaria Activity Score over 7 days (UAS7), Urticaria Control Test (UCT), and CU-specific quality of life (CU-QOL). EQ-5D utility index scores were compared according to urticaria control status and disease severity. Conditional process analysis (CPA) was used to map EQ-5D utility scores from UAS7 and UCT. RESULTS: Greater EQ-5D utility values were obtained in patients with better urticaria control (0.91 ± 0.10 for well controlled CU, 0.84 ± 0.12 for partly controlled, 0.77 ± 0.14 for uncontrolled, P < 0.001). According to CU severity, mean utility values were ranged from 0.746 (severe, UAS7 ≥ 28) to 0.860 (moderate), 0.878 (mild), and 0.953 (urticaria free). CPA suggested that UAS7 was directly correlated with UCT (regression coefficient, -0.251; 95% confidence interval [CI], -0.278, -0.223; P < 0.001) and EQ-5D utility (-0.002; 95% CI, -0.003, -0.001; P = 0.007) after controlling for age, sex, urticaria duration, and combined allergic diseases. CONCLUSIONS: EQ-5D values increased with improvement in urticaria control and decreased with urticaria severity. A predictive model mapping EQ-5D utility from UAS7 and UCT scores suggested that EQ-5D can be useful for the pharmacoeconomic evaluation of individualized treatments for CU patients.

Correlation between Drop Impact Energy and Residual Compressive Strength According to the Lamination of CFRP with EVA Sheets.

Carbon-fiber-reinforced plastic is an important building material; however, its application is limited because of its brittleness, leading to vulnerability under shock. Thus, the strength performance of carbon-fiber-reinforced plastics needs to be improved. Here, the drop impact test was conducted to analyze the impact energy and fracture characteristics of carbon-fiber-reinforced plastics and ethylene vinyl acetate sheets. The compression after impact test was performed to assess the residual compressive strength. The thermal energy generated was measured as change in temperature at the time of fracture to investigate the relationship between thermal and mechanical properties. The impact absorption efficiency of 100% was achieved when the carbon-fiber-reinforced plastics specimen was laminated with four or more sheets of ethylene vinyl acetate. The thermal energy generated during impact, the impact load, and the compression after impact test strength was reduced with the increasing number of laminated ethylene vinyl acetate layers. Our results showed that, by carefully selecting the optimal conditions of fabricating the carbon-fiber-reinforced plastic/ethylene vinyl acetate composites, carbon composite materials can be used for impact mitigation.

Clinical and molecular distinctions in patients with refractory colon cancer who benefit from regorafenib treatment.

Regorafenib (Stivarga, BAY 73-4506; Bayer Pharma AG, Berlin, Germany) is a novel oral multikinase inhibitor that blocks the activity of several protein kinases. However, few guidelines exist for novel biomarkers to select patients who will likely benefit from regorafenib treatment. Metastatic colorectal cancer (mCRC) patients treated with regorafenib were evaluated in this study. Tumor tissues of these patients were subjected to next-generation sequencing-based cancer panel tests. The relationship between molecular profiling and efficacy of regorafenib was analyzed. Among the 76 mCRC patients, the median age was 58 years (range 22-79 years), and 73.7% received regorafenib as a third-line therapy. The primary tumor locations were the right side (n = 15, 19.8%) and the left side (n = 61, 80.2%). Most patients (97.4%) had received prior anti-angiogenetic agents, and a prior anti-Epidermal Growth Factor Receptor (EGFR) agent had been administered to 32.9%. Of these 76 patients, 65 were evaluated to determine the efficacy of treatment. We observed zero complete responses, seven confirmed partial responses (PR 9.2%), 26 stable disease states (34.2%), and 32 disease progressions (42.1%). The overall confirmed response rate and the disease control rate were 9.2% and 43.4%, respectively. Genomic analysis revealed that APC mutations were significant in patients who demonstrated a tumor response to regorafenib (p < 0.05). Interestingly, FGFR1 amplification was detected in only three of 76 patients (3.9%), and these three patients achieved a PR to regorafenib. The median progression-free survival time was 2.8 months (95% Confidence Interval [CI] 1.6-4.0). Patients with BRAF mutation and/or SMAD4 mutation had significantly worse progression-free survival (PFS) than those without such a mutation. On pathway analysis, Tumor Growth Factor (TGF)-beta pathways were significantly associated with worse PFS. We found that efficacy of regorafenib might be correlated with specific genetic aberrations, such as APC mutation and FGFR1 amplification. In addition, SMAD4 mutation and TGF-beta pathway were associated with worse PFS after regorafenib. We found that efficacy of regorafenib might be correlated with specific genetic aberrations, such as APC mutation and FGFR1 amplification. In addition, SMAD4 mutation and the TGF-beta pathway were associated with worse PFS after regorafenib.

Effective systemic siRNA delivery using dual-layer protected long-circulating nanohydrogel containing an inorganic core.

Systemic delivery of small interfering RNA (siRNA) has been mainly impeded by enzymatic degradation and poor cellular uptake. Calcium phosphate (CaP) has been considered a potential candidate for siRNA delivery because of its excellent biocompatibility and capability of entrapping siRNA in the crystal core. Based on the property of 3,4-dihydroxy-l-phenylalanine (dopa) binding to the surface of the CaP crystal, dual hydrogel layers consisting of a macromolecular dextran (dex) and polyethylene glycol (PEG) were introduced on the surface of the inorganic CaP core for prolonged circulation. Dextran conjugated with dopa and polyethylene glycol (PEG) (PEG-dex-dopa) can effectively control the overgrowth of the CaP/siRNA core and stabilize it by dual electrically neutral hydrophilic layers of dextran and PEG, which additionally provide reduced hepatic accumulation and systemic clearance. The dual shield of PEG-dex-dopa nanohydrogel containing a CaP/siRNA core (PEG-dex-dopa/CaP/siRNA) significantly improved the pharmacokinetic behaviors of siRNA after systemic administration, resulting in its increased distribution to tumors and the effective inhibition of tumor growth by silencing vascular endothelial growth factor (VEGF) gene expression through the enhanced permeability and retention (EPR) effect.

Enhanced Transfection of Human Mesenchymal Stem Cells Using a Hyaluronic Acid/Calcium Phosphate Hybrid Gene Delivery System.

Human mesenchymal stem cells (hMSCs) show enormous potential in regenerative medicine and tissue engineering. However, current use of hMSCs in clinics is still limited because there is no appropriate way to control their behavior in vivo, such as differentiation to a desired cell type. Genetic modification may provide an opportunity to control the cells in an active manner. One of the major hurdles for genetic manipulation of hMSCs is the lack of an efficient and safe gene delivery system. Herein, biocompatible calcium phosphate (CaP)-based nanoparticles stabilized with a catechol-derivatized hyaluronic acid (dopa-HA) conjugate were used as a carrier for gene transfection to hMSCs for improved differentiation. Owing to the specific interactions between HA and CD44 of bone marrow-derived hMSCs, dopa-HA/CaP showed significantly higher transfection in hMSCs than branched polyethylenimine (bPEI, MW 25 kDa) with no cytotoxicity. The co-delivery of a plasmid DNA encoding bone morphogenetic protein 2 (BMP-2 pDNA) and micro RNA 148b (miRNA-148b) by dopa-HA/CaP achieved significantly improved osteogenic differentiation of hMSCs.

N-doped graphene-carbon nanotube hybrid networks attaching with gold nanoparticles for glucose non-enzymatic sensor.

Herein, we successfully developed a novel three dimensional (3D) opened networks based on nitrogen doped graphene­carbon nanotubes attaching with gold nanoparticles (N-GR-CNTs/AuNPs) to apply for non-enzymatic glucose determination. It was demonstrated that the N-GR-CNTs/AuNPs modified electrode exhibited good behavior for glucose detection with a long linear range of 2 µM to 19.6 mM, high sensitivity of 0.9824 µA·mM-1·cm-2, low detection limit of 500 nM, and negligible interference effect. The high performance of the N-GR-CNTs/AuNPs based sensor was assumed due to the outstanding catalytic activity of AuNPs well dispersing on N-GR-CNTs networks, which exhibited as a perfect supporting scaffold due to the enhanced electrical conductivity and large surface area. The obtained results indicated that the N-GR-CNTs/AuNPs hybrid is highly promising for sensitive and selective detection of glucose in sensor application.

Smart vaccine delivery based on microneedle arrays decorated with ultra-pH-responsive copolymers for cancer immunotherapy.

Despite the tremendous potential of DNA-based cancer vaccines, their efficacious delivery to antigen presenting cells to stimulate both humoral and cellular response remains a major challenge. Although electroporation-based transfection has improved performance, an optimal strategy for safe and pain-free vaccination technique remains elusive. Herein, we report a smart DNA vaccine delivery system in which nanoengineered DNA vaccine was laden on microneedles (MNs) assembled with layer-by-layer coating of ultra-pH-responsive OSM-(PEG-PAEU) and immunostimulatory adjuvant poly(I:C), a synthetic double stranded RNA. Transcutaneous application of MN patches onto the mice skin perforate the stratum corneum with minimal cell damage; subsequent disassembly at the immune-cell-rich epidermis/dermis allows the release of adjuvants and DNA vaccines, owing to the ultra-sharp pH-responsive nature of OSM-(PEG-PAEU). The released adjuvant and DNA vaccine can enhance dendritic cell maturation and induce type I interferons, and thereby produce antigen-specific antibody that can achieve the antibody-dependent cell-mediated cytotoxicity (ADCC) and CD8+ T cell to kill cancer cells. Strikingly, transcutaneous application of smart vaccine formulation in mice elicited 3-fold greater frequencies of Anti-OVA IgG1 serum antibody and 3-fold excess of cytotoxic CD8+ T cell than soluble DNA vaccine formulation. As a consequence, the formulation rejected the murine B16/OVA melanoma tumors in C57BL/6 mice through the synergistic activation of antigen-specific ADCC and cytotoxic CD8+ T cells. The maneuvered use of vaccine and adjuvant poly(I:C) in MNs induces humoral and cellular immunity, which provides a promising vaccine technology that shows improved efficacy, compliance, and safety.

Microneedle arrays coated with charge reversal pH-sensitive copolymers improve antigen presenting cells-homing DNA vaccine delivery and immune responses.

Successful delivery of a DNA vaccine to antigen-presenting cells and their subsequent stimulation of CD4+ and CD8+ T cell immunity remains an inefficient process. In general, the delivery of prophylactic vaccines is mainly mired by low transfection efficacy, poor immunogenicity, and safety issues from the materials employed. Currently, several strategies have been exploited to improve immunogenicity, but an effective strategy for safe and pain-free delivery of DNA vaccines is complicated. Herein, we report the rapid delivery of polyplex-based DNA vaccines using microneedle arrays coated with a polyelectrolyte multilayer assembly of charge reversal pH-responsive copolymer and heparin. The charge reversal pH-responsive copolymer, composed of oligo(sulfamethazine)-b-poly(ethylene glycol)-b-poly(amino urethane) (OSM-b-PEG-b-PAEU), was used as a triggering layer in the polyelectrolyte multilayer assembly on microneedles. Charge reversal characteristics of this copolymer, that is, the OSM-b-PEG-b-PAEU copolymer exhibit, positive charge at low pH (pH4.03) and becoming negative charge when exposed to physiological pH conditions (pH7.4), allowing the facile assembly and disassembly of polyelectrolyte multilayers. The electrostatic repulsion between heparin and OSM-b-PEG-b-PAEU charge reversal copolymer triggered the release of DNA vaccines. DNA vaccines laden on microneedles are effectively transfected into RAW 264.7 macrophage cells in vitro. Vaccination of BALB/c mice by DNA vaccine-loaded microneedle arrays coated with a polyelectrolyte multilayer generated antigen-specific robust immune responses. These findings provide potential strategy of charge reversal pH-responsive copolymers coated microneedles for DNA vaccine delivery.

Inhibition of Tumor Growth via Systemic siRNA Delivery Using Reducible Bile Acid-Conjugated Polyethylenimine.

RNA interference (RNAi), mediated by small interfering RNA (siRNA), has been considered as a potential therapeutic agent for cancer owing to its ability to suppress target genes in a sequence-specific manner. In this study, a conjugate of the low molecular weight (MW) polyethylenimine (PEI) (MW 1800) and deoxycholic acid (DA) was further modified with 4-fluorothiophenol (FTP) (TP-DA-PEI) to achieve systemic siRNA delivery. The thiophenol group would be involved with disulfide bonds between the polymer chains and siRNA modified with free thiols (thiol-siRNA) to form and π⁻π interactions between the pendent aromatic groups and coprostane ring of the bile acid. The TP-DA-PEI conjugates could generate stable nanoparticles with thiol-siRNA. The TP-DA-PEI conjugate not only achieved enhanced intracellular uptake, serum stability, and transfection efficiency, but also showed high accumulation of TP-DA-PEI/thiol-siRNA polyplexes and significant tumor growth inhibition effect in tumor-bearing mice after systemic administration.