High-performance and low-power source-gated transistors enabled by a solution-processed metal oxide homojunction.

Cost-effective fabrication of mechanically flexible low-power electronics is important for emerging applications including wearable electronics, artificial intelligence, and the Internet of Things. Here, solution-processed source-gated transistors (SGTs) with an unprecedented intrinsic gain of ~2,000, low saturation voltage of +0.8 ± 0.1 V, and a ~25.6 µW power consumption are realized using an indium oxide In2O3/In2O3:polyethylenimine (PEI) blend homojunction with Au contacts on Si/SiO2. Kelvin probe force microscopy confirms source-controlled operation of the SGT and reveals that PEI doping leads to more effective depletion of the reverse-biased Schottky contact source region. Furthermore, using a fluoride-doped AlOx gate dielectric, rigid (on a Si substrate) and flexible (on a polyimide substrate) SGTs were fabricated. These devices exhibit a low driving voltage of +2 V and power consumption of ~11.5 µW, yielding inverters with an outstanding voltage gain of >5,000. Furthermore, electrooculographic (EOG) signal monitoring can now be demonstrated using an SGT inverter, where a ~1.0 mV EOG signal is amplified to over 300 mV, indicating significant potential for applications in wearable medical sensing and human-computer interfacing.

Highly stretchable organic electrochemical transistors with strain-resistant performance.

Realizing fully stretchable electronic materials is central to advancing new types of mechanically agile and skin-integrable optoelectronic device technologies. Here we demonstrate a materials design concept combining an organic semiconductor film with a honeycomb porous structure with biaxially prestretched platform that enables high-performance organic electrochemical transistors with a charge transport stability over 30-140% tensional strain, limited only by metal contact fatigue. The prestretched honeycomb semiconductor channel of donor-acceptor polymer poly(2,5-bis(2-octyldodecyl)-3,6-di(thiophen-2-yl)-2,5-diketo-pyrrolopyrrole-alt-2,5-bis(3-triethyleneglycoloxy-thiophen-2-yl) exhibits high ion uptake and completely stable electrochemical and mechanical properties over 1,500 redox cycles with 104 stretching cycles under 30% strain. Invariant electrocardiogram recording cycles and synapse responses under varying strains, along with mechanical finite element analysis, underscore that the present stretchable organic electrochemical transistor design strategy is suitable for diverse applications requiring stable signal output under deformation with low power dissipation and mechanical robustness.

Evolutionary Diversity of Coxsackievirus A6 Causing Severe Hand, Foot, and Mouth Disease - China, 2012-2023.

Introduction: Coxsackievirus A6 (CVA6) has emerged as a significant pathogen responsible for severe cases of hand, foot, and mouth disease (HFMD). This study aims to delineate the demographic characteristics and analyze the viral evolution of severe HFMD associated with CVA6, thereby assisting in its surveillance and management. Methods: In this investigation, 74 strains of CVA6 were isolated from samples collected from severe HFMD cases between 2012 and 2023. The VP1 gene sequences of CVA6 were amplified and analyzed to assess population historical dynamics and evolutionary characteristics using BEAST, DnaSP6, and PopART. Results: A significant portion (94.4%) of severe CVA6-associated HFMD cases (51 out of 54, with 20 lacking age information) were children under 5 years old. Among the 74 CVA6 strains analyzed, 72 belonged to the D3a sub-genotype, while only two strains were D2 sub-genotype. The average genetic distance between VP1 sequences prior to 2015 was 0.027, which increased to 0.051 when compared to sequences post-2015. Historical population dynamics analysis indicated three significant population expansions of severe CVA6-associated HFMD during 2012-2013, 2013-2014, and 2019-2020, resulting in the formation of 65 distinct haplotypes. Consistent with the MCC tree findings, transitioning between regional haplotypes required multiple base substitutions, showcasing an increase in population diversity during the evolutionary process (from 14 haplotypes in 2013 to 55 haplotypes over the subsequent decade). Conclusions: CVA6, associated with severe HFMD, is evolving and presents a risk of outbreak occurrence. Thus, enhanced surveillance of severe HFMD is imperative.

Facile synthesis of monodispersed Fe2O3 nanoparticles and its cellular uptake and cytotoxicity studies.

Monodispersed Fe2O3 nanoparticles were fabricated with a facile hydrothermal synthetic route by using Fe(NO3)3 x 7H2O and glycin as reagents without using any templates or surfactants in this report. The prepared nanoparticles were pure hexagonal alpha-Fe2O3 particles from the characterization of XRD analysis. The Fe2O3 nanoparticles with a narrow size distribution and a mean diameter of - 50 nm can be well dispersed in water. Cellular uptake and cellular responses of the as-prepared Fe2O3 nanoparticles for human cancer cells have been studied. The Fe2O3 nanoparticles can be readily uptake by the cells, but no obvious oxidative damages in the cells can be detected after an incubation of 24 h. Also the treatment of Fe2O3 nanoparticles did not induce any changes in cell viability and cell proliferation. These results demonstrate that the Fe2O3 nanoparticles prepared with our method are remarkably biocompatible, which can be used as a substitute with high biosafety for the present iron oxides materials in different kinds of applications.

Collagen biomaterials promote the regenerative repair of abdominal wall defects in Bama miniature pigs.

Due to adhesion and rejection of recent traditional materials, it is still challenging to promote the regenerative repair of abdominal wall defects caused by different hernias or severe trauma. However, biomaterials with a high biocompatibility and low immunogenicity have exhibited great potential in the regeneration of abdominal muscle tissue. Previously, we have designed a biological collagen scaffold material combined with growth factor, which enables a fusion protein-collagen binding domain (CBD)-basic fibroblast growth factor (bFGF) to bind and release specifically. Though experiments in rodent animals have indicated the regeneration function of CBD-bFGF modified biological collagen scaffolds, its translational properties in large animals or humans are still in need of solid evidence. In this study, the abdominal wall defect model of Bama miniature pigs was established by artificial operations, and the defective abdominal wall was sealed with or without a polypropylene patch, and unmodified and CBD-bFGF modified biological collagen scaffolds. Results showed that a recurrent abdominal hernia was observed in the defect control group (without the use of mesh). Although the polypropylene patch can repair the abdominal wall defect, it also induced serious adhesion and inflammation. Meanwhile, both kinds of collagen biomaterials exhibited positive effects in repairing abdominal wall defects and reducing regional adhesion and inflammation. However, CBD-bFGF-modified collagen biomaterials failed to induce the regenerative repair reported in rat experiments. In addition, unmodified collagen biomaterials induced abdominal wall muscle regeneration rather than fibrotic repair. These results indicated that the unmodified collagen biomaterials are a better option among translational patches for the treatment of abdominal wall defects.

Effectiveness of a Brief Mindfulness-Based Intervention of "STOP touching your face" During the COVID-19 Pandemic: a Randomized Controlled Trial.

Objectives: Avoiding touching the eyes, nose, and mouth (T-zone) is a strategy to reduce the spread of COVID-19. This study evaluated the effectiveness of a brief mindfulness-based intervention (MBI) named "STOP (Stop, Take a Breath, Observe, Proceed) touching your face" for reducing face-touching behavior. Methods: In this online-based, two-arm, wait-list, randomized controlled trial, eligible participants were randomly assigned to the intervention (n = 545) or control group (n = 545). The results of 60-min self-monitoring of face-touching behavior were reported before and after the intervention. Reduction of the percentage of T-zone touching was the primary outcome, and reduction of face-touching frequency was a key secondary outcome. Outcomes were analyzed on an intention-to-treat (ITT) basis with a complete case analysis (CCA). Results: ITT analysis revealed that the percentage of T-zone touching was significantly reduced by 8.1% in the intervention group (from 81.1 to 73.0%, RR = 0.901, OR = 0.631, RD = - 0.081, p = 0.002), and insignificantly reduced by 0.6% in the control group (from 80.0 to 79.4%, p = 0.821). Fewer participants performed T-zone touching in the intervention group than in the control group (73.0% vs. 79.4%, RR = 0.919, OR = 0.700, RD = - 0.064, p = 0.015) after the intervention, and there was a greater reduction of T-zone touching frequency in the intervention group than in the control group [mean ± SD: 1.7 ± 5.13 vs. 0.7 ± 3.98, mean difference (95% CI): 1.03 (0.48 to 1.58), p < 0.001, Cohen's d = - 0.218]. The above results were further confirmed by CCA. Conclusions: This brief mindfulness-based intervention was potentially effective at reducing the spread of COVID-19 and could be further investigated as an intervention for preventing other infectious diseases spread by hand-to-face touching. Trial Registration: ClinicalTrials.gov NCT04330352. Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-022-02019-x.

Genomic Epidemiology and Phylodynamic Analysis of Enterovirus A71 Reveal Its Transmission Dynamics in Asia.

Enterovirus A71 (EV-A71) is one of the main pathogens causing hand, foot, and mouth disease (HFMD) outbreaks in Asian children under 5 years of age. In severe cases, it can cause neurological complications and be life-threatening. In this study, 200 newly sequenced EV-A71 whole-genome sequences were combined with 772 EV-A71 sequences from GenBank for large-scale analysis to investigate global EV-A71 epidemiology, phylogeny, and Bayesian phylodynamic characteristics. Based on the phylogenetic analysis of the EV-A71 3Dpol region, six new evolutionary lineages (lineages B, J, K, O, P, and Q) were found in this study, and the number of evolutionary lineages was expanded from 11 to 17. Temporal dynamics and recombination breakpoint analyses based on genotype C revealed that recombination of nonstructural protein-coding regions, including 3Dpol, is an important reason for the emergence of new lineages. The EV-A71 epidemic in the Asia-Pacific region is complex, and phylogeographic analysis found that Vietnam played a key role in the spread of subgenotypes B5 and C4. The origin of EV-A71 subgenotype C4 in China is East China, which is closely related to the prevalence of subgenotype C4 in the south and throughout China. Selection pressure analysis revealed that, in addition to VP1 amino acid residues VP1-98 and VP1-145, which are associated with EV-A71 pathogenicity, amino acid residues VP1-184 and VP1-249 were also positively selected, and their functions still need to be determined by biology and immunology. This study aimed to provide a solid theoretical basis for EV-A71-related disease surveillance and prevention, antiviral research, and vaccine development through a comprehensive analysis. IMPORTANCE EV-A71 is one of the most important pathogens causing HFMD outbreaks; however, large-scale studies of EV-A71 genomic epidemiology are currently lacking. In this study, 200 new EV-A71 whole-genome sequences were determined. Combining these with 772 EV-A71 whole-genome sequences in the GenBank database, the evolutionary and transmission characteristics of global and Asian EV-A71 were analyzed. Six new evolutionary lineages were identified in this study. We also found that recombination in nonstructural protein-coding regions, including 3Dpol, is an important cause for the emergence of new lineages. The results provided a solid theoretical basis for EV-A71-related disease surveillance and prevention, antiviral research, and vaccine development.

Removal of typical endocrine disrupting chemicals by membrane bioreactor: in comparison with sequencing batch reactor.

The removal of endocrine disrupting chemicals (EDCs) by a laboratory-scale membrane bioreactor (MBR) fed with synthetic sewage was evaluated and moreover, compared with that by a sequencing batch reactor (SBR) operated under same conditions in parallel. Eight kinds of typical EDCs, including 17ß-estradiol (E2), estrone (E1), estriol (E3), 17α-ethynilestradiol (EE2), 4-octylphenol (4-OP), 4-nonylphenol (4-NP), bisphenol A (BPA) and nonylphenol ethoxylates (NPnEO), were spiked into the feed. Their concentrations in influent, effluent and supernatant were determined by gas chromatography-mass spectrometry method. The overall estrogenecity was evaluated as 17ß-estradiol equivalent quantity (EEQ), determined via yeast estrogen screen (YES) assay. E2, E3, BPA and 4-OP were well removed by both MBR and SBR, with removal rates more than 95% and no significant differences between the two reactors. However, with regard to the other four EDCs, of which the removal rates were lower, MBR performed better. Comparison between supernatant and effluent of the two reactors indicated that membrane separation of sludge and effluent, compared with sedimentation, can relatively improve elimination of target EDCs and total estrogenecity. By applying different solids retention times (SRTs) (5, 10, 20 and 40 d) to the MBR, 10 and 5 d were found to be the lower critical SRTs for efficient target EDCs and EEQ removal, respectively.

GLUT1 targeting and hypoxia-activating polymer-drug conjugate-based micelle for tumor chemo-thermal therapy.

PURPOSE: Mitochondria are closely correlated with the proliferation and metastasis of tumor for providing suitable micro-environment and energy supply. Herein, we construct a glucose transporter 1 (GLUT1) targeting and hypoxia activating polyprodrug-based micelle (Glu-PEG-Azo-IR808-S-S-PTX) for mitochondria-specific drug delivery and tumor chemo-thermal therapy. RESULTS: The micelle was characterized by hypoxia-sensitive PEG outer layer detachment, high photo-thermal conversion efficiency, and glutathione (GSH)-sensitive paclitaxel （PTX） release. It showed GLUT1 specifically cellular uptake and hypoxia-sensitive mitochondria targeting on A549 cell. In vivo fluorescence imaging confirmed the micelle also could selectively accumulate in tumor and its mitochondria on A549 tumor-bearing nude mice. Consequently, it not only exhibited higher cytotoxicity, apoptosis rate, and metastasis inhibition rate on A549 cells, but also better tumor growth and metastasis inhibition rate on tumor-bearing nude mice and lower whole-body toxicity. The mechanism might be caused by destroying mitochondria and down-regulating ATP production. CONCLUSION: This study provided a GLUT1 targeting, hypoxia, and reductive responsive nanomedicine that hold the potential to be exploited for tumor therapy.

Docetaxel loaded mPEG-PLA nanoparticles for sarcoma therapy: preparation, characterization, pharmacokinetics, and anti-tumor efficacy.

Sarcoma represents one of the most common malignant tumors with poor treatment outcomes and prognosis. Docetaxel (DTX) is acknowledged as one of the most important chemotherapy agents. The aim of this study was to improve the efficacy of docetaxel by incorporation into the mPEG-PLA nanoparticle (DTX NP) for the treatment of sarcoma. The DTX NP was prepared by emulsion solvent diffusion method and the prescription and preparation process were optimized through a single factor experiment. The optimized DTX NP was characterized by drug loading, encapsulation efficiency, drug release, etc. Then, the pharmacokinetics was conducted on rats and tumor-bearing ICR mice. Finally, the anti-tumor efficacy of DTX NP with different dosages was evaluated on tumor-bearing ICR mice. The optimized DTX NP was characterized by around 100 nm sphere nanoparticles, sustained in vitro drug release with no obvious burst drug release. Compared with DTX injection, the AUC of DTX NP increased by 94.7- and 35.1-fold on the rats and tumor-bearing ICR mice models, respectively. Moreover, the intra-tumoral drug concentration increased by 5.40-fold. The tumor inhibition rate of DTX NP reached 94.66%, which was 1.24 times that of DTX injection (76.11%) at the same dosage, and the bodyweight increase rate was also higher than the DTX injection. The study provided a DTX NP, which could significantly improve the bioavailability and therapeutic efficacy of DTX as well as reduced its toxicity. It possessed a certain prospect of application for sarcoma treatment.

A Large-Scale Outbreak of Echovirus 30 in Gansu Province of China in 2015 and Its Phylodynamic Characterization.

BACKGROUND: Echovirus 30 (E-30) has been investigated and reported worldwide and is closely associated with several infectious diseases, including encephalitis; myocarditis; and hand, foot, and mouth disease. Although many E-30 outbreaks associated with encephalitis have been reported around the world, it was not reported in northwest China until 2015. METHODS: The clinical samples, including the feces, serum, throat swabs, and cerebrospinal fluid, were collected for this study and were analyzed for diagnosis. E-30 was isolated and processed according to the standard procedures. The epidemiological and phylogenetic analysis were performed to indicate the characteristics of E-30 outbreaks and phylodynamics of E-30 in China. RESULTS: The E-30 outbreaks affected nine towns of Gansu Province in 2015, starting at a school of Nancha town and spreading to other towns within 1 month. The epidemiological features showed that children aged 6-15 years were more susceptible to E-30 infection. The genotypes B and C cocirculated in the world, whereas the latter dominated the circulation of E-30 in China. The genome sequences of this outbreak present 99.3-100% similarity among these strains, indicating a genetic-linked aggregate outbreak of E-30 in this study. Two larger genetic diversity expansions and three small fluctuations of E-30 were observed from 1987 to 2016 in China, which revealed the oscillating patterns of E-30 in China. In addition, the coastal provinces of China, such as Zhejiang, Fujian, and Shandong, were initially infected, followed by other parts of the country. The E-30 strains isolated from mainland of China may have originated from Taiwan of China in the last century. CONCLUSION: The highly similar E-30 genomes in this outbreak showed an aggregate outbreak of E-30, with nine towns affected. Our results suggested that, although the genetic diversity of E-30 oscillates, the dominant lineages of E-30 in China has complex genetic transmission. The coastal provinces played an important role in E-30 spread, which implied further development of effective countermeasures. This study provides a further insight into the E-30 outbreak and transmission and illustrates the importance of valuable surveillance in the future.

Genetic recombination in fast-spreading coxsackievirus A6 variants: a potential role in evolution and pathogenicity.

Hand, foot, and mouth disease (HFMD) is a common global epidemic. From 2008 onwards, many HFMD outbreaks caused by coxsackievirus A6 (CV-A6) have been reported worldwide. Since 2013, with a dramatically increasing number of CV-A6-related HFMD cases, CV-A6 has become the predominant HFMD pathogen in mainland China. Phylogenetic analysis based on the VP1 capsid gene revealed that subtype D3 dominated the CV-A6 outbreaks. Here, we performed a large-scale (near) full-length genetic analysis of global and Chinese CV-A6 variants, including 158 newly sequenced samples collected extensively in mainland China between 2010 and 2018. During the global transmission of subtype D3 of CV-A6, the noncapsid gene continued recombining, giving rise to a series of viable recombinant hybrids designated evolutionary lineages, and each lineage displayed internal consistency in both genetic and epidemiological features. The emergence of lineage -A since 2005 has triggered CV-A6 outbreaks worldwide, with a rate of evolution estimated at 4.17 × 10-3 substitutions site- 1 year-1 based on a large number of monophyletic open reading frame sequences, and created a series of lineages chronologically through varied noncapsid recombination events. In mainland China, lineage -A has generated another two novel widespread lineages (-J and -L) through recombination within the enterovirus A gene pool, with robust estimates of occurrence time. Lineage -A, -J, and -L infections presented dissimilar clinical manifestations, indicating that the conservation of the CV-A6 capsid gene resulted in high transmissibility, but the lineage-specific noncapsid gene might influence pathogenicity. Potentially important amino acid substitutions were further predicted among CV-A6 variants. The evolutionary phenomenon of noncapsid polymorphism within the same subtype observed in CV-A6 was uncommon in other leading HFMD pathogens; such frequent recombination happened in fast-spreading CV-A6, indicating that the recovery of deleterious genomes may still be ongoing within CV-A6 quasispecies. CV-A6-related HFMD outbreaks have caused a significant public health burden and pose a great threat to children's health; therefore, further surveillance is greatly needed to understand the full genetic diversity of CV-A6 in mainland China.

Enhanced anti-hepatocarcinoma efficacy by GLUT1 targeting and cellular microenvironment-responsive PAMAM-camptothecin conjugate.

The efficient targeting of drugs to tumor cell and subsequent rapid drug release remain primary challenges in the development of nanomedicines for cancer therapy. Here, we constructed a glucose transporter 1 (GLUT1)-targeting and tumor cell microenvironment-sensitive drug release Glucose-PEG-PAMAM-s-s-Camptothecin-Cy7 (GPCC) conjugate to tackle the dilemma. The conjugate was characterized by a small particle size, spherical shape, and glutathione (GSH)-sensitive drug release. In vitro tumor targeting was explored in monolayer (2D) and multilayer tumor spheroid (3D) HepG2 cancer cell models (GLUT1+). The cellular uptake of GPCC was higher than that in the control groups and that in normal L02 cells (GLUT1-), likely due to the conjugated glucose moiety. Moreover, the GPCC conjugate exhibited stronger cytotoxicity, higher S arrest and enhanced apoptosis and necrosis rate in HepG2 cells than control groups but not L02 cells. However, the cytotoxicity of GPCC was lower than that of free CPT, which could be explained by the slower release of CPT from the GPCC compared with free CPT. Additional in vivo tumor targeting experiments demonstrated the superior tumor-targeting ability of the GPCC conjugate, which significantly accumulated in tumor meanwhile minimize in normal tissues compared with control groups. The GPCC conjugate showed better pharmacokinetic properties, enabling a prolonged circulation time and increased camptothecin area under the curve (AUC). These features contributed to better therapeutic efficacy and lower toxicity in H22 hepatocarcinoma tumor-bearing mice. The GLUT1-targeting, GSH-sensitive GPCC conjugate provides an efficient, safe and economic approach for tumor cell targeted drug delivery.

Overcoming Multidrug Resistance through the GLUT1-Mediated and Enzyme-Triggered Mitochondrial Targeting Conjugate with Redox-Sensitive Paclitaxel Release.

Multidrug resistance (MDR) is thought to be the major obstacle leading to the failure of paclitaxel (PTX) chemotherapy. To solve this problem, a glucose transporter-mediated and matrix metalloproteinase 2 (MMP2)-triggered mitochondrion-targeting conjugate [glucose-polyethylene glycol (PEG)-peptide-triphenylphosponium-polyamidoamine (PAMAM)-PTX] composed of a PAMAM dendrimer and enzymatic detachable glucose-PEG was constructed for mitochondrial delivery of PTX. The conjugate was characterized by a 30 nm sphere particle, MMP2-sensitive PEG outer layer detachment from PAMAM, and glutathione (GSH)-sensitive PTX release. It showed higher cellular uptake both in glucose transporter 1 (GLUT1) overexpressing MCF-7/MDR monolayer cell (2D) and multicellular tumor spheroids (3D). The subcellular location study showed that it could specifically accumulate in the mitochondria. Moreover, it exhibited higher cytotoxicity against MCF-7/MDR cells, which significantly reverse the MDR of MCF-7/MDR cells. The MDR reverse might be caused by reducing the ATP content through destroying the mitochondrial membrane as well as by down-regulating P-gp expression. In vivo imaging and tissue distribution indicated more conjugate accumulated in the tumor of the tumor-bearing mice model. Consequently, the conjugate showed better tumor inhibition rate and lower body weight loss, which demonstrated that it possessed high efficiency and low toxicity. This study provides glucose-mediated GLUT targeting, MMP2-responsive PEG detachment, triphenylphosponium-mediated mitochondria targeting, and a GSH-sensitive intracellular drug release conjugate that has the potential to be exploited for overcoming MDR of PTX.

Enhanced immunofluorescence detection of a protein marker using a PAA modified ZnO nanorod array-based microfluidic device.

Zinc oxide (ZnO) often serves as protein microarray substrates owing to its outstanding fluorescence enhancement effect. However, the integration of functional substrates with microfluidic technology to detect cancer biomarkers still needs to be optimized and promoted, for example, the optimization of micro/nanostructure and hydrophilic modification strategies for fluorescence immunoassays. Here, ZnO nanorod arrays were constructed on the inner wall of glass capillaries through a microfluidic chemical method, and the electrostatic layer by layer self-assembly was applied to modify the nanorod array with hydrophilic polyelectrolyte-polyacrylic acid (PAA). The effects of the flow rate and the reagent concentration on the morphology of the ZnO nanorod array were investigated. The ZnO nanorod array-based glass capillary, prepared at 25 µL min-1 for 4 min with 50 mM Zn2+ in solution, showed a remarkable enhancement in fluorescence performance. In addition, the introduction of PAA suppressed the interference of nonspecific protein and improved the antibody loading capacity effectively. In the detection of carcinoembryonic antigen, the limit of detection reached 100 fg mL-1, which indicated that the ZnO@PAA nanorod array-based microfluidic device exhibits remarkable fluorescence detection performance towards protein markers and possesses potential to be applied to point-of-care diagnostics and high throughput cancer biomarker detection.

Temperature-Sensitive Gold Nanoparticle-Coated Pluronic-PLL Nanoparticles for Drug Delivery and Chemo-Photothermal Therapy.

Gold nanoparticle-coated Pluronic-b-poly(L-lysine) nanoparticles (Pluronic-PLL@Au NPs) were synthesized via an easy one-step method and employed as carriers for the delivery of paclitaxel (PTX) in chemo-photothermal therapy, in which Pluronic-PLL acts as the reductant for the formation of AuNPs without the need for an additional reducing agent. METHODS: The deposition of AuNPs on the surface of Pluronic-PLL micelles and the thermal response of the system were followed via ultraviolet-visible spectroscopy and dynamic light scattering. Calcein-AM and MTT assays were used to study the cell viability of MDA-MB-231 cells treated with PTX-loaded Pluronic-PLL@Au NPs, and we then irradiated the cells with NIR light. RESULTS: An obvious temperature response was observed for the Pluronic-PLL@Au NPs. Blood compatibility and in vitro cytotoxicity assays confirmed that the Pluronic-PLL@Au NPs have excellent biocompatibility. Compared to Taxol, the PTX-loaded Pluronic-PLL@Au NPs exhibited higher cytotoxicity in MDA-MB-231 cells. All of these results and confocal laser scanning microscopy analysis results suggest that Pluronic-PLL@Au NPs greatly enhance the cellular uptake efficiency of the drug. CONCLUSION: As confirmed by in vitro and in vivo studies, the combination of chemotherapy and photothermal therapy can cause more damage than chemo- or photothermal therapy did alone, demonstrating the synergistic effect of chemo-photothermal treatment. Thus, the as-prepared Pluronic-PLL@Au NPs are promising for chemo-photothermal therapy.

In vivo study of doxorubicin-loaded cell-penetrating peptide-modified pH-sensitive liposomes: biocompatibility, bio-distribution, and pharmacodynamics in BALB/c nude mice bearing human breast tumors.

In vivo evaluation of drug delivery vectors is essential for clinical translation. In BALB/c nude mice bearing human breast cancer tumors, we investigated the biocompatibility, pharmacokinetics, and pharmacodynamics of doxorubicin (DOX)-loaded novel cell-penetrating peptide (CPP)-modified pH-sensitive liposomes (CPPL) (referred to as CPPL(DOX)) with an optimal CPP density of 4%. In CPPL, a polyethylene glycol (PEG) derivative formed by conjugating PEG with stearate via acid-degradable hydrazone bond (PEG2000-Hz-stearate) was inserted into the surface of liposomes, and CPP was directly attached to liposome surfaces via coupling with stearate to simultaneously achieve long circulation time in blood and improve the selectivity and efficacy of CPP for tumor targeting. Compared to PEGylated liposomes, CPPL enhanced DOX accumulation in tumors up to 1.9-fold (p<0.01) and resulted in more cell apoptosis as a result of DNA disruption as well as a relatively lower tumor growth ratio (T/C%). Histological examination did not show any signs of necrosis or inflammation in normal tissues, but large cell dissolving areas were found in tumors following the treatment of animals with CPPL(DOX). Our findings provide important and detailed information regarding the distribution of CPPL(DOX) in vivo and reveal their abilities of tumor penetration and potential for the treatment of breast cancer.

An efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery.

Cell-penetrating peptides (CPPs) as small molecular transporters with abilities of cell penetrating, internalization, and endosomal escape have potential prospect in drug delivery systems. However, a bottleneck hampering their application is the poor specificity for cells. By utilizing the function of hydration shell of polyethylene glycol (PEG) and acid sensitivity of hydrazone bond, we constructed a kind of CPP-modified pH-sensitive PEGylated liposomes (CPPL) to improve the selectivity of these peptides for tumor targeting. In CPPL, CPP was directly attached to liposome surfaces via coupling with stearate (STR) to avoid the hindrance of PEG as a linker on the penetrating efficiency of CPP. A PEG derivative by conjugating PEG with STR via acid-degradable hydrazone bond (PEG2000-Hz-STR, PHS) was synthesized. High-performance liquid chromatography and flow cytometry demonstrated that PHS was stable at normal neutral conditions and PEG could be completely cleaved from liposome surface to expose CPP under acidic environments in tumor. An optimal CPP density on liposomes was screened to guaranty a maximum targeting efficiency on tumor cells as well as not being captured by normal cells that consequently lead to a long circulation in blood. In vitro and in vivo studies indicated, in 4 mol% CPP of lipid modified system, that CPP exerted higher efficiency on internalizing the liposomes into targeted subcellular compartments while remaining inactive and free from opsonins at a maximum extent in systemic circulation. The 4% CPPL as a drug delivery system will have great potential in the clinical application of anticancer drugs in future.

Nafion covered core-shell structured Fe3O4@graphene nanospheres modified electrode for highly selective detection of dopamine.

Nafion covered core-shell structured Fe3O4@graphene nanospheres (GNs) modified glassy carbon electrode (GCE) was successfully prepared and used for selective detection dopamine. Firstly, the characterizations of hydro-thermal synthesized Fe3O4@GNs were investigated by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and Raman spectroscopy. Then Fe3O4@GNs/Nafion modified electrode exhibited excellent electrocatalytic activity toward the oxidations of dopamine (DA). The interference test showed that the coexisted ascorbic acid (AA) and uric acid (UA) had no electrochemical interference toward DA. Under the optimum conditions, the broad linear relationship was obtained in the experimental concentration from 0.020 µM to 130.0 µM with the detection limit (S/N=3) of 0.007 µM. Furthermore, the core-shell structured Fe3O4@GNs/Nafion/GCE was applied to the determination of DA in real samples and satisfactory results were got, which could provide a promising platform to develop excellent biosensor for detecting DA.