PubTransformer

A site to transform Pubmed publications into these bibliographic reference formats: ADS, BibTeX, EndNote, ISI used by the Web of Knowledge, RIS, MEDLINE, Microsoft's Word 2007 XML.

Zhuo Chen - Top 30 Publications

Detection and delineation of squamous neoplasia with hyperspectral imaging in a mouse model of tongue carcinogenesis.

yperspectral imaging (HSI) holds the potential for the noninvasive detection of cancers. Oral cancers are often diagnosed at a late stage when treatment is less effective and the mortality and morbidity rates are high. Early detection of oral cancer is, therefore, crucial in order to improve the clinical outcomes. To investigate the potential of HSI as a non-invasive diagnostic tool, an animal study was designed to acquire hyperspectral images of in vivo and ex vivo mouse tongues from a chemically induced tongue carcinogenesis model. A variety of machine-learning algorithms, including discriminant analysis, ensemble learning, and support vector machines, were evaluated for tongue neoplasia detection using HSI and were validated by the reconstructed pathological gold-standard maps. The diagnostic performance of HSI, autofluorescence imaging, and fluorescence imaging were compared in this study. Color-coded prediction maps were generated to display the predicted location and distribution of premalignant and malignant lesions. This study suggests that hyperspectral imaging combined with machine-learning techniques can provide a non-invasive tool for the quantitative detection and delineation of squamous neoplasia. Detection and delineation of tongue neoplasia with hyperspectral imaging validated by the pathological gold standard.

Chinese herbal medicine Dengzhan Xixin injection for acute ischemic stroke: A systematic review and meta-analysis of randomised controlled trials.

To evaluate the effectiveness and safety of Chinese herbal medicine Dengzhan Xixin (Erigeron breviscapus) injection for acute ischemic stroke.

Full color waveguide liquid crystal display.

We developed a waveguide liquid crystal display from a liquid crystal (LC)/polymer composite. It does not need polarizers or color filters. It is illuminated by color LEDs installed on its edge. The light produced by the edge LEDs is coupled into the display and then waveguided through the display. When the LC is in the transparent state, the incident light is waveguided through and no light comes out of the viewing side of the display. When the LC is in the scattering state, the incident light is scattered and comes out of the display. It can be used either for transparent display or for direct view display. The composite has a submillisecond response time, and a field sequential scheme can be used to display full color images. Because the display does not need polarizers or color filters, its energy efficiency is much higher than current liquid crystal displays.

Two BRM Promoter Polymorphisms Predict Poor Survival in Patients with Hepatocellular Carcinoma.

Polymorphisms in the promoter of the BRM gene, a critical subunit of the chromatin remodeling SWI/SNF complex, have previously been implicated in risk and prognosis in Caucasian-predominant lung, head and neck, esophageal, and pancreatic cancers, and in hepatocellular cancers in Asians. We investigated the role of these polymorphisms in hepatocellular carcinoma (HCC) risk and prognosis.

Meta-Analysis Comparing Metoprolol and Carvedilol on Mortality Benefits in Patients With Acute Myocardial Infarction.

Although carvedilol, a nonselective beta-blocker with alpha-adrenergic blocking and multiple ancillary activities, has been demonstrated to be superior to metoprolol in chronic heart failure, it remains unclear whether the superiority of carvedilol still exists in myocardial infarction (MI). Therefore, we performed a network meta-analysis of randomized controlled trials (RCTs) to compare the 2 drugs in patients with MI. All RCTs that compared either 2 of the following interventions, carvedilol, metoprolol, and placebo, for the treatment of MI were included. The Cochrane Collaboration Central Register of Controlled Trials, Embase, and PubMed were searched thoroughly for potential eligible studies. Finally, 12 RCTs involving 61,081 patients were included. Pooled results showed that compared with placebo, carvedilol and metoprolol significantly reduced composite cardiovascular events (risk ratio [RR] 0.63; 95% credible interval [CrI] 0.41, 0.85 for carvedilol; RR 0.78; 95% CrI 0.65, 0.93 for metoprolol) and re-infarction (RR 0.57; 95% CrI 0.37, 0.84 for carvedilol; RR 0.77; 95% CrI 0.62, 0.91 for metoprolol) in patients with MI. However, neither carvedilol nor metoprolol showed significant benefits on all-cause death, cardiovascular death, revascularization, and rehospitalization. Also, no obvious difference was found when comparing carvedilol and metoprolol on primary or secondary outcomes. In conclusion, there is insufficient evidence supporting the superiority of carvedilol over metoprolol for the treatment of MI. Further studies are needed to confirm our findings.

BRCA Genetic Testing and Receipt of Preventive Interventions Among Women Aged 18-64 Years with Employer-Sponsored Health Insurance in Nonmetropolitan and Metropolitan Areas - United States, 2009-2014.

Genetic testing for breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) gene mutations can identify women at increased risk for breast and ovarian cancer. These testing results can be used to select preventive interventions and guide treatment. Differences between nonmetropolitan and metropolitan populations in rates of BRCA testing and receipt of preventive interventions after testing have not previously been examined.

Preparation, characterization and toxicity evaluation of amphotericin B loaded MPEG-PCL micelles and its application for buccal tablets.

Oral candidiasis or thrush is a fungal infection due to Candida albicans, causing discomfort in areas inside mouth or tongue. The clinical application of antifungal reagent amphotericin B (AMB), which is believed to offer a better treatment for oral candidiasis, is greatly compromised by its toxicities (mainly nephrotoxicity) and poor solubility. In order to overcome these issues, we characterized AMB-loaded MPEG-PCL micelles in vitro and in vivo. In addition, the antifungal activities of AMB/MPEG-PCL micelles-loaded buccal tablet were also evaluated in vitro. We found that micelles system could significantly improve the solubility of AMB yet reduce the overall toxicity, while the buccal tablet system is capable to suppress C. albicans biofilm formation. Furthermore, the toxicity of the buccal tablet system is also reduced compared with other standard preparations. Therefore, the prepared tablet with AMB-loaded MPEG-PCL micelles as oral topical preparations has the potential to improve current treatment of superficial oral C. albicans infections.

Corrigendum: In situ targeted MRI detection of Helicobacter pylori with stable magnetic graphitic nanocapsules.

This corrects the article DOI: 10.1038/ncomms15653.

Synthesis and biological evaluation of pyridinium-functionalized carbazole derivatives as promising antibacterial agents.

Various pyridinium-functionalized carbazole derivatives were constructed by coupling the key fragments of carbazole skeleton and pyridinium nucleus in a single molecular architecture. Antibacterial bioassays revealed that some of the title compounds displayed impressive bioactivities against plant pathogens such as Xanthomonas oryzae pv. oryzae, Ralstonia solanacearum, and Xanthomonas axonopodis pv. citri with minimal EC50 values of up to 0.4, 0.3, and 0.3mg/L, respectively. These bioactivities were achieved by systematically tuning and optimizing bridging linker, alkyl length of the tailor, and substituents on the carbazole scaffold. Compared with the bioactivity of the lead compound (AP-10), antibacterial efficacy dramatically increased by approximately 13-, 104- and 21-fold. This finding suggested that these compounds can serve as new lead compounds in research on antibacterial chemotherapy.

Synthesis and antiviral evaluation of novel 1,3,4-oxadiazole/thiadiazole-chalcone conjugates.

A series of novel 1,3,4-oxadiazole/thiadiazole-chalcone conjugates were synthesized and their in vitro and in vivo antiviral activities were evaluated via microscale thermophoresis method and half-leaf method, respectively. The in vitro results indicated that compounds 7g, 7l, 8h, and 8l displayed good antiviral activity against TMV, with the binding constant values of 5.93, 6.15, 6.02, and 5.04μM, respectively, which were comparable to that of Ninnanmycin (6.78μM) and even better than that of Ribavirin (99.25μM). The in vivo results demonstrated that compounds 7g, 7l, 8h, and 8l exhibited remarkable anti-TMV activity with the EC50 values of 33.66, 33.97, 33.87 and 30.57µg/mL, respectively, which were comparable to that of Ningnanmycin (36.85µg/mL) and superior to that of Ribavirin (88.52µg/mL). Interestingly, the trend of antiviral activity in vivo was consistent with the in vitro results.

Modeling of coarctation of aorta in human fetuses using 3D/4D fetal echocardiography and computational fluid dynamics.

We sought to develop a hemodynamic model of aortic and ductal arches using computational fluid dynamics (CFD) and 3D/4D spatio-temporal image correlation (STIC) fetal echocardiography and to investigate the hemodynamics of coarctation of aorta (CoA) in human fetuses using this approach.

Tumor Microenvironment in Treatment of Glioma.

Glioma is one of the most malignant and fatal tumors in adults. Researchers and physicians endeavor to improve clinical efficacy towards it but made little achievement. In recent years, people have made advances in understanding characteristics and functions of tumor microenvironment and its role in different processes of tumor. In this paper, we describe the effects of tumor microenvironment on glioma proliferation, invasion and treatments. By explaining underlying mechanisms and enumerating new therapy strategies employing tumor microenvironment, we aim to provide novel ideas to improve clinical outcomes of glioma.

A pH-sensitive methenamine mandelate-loaded nanoparticle induces DNA damage and apoptosis of cancer cells.

Methenamine mandelate is a urinary antibacterial agent, which can be converted to formaldehyde in urine that has a relatively low pH of average 5.5-6.8. Here, we prepare a pH-sensitive PLGA-based nanoparticle containing both methenamine mandelate and NaHCO3. Methenamine mandelate/NaHCO3-coloaded nanoparticle could enter cells via endosome/lysosome pathway. The pH in lysosomes and endo-lysosomes is approximately 5.0. In the acidic environment, NaHCO3 reacts with proton and produce CO2 bubbles, which burst nanoparticles and lead to the rapidly release of methenamine mandelate. Meanwhile, methenamine mandelate was then quickly converted to a sufficient amount of formaldehyde in this acidic environment, which induced DNA damage and DNA damage response (DDR). Consequently, methenamine mandelate/NaHCO3-coloaded nanoparticles caused cell cycle arrest, cell growth inhibition and apoptosis of cancer cells. Moreover, methenamine mandelate/NaHCO3-coloaded nanoparticles also show intensive inhibitory effect on the growth of MCF-7 xenograft tumor in vivo. Therefore, methenamine mandelate/NaHCO3-coloaded nanoparticle is a promising type of formulation for the treatment of cancer, which could give the "old drug" methenamine mandelate a new anti-cancer function in clinical.

Green Tea Polyphenols Ameliorate the Early Renal Damage Induced by a High-Fat Diet via Ketogenesis/SIRT3 Pathway.

Several reports in the literature have suggested the renoprotective effects of ketone bodies and green tea polyphenols (GTPs). Our previous study found that GTP consumption could elevate the renal expression of the ketogenic rate-limiting enzyme, which was decreased by a high-fat diet (HFD) in rats. Here, we investigated whether ketogenesis can mediate renoprotection by GTPs against an HFD.

Fluorescent Functionalization across Quaternary Structure in a Virus-like Particle.

Proteinaceous nanomaterials and, in particular, virus-like particles (VLPs) have emerged as robust and uniform platforms that are seeing wider use in biomedical research. However, there are a limited number of bioconjugation reactions for functionalizing the capsids, and very few of those involve functionalization across the supramolecular quaternary structure of protein assemblies. In this work, we exploit the recently described dibromomaleimide moiety as part of a bioconjugation strategy on VLP Qβ to break and rebridge the exposed and structurally important disulfides in good yields. Not only was the stability of the quaternary structure retained after the reaction, but the newly functionalized particles also became brightly fluorescent and could be tracked in vitro using a commercially available filter set. Consequently, we show that this highly efficient bioconjugation reaction not only introduces a new functional handle "between" the disulfides of VLPs without compromising their thermal stability but also can be used to create a fluorescent probe.

Degradation of polyvinyl alcohol (PVA) by UV/chlorine oxidation: Radical roles, influencing factors, and degradation pathway.

Polyvinyl alcohol (PVA) is widely used in industry but is difficult to degrade. In this study, the synergistic effect of UV irradiation and chlorination on degradation of PVA was investigated. UV irradiation or chlorination alone did not degrade PVA. By contrast, UV/chlorine oxidation showed good efficiency for PVA degradation via generation of active free radicals, such as OH and Cl. The relative importance of these two free radicals in the oxidation process was evaluated, and it was shown that OH contributed more to PVA degradation than Cl did. The degradation of PVA followed pseudo first order kinetics. The rate constant k increased linearly from 0 min(-1) to 0.3 min(-1) with increasing chlorine dosage in range of 0 mg/L to 20 mg/L. However, when the chlorine dosage was increased above 20 mg/L, scavenging effect of free radicals occurred, and the degradation efficiency of PVA did not increase much more. Acidic media increased the degradation efficiency of PVA by UV/chlorine oxidation more than basic or neutral media because of the higher ratio of [HOCl]/[OCl(-)], higher free radical quantum yields, and the lower free radical quenching effect under acidic conditions. Results of Fourier Transform Infrared Spectroscopy showed that carbonyl groups in degradation products were formed during UV/chlorine oxidation, and a possible degradation pathway via alcohol to carbonyl was proposed.

Neural decoding of attentional selection in multi-speaker environments without access to clean sources.

People who suffer from hearing impairments can find it difficult to follow a conversation in a multi-speaker environment. Current hearing aids can suppress background noise; however, there is little that can be done to help a user attend to a single conversation amongst many without knowing which speaker the user is attending to. Cognitively controlled hearing aids that use auditory attention decoding (AAD) methods are the next step in offering help. Translating the successes in AAD research to real-world applications poses a number of challenges, including the lack of access to the clean sound sources in the environment with which to compare with the neural signals. We propose a novel framework that combines single-channel speech separation algorithms with AAD.

Double Fano resonances in individual metallic nanostructure for high sensing sensitivity.

In this paper, we report the design and observation of double Fano resonances (DFRs) in an individual symmetry reduced nanostructure and the induced high sensing sensitivity. Such a plasmonic nanostructure consists of a partially overlapped double metallic nanotriangles with unequal sizes fabricated by using the fast and low-cost angle-resolved nanosphere lithography. Symmetry breaking generates two narrow quadrupolar dark modes, which further enhance the coupling with fundamental bright dipole modes within the same structure, manifesting the effect of DFRs. The resonance wavelength and line shape of DFRs can be tailored by changing the degree of asymmetry as well as the size of the designed nanostructure. Based on DFRs, a high sensitivity to dielectric environment with a maximum figure of merit of 35 is measured. Due to fast manufacturing process with high reproducibility and high structural tunability, the fabricated individual metallic nanostructure provides an opportunity to significant potential applications in localized surface plasmon resonance (LSPR) based single or double-wavelength sensors in the near-infrared region.

Chinese isms dimensions in mainland China and Taiwan: Convergence and extension of American isms dimensions.

Previous studies of American English isms terms have uncovered as many as five broad factors: tradition-oriented religiousness (TR), subjective spirituality (SS), communal rationalism (CR), unmitigated self-interest (USI), and inequality aversion (IA). The present studies took a similar lexical approach to investigate the Chinese-language isms structures in both mainland China and Taiwan.

Surface chemistry and stability of metastable corundum-type In2O3.

To account for the explanation of an eventual sensing and catalytic behavior of rhombohedral In2O3 (rh-In2O3) and the dependence of the metastability of the latter on gas atmospheres, in situ electrochemical impedance spectroscopic (EIS), Fourier-transform infrared spectroscopic (FT-IR), in situ X-ray diffraction and in situ thermogravimetric analyses in inert (helium) and reactive gases (hydrogen, carbon monoxide and carbon dioxide) have been conducted to link the gas-dependent electrical conductivity features and the surface chemical properties to its metastability towards cubic In2O3. In particular, for highly reducible oxides such as In2O3, for which not only the formation of oxygen vacancies, but deep reduction to the metallic state (i.e. metallic indium) also has to be taken into account, this approach is imperative. Temperature-dependent impedance features are strongly dependent on the respective gas composition and are assigned to distinct changes in either surface adsorbates or free charge carrier absorbance, allowing for differentiating and distinguishing between bulk reduction-related features from those directly arising from surface chemical alterations. For the measurements in an inert gas atmosphere, this analysis specifically also included monitoring the fate of differently bonded, and hence, differently reactive, hydroxyl groups. Reduction of rh-In2O3 proceeds to a large extent indirectly via rh-In2O3 → c-In2O3 → In metal. As deduced from the CO and CO2 adsorption experiments, rhombohedral In2O3 exhibits predominantly Lewis acidic surface sites. The basic character is less pronounced, directly explaining the previously observed high (inverse) water-gas shift activity and the low CO2 selectivity in methanol steam reforming.

Graphitic nanocapsules: design, synthesis and bioanalytical applications.

Graphitic nanocapsules are emerging nanomaterials which are gaining popularity along with the development of carbon nanomaterials. Their unique physical and chemical properties, as well as good biocompatibility, make them desirable agents for biomedical and bioanalytical applications. Through rational design, integrating graphitic nanocapsules with other materials provides them with additional properties which make them versatile nanoplatforms for bioanalysis. In this feature article, we present the use and performance of graphitic nanocapsules in a variety of bioanalytical applications. Based on their chemical properties, the specific merits and limitations of magnetic, hollow, and noble metal encapsulated graphitic nanocapsules are discussed. Detection, multi-modal imaging, and therapeutic applications are included. Future directions and potential solutions for further biomedical applications are also suggested.

Molecular Hyperthermia: Spatiotemporal Protein Unfolding and Inactivation by Nanosecond Plasmonic Heating.

Spatiotemporal control of protein structure and activity in biological systems has important and broad implications in biomedical sciences as evidenced by recent advances in optogenetic approaches. Here, this study demonstrates that nanosecond pulsed laser heating of gold nanoparticles (GNP) leads to an ultrahigh and ultrashort temperature increase, coined as "molecular hyperthermia", which causes selective unfolding and inactivation of proteins adjacent to the GNP. Protein inactivation is highly dependent on both laser pulse energy and GNP size, and has a well-defined impact zone in the nanometer scale. It is anticipated that the fine control over protein structure and function enabled by this discovery will be highly enabling within a number of arenas, from probing the biophysics of protein folding/unfolding to the nanoscopic manipulation of biological systems via an optical trigger, to developing novel therapeutics for disease treatment without genetic modification.

Caffeine inhibits hypothalamic A1R to excite oxytocin neuron and ameliorate dietary obesity in mice.

Caffeine, an antagonist of the adenosine receptor A1R, is used as a dietary supplement to reduce body weight, although the underlying mechanism is unclear. Here, we report that adenosine level in the cerebrospinal fluid, and hypothalamic expression of A1R, are increased in the diet-induced obesity (DIO) mouse. We find that mice with overexpression of A1R in the neurons of paraventricular nucleus (PVN) of the hypothalamus are hyperphagic, have glucose intolerance and high body weight. Central or peripheral administration of caffeine reduces the body weight of DIO mice by the suppression of appetite and increasing of energy expenditure. We also show that caffeine excites oxytocin expressing neurons, and blockade of the action of oxytocin significantly attenuates the effect of caffeine on energy balance. These data suggest that caffeine inhibits A1Rs expressed on PVN oxytocin neurons to negatively regulate energy balance in DIO mice.

Preparation, characterization, and evaluation of amphotericin B-loaded MPEG-PCL-g-PEI micelles for local treatment of oral Candida albicans.

Fatal Candida albicans infections in the mucosal system can occur in association with immune-compromised diseases and dysbacteriosis. Currently, amphotericin B (AmB) is considered to be the most effective antibiotic in the treatment of C. albicans infections, but its clinical application is limited by side effects and poor bioavailability. In order to use AmB in the local treatment of oral C. albicans infections, AmB/MPEG-PCL-g-PEI (monomethoxy poly(ethylene glycol)-poly(epsilon-caprolactone)-graft-polyethylenimine, MPP) micelles were prepared. A series of characterizations were performed. The micelles allowed a sustained in vitro release in both normal oral conditions (pH 6.8) and C. albicans infection conditions (pH 5.8). Then, buccal tablets containing freeze-dried powder of AmB/MPP micelles were produced by direct compression process and evaluated as regards to weight variation, hardness, and friability. In vitro drug release of the buccal tablets was measured in both the United States Pharmacopeia dissolution apparatus and the dissolution rate test apparatus, which was previously designed for simulating in vivo conditions of the oral cavity. The buccal tablets could sustainably release within 8 h and meet the antifungal requirements. Regarding safety assessment of AmB/MPP micelles, in vivo histopathological data showed no irritation toward buccal mucosa of the rats in both optical microscopy and ultrastructure observation of the tissues. MTT experiment proved that AmB/MPP micelles reduced the cytotoxicity of AmB. The micelles delivered through the gastrointestinal route were also found to be non-systemic toxicity by liquid chromatography-mass spectrometry analysis. Furthermore, the antifungal action of AmB/MPP micelles was evaluated. Although AmB/MPP had no obvious improvement as compared to AmB alone in the antifungal effect on planktonic C. albicans, the micelles significantly enhanced the antifungal activity against the biofilm state of C. albicans. Thus, it was concluded that AmB/MPP micelles represent a promising novel drug delivery system for the local treatment of oral C. albicans infections.

Immunomodulatory mechanism of Bushen Huoxue Recipe alleviates cyclophosphamide-induced diminished ovarian reserve in mouse model.

Bushen Huoxue recipe (BHR) is a Chinese herbal prescription composed of ten herbs and it is widely used for the treatment of diminished ovarian reserve (DOR). This study investigates the potentially beneficial effects and underlying mechanism of BHR on a cyclophosphamide (CTX) induced model of DOR in mice.

In situ targeted MRI detection of Helicobacter pylori with stable magnetic graphitic nanocapsules.

Helicobacter pylori infection is implicated in the aetiology of many diseases. Despite numerous studies, a painless, fast and direct method for the in situ detection of H. pylori remains a challenge, mainly due to the strong acidic/enzymatic environment of the gastric mucosa. Herein, we report the use of stable magnetic graphitic nanocapsules (MGNs), for in situ targeted magnetic resonance imaging (MRI) detection of H. pylori. Several layers of graphene as the shell effectively protect the magnetic core from corrosion while retaining the superior contrast effect for MRI in the gastric environment. Boronic-polyethylene glycol molecules were synthesized and modified on the MGN surface for targeted MRI detection. In a mouse model of H. pylori-induced infection, H. pylori was specifically detected through both T2-weighted MR imaging and Raman gastric mucosa imaging using functionalized MGNs. These results indicated that enhancement of MRI using MGNs may be a promising diagnostic and bioimaging platform for very harsh conditions.

No association of TNF-α-308G/A polymorphisms with head and neck cancer risk: A PRISMA-compliant meta-analysis.

A number of studies had reported the association between tumor necrosis factor-alpha (TNF-α) gene polymorphisms and head and neck cancer (HNC) risk. However, the results remained controversial. Therefore, we performed a meta-analysis to derive a more precise evaluation of the association between TNF-α-308G/A polymorphism and overall HNC risk and evaluated influence of cancer types and ethnicities.

Highly reproducible improved label-free quantitative analysis of cellular phosphoproteome by optimization of LC-MS/MS gradient and analytical column construction.

Expanding the sequencing depth of the peptides with a statistically significant quantitative change derived from a biological stimulation is critical. Here we demonstrate that optimization of LC gradient and analytical column construction can reveal over 30,000 unique peptides and 23,000 phosphopeptides at high confidence. The quantitative reproducibility of different analytical workflows was evaluated by comparing the phosphoproteome of CD3/4 stimulated and unstimulated T-cells as a model system. A fritless, 50cm-long column packed with 1.9μm particles operated with a standard pressure HPLC significantly improved the sequencing depth 51% and decreased the selected ion chromatogram peak spreading. Most importantly, under the optimal workflow we observed an improvement of over 300% in detection of significantly changed phosphopeptides in the stimulated cells compared with the other workflows. The discovery power of the optimized column configuration was illustrated by identification of significantly altered phosphopeptides harboring novel sites from proteins previously established as important in T cell signaling including A-Raf, B-Raf, c-Myc, CARMA1, Fyn, ITK, LAT, NFAT1/2/3, PKCα, PLCγ1/2, RAF1, and SOS1. Taken together, our results reveal the analytical power of optimized chromatography using sub 2μm particles for the analysis of the T cell phosphoproteome to reveal a vast landscape of significantly altered phosphorylation changes in response to T cell receptor stimulation.

Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido4,5-d1,3oxazin-2-ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors.

Epidermal growth factor receptor (EGFR) T790M acquired drug-resistance mutation has become a major clinical challenge for the therapy of non-small cell lung cancer. Here, we applied a structure-guided approach on the basis of the previous reported EGFR inhibitor (compound 9), and designed a series of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one derivatives as novel mutant-selective EGFR inhibitors. Finally, the most representative compound 20a was identified, which showed high selectivity at both enzymatic and cellular levels against EGFR(L858R/T790M) (H1975 cell lines) over EGFR(WT) (A431 cell lines). The representative compound 20a also showed promising antitumor efficiency in the in vivo antitumor efficacy study of H1975 xenograft mouse model driven by EGFR(L858R/T790M). These results provide a new scaffold for the treatment of dual-mutant-driven non-small cell lung cancer.

Folate-targeted polymersomes loaded with both paclitaxel and doxorubicin for the combination chemotherapy of hepatocellular carcinoma.

Combination chemotherapy is a promising method of improving cancer treatment, but the distinct pharmacokinetics of combined drugs and non-specific drug distribution slow down the development in the clinic. In this study, folate (FA) receptor-targeted polymersomes with apparent bilayered lamellar structure were successfully developed to co-encapsulate a hydrophobic-hydrophilic chemotherapeutic drug pair (PTX and DOX) in a single vesicle for enhancing the combination chemotherapeutic effect. Hydrophobic PTX was loaded into the thick hydrophobic lamellar membrane by the self-assembly of triblock copolymer PCL8000-PEG8000-PCL8000, while hydrophilic DOX was encapsulated into the hydrophilic reservoir using a trans-membrane ammonium sulfate gradient method. In vitro release study indicated that the drugs were released from the polymersomes in a controlled and sustained manner. Cellular uptake study indicated that FA-targeted Co-PS had higher internalization efficiency in FA receptor-overexpressing BEL-7404 cells than non-targeted Co-PS. In vitro cytotoxicity assay demonstrated that FA-targeted Co-PS exhibited less cytotoxic effect than free drug cocktail, but suppressed the growth of tumor cells more efficiently than non-targeted Co-PS. Ex vivo imaging biodistribution studies revealed that FA-targeted Co-PS led to highly efficient targeting and accumulation in the BEL-7404 xenograft tumor. Furthermore, the in vivo antitumor study showed that the combination chemotherapy of polymersomes to BEL-7404 tumor via intravenous injection was superior to free drug cocktail treatment, and the FA-targeted Co-PS exhibited significantly higher tumor growth inhibition than non-targeted Co-PS group. Therefore, the newly developed FA-targeted co-delivery polymersomes hold great promise for simultaneous delivery of multiple chemotherapeutics and would have great potential in tumor-targeting and combination chemotherapy.