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1.
Sci Adv ; 7(4)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33523953

RESUMO

Wearable sensing technology is an essential link to future personalized medicine. However, to obtain a complete picture of human health, it is necessary but challenging to track multiple analytes inside the body simultaneously. Here, we present a wearable plasmonic-electronic sensor with "universal" molecular recognition ability. Flexible plasmonic metasurface with surface-enhanced Raman scattering (SERS)-activity is introduced as the fundamental sensing component in a wearable sensor since we solved the technical challenge of maintaining the plasmonic activities of their brittle nanostructures under various deformations. Together with a flexible electronic sweat extraction system, our sensor can noninvasively extract and "fingerprint" analytes inside the body based on their unique SERS spectra. As a proof-of-concept example, we successfully monitored the variation of trace-amounts drugs inside the body and obtained an individual's drug metabolic profile. Our sensor bridges the existing gap in wearable sensing technology by providing a universal, sensitive molecular tracking means to assess human health.

2.
J Am Chem Soc ; 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33587623

RESUMO

Engineering a stable solid electrolyte interphase (SEI) is one of the critical maneuvers in improving the performance of a lithium anode for high-energy-density rechargeable lithium batteries. Herein, we build a fluorinated lithium/sodium hybrid interphase via a facile electroless electrolyte-soaking approach to stabilize the repeated plating/stripping of lithium metal. Jointed experimental and computational characterizations reveal that the fluorinated hybrid SEI mainly consisting of NaF, LiF, LixPOyFz, and organic components features a mosaic polycrystalline structure with enriched grain boundaries and superior interfacial properties toward Li. This LiF/NaF hybrid SEI exhibits improved ionic conductivity and mechanical strength in comparison to the SEI without NaF. Remarkably, the fluorinated hybrid SEI enables an extended dendrite-free cycling of metallic Li over 1300 h at a high areal capacity of 10 mAh cm-2 in symmetrical cells. Furthermore, full cells based on the LiFePO4 cathode and hybrid SEI-protected Li anode sustain long-term stability and good capacity retention (96.70% after 200 cycles) at 0.5 C. This work could provide a new avenue for designing robust multifunctional SEI to upgrade the metallic lithium anode.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33497191

RESUMO

Metallic lithium is one of the most promising anode materials to build next generation electrochemical power sources such as Li-air, Li-sulfur, and solid-state lithium batteries. The implementation of rechargeable Li-based batteries is plagued by issues including dendrites, pulverization, and an unstable solid electrolyte interface (SEI). Herein, we report the use of nanostructured CuO in situ grown on commercial copper foil (CuO@Cu) via chemical etching as a Li-reservoir substrate to stabilize SEI formation and Li stripping/plating. The lithiophilic interconnected CuO layer enhances electrolyte wettability. Besides, a mechanically stable Li2O- and LiF-rich SEI is generated on CuO@Cu during initial discharge, which permits dense and uniform lithium deposition upon subsequent cycling. Compared with bare Cu, the CuO@Cu electrode exhibits superior performance in terms of Coulombic efficiency, discharge/charge overpotentials, and cyclability. By pairing with the Li-CuO@Cu anodes, full cells with LiFePO4 and LiNi1/3Mn1/3Co1/3O2 cathodes sustain 300 cycles with 98.8% capacity retention at 1 C and deliver a specific capacity of 80 mAh g-1 at 10 C, respectively. This work would shed light on the design of advanced current collectors with SEI modulation to upgrade lithium anodes.

4.
Drug Dev Ind Pharm ; : 1-29, 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33295825

RESUMO

Gastric cancer is one of the leading causes of cancer-related death worldwide with a poor prognosis. Gastric cancer is usually treated with surgery and chemotherapy, accompanied by a high rate of metastasis and recurrence. In this paper, R8 (RRRRRRRR) modified vinorelbine plus schisandrin B liposomes had been successfully constructed for treating gastric cancer. In the liposomes, R8 was used to enhance the intracellular uptake, schisandrin B was incorporated into liposomes for inhibiting tumor cells metastasis, and vinorelbine was encapsulated into liposomes as antitumor drugs. Studies were performed on BGC-823 cells in vitro and were verified in the BGC-823 cell xenografts nude mice in vivo. Results in vitro demonstrated that the targeting liposomes could induce BGC-823 cells apoptosis, inhibit the metastasis of tumor cells, and increase targeting effects to tumor cells. Meanwhile, action mechanism studies showed that the targeting liposomes could down-regulate VEGF, VE-Cad, HIF-1a, PI3K, MMP-2 and FAK to inhibit tumor metastasis. In vivo results exhibited that the targeting liposomes displayed an obvious antitumor efficacy by accumulating selectively in tumor site and induce tumor cell apoptosis. Hence, R8 modified vinorelbine plus schisandrin B liposomes might provide a safe and efficient therapy strategy for gastric cancer.

5.
Acta Pharm Sin B ; 10(9): 1730-1740, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33088692

RESUMO

The combination of paclitaxel (PTX) and doxorubicin (DOX) has been widely used in the clinic. However, it remains unsatisfied due to the generation of severe toxicity. Previously, we have successfully synthesized a prodrug PTX-S-DOX (PSD). The prodrug displayed comparable in vitro cytotoxicity compared with the mixture of free PTX and DOX. Thus, we speculated that it could be promising to improve the anti-cancer effect and reduce adverse effects by improving the pharmacokinetics behavior of PSD and enhancing tumor accumulation. Due to the fact that copper ions (Cu2+) could coordinate with the anthracene nucleus of DOX, we speculate that the prodrug PSD could be actively loaded into liposomes by Cu2+ gradient. Hence, we designed a remote loading liposomal formulation of PSD (PSD LPs) for combination chemotherapy. The prepared PSD LPs displayed extended blood circulation, improved tumor accumulation, and more significant anti-tumor efficacy compared with PSD NPs. Furthermore, PSD LPs exhibited reduced cardiotoxicity and kidney damage compared with the physical mixture of Taxol and Doxil, indicating better safety. Therefore, this novel nano-platform provides a strategy to deliver doxorubicin with other poorly soluble antineoplastic drugs for combination therapy with high efficacy and low toxicity.

6.
Int J Pharm ; 590: 119920, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33002539

RESUMO

Liposomes represent one of the most successful nano-drug delivery systems among enormous nano-carriers. Although great progress has been made in conventional liposomes, the emerging shortcomings still impair the therapeutic index. The proposal of stimuli-responsive phospholipid-drug conjugates (PDCs)-based nanovesicles solves the challenges that conventional liposomes are faced with, showing great potential for cancer diagnosis and therapy. Herein, we intend to overview the current progress and unique advantages of stimuli-responsive PDCs-based nanovesicles. First, the challenges of conventional liposomes and the development of PDCs-based nanovesicles are summarized. Next, the stimuli-responsive elements used in current stimuli-responsive PDCs-based nanovesicles are outlined. Then, the unique superiorities of stimuli-responsive PDCs-based nanovesicles for drug delivery and theranostics are highlighted in detail. Finally, the future opportunities and challenges of stimuli-responsive PDCs-based nanovesicles for clinical translation are put forward.

7.
Front Microbiol ; 11: 1696, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793160

RESUMO

African swine fever (ASF), caused by African swine fever virus (ASFV), is a devastating infectious disease of domestic pigs and wild boars, and has tremendous negative socioeconomic impact on the swine industry and food security worldwide. It is characterized as a notifiable disease by World Organisation for Animal Health (OIE). No effective vaccine or treatment against ASF has so far been available. Early detection and rapid diagnosis are of potential significance to control the spread of ASF. Recombinase-based isothermal amplification assay, recombinase polymerase amplification (RPA) developed by TwistDx (Cambridge, United Kingdom) or recombinase-aided amplification (RAA) by Qitian (Wuxi, China), is becoming a molecular tool for the rapid, specific, and cost-effective identification of multiple pathogens. In this study, we aim to investigate if RPA/RAA can be a potential candidate for on-site, rapid and primary detection of ASFV. A panel of 152 clinical samples previously well-characterized by OIE-recommended qPCR was enrolled in this study, including 20 weak positive (Ct value ≥ 30) samples. This panel was consisted of different types, such as EDTA-blood, spleen, lung, lymph node, kidney, tonsil, liver, brain. We evaluated two recombinase-based isothermal amplification assays, RPA or RAA, by targeting the ASFV B646L gene (p72), and validated the clinical performance in comparison with OIE real-time PCR. Our result showed that the analytical sensitivity of RPA and RAA was as 93.4 and 53.6 copies per reaction, respectively at 95% probability in 16 min, at 39°C. They were universally specific for all 24 genotypes of ASFV and no cross reaction to other pathogens including Classical swine fever virus (CSV), Foot-and-mouth disease virus (FMDV), Pseudorabies virus, Porcine circovirus 2 (PCV2), Porcine Reproductive and respiratory syndrome virus (PPRSV). The results on detection of various kinds of clinical samples indicated an excellent diagnostic agreement between RPA, RAA and OIE real-time PCR method, with the kappa value of 0.960 and 0.973, respectively. Compared to real-time PCR, the specificity of both RPA and RAA was 100% (94.40% ∼ 100%, 95% CI), while the sensitivity was 96.59% (90.36% ∼ 99.29%, 95% CI) and 97.73% (92.03% ∼ 99.72%, 95% CI), respectively. Our data demonstrate that the developed recombinase-based amplification assay (RPA/RAA), promisingly equipped with field-deployable instruments, offers a sensitive and specific platform for the rapid and reliable detection of ASFV, especially in the resource-limited settings for the purpose of screening and surveillance of ASF.

8.
Proc Natl Acad Sci U S A ; 117(35): 21391-21402, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817423

RESUMO

Syntaxin17, a key autophagosomal N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, can associate with ATG8 family proteins SNAP29 and VAMP8 to facilitate the membrane fusion process between the double-membraned autophagosome and single-membraned lysosome in mammalian macroautophagy. However, the inherent properties of Syntaxin17 and the mechanistic basis underlying the interactions of Syntaxin17 with its binding proteins remain largely unknown. Here, using biochemical, NMR, and structural approaches, we systemically characterized Syntaxin17 as well as its interactions with ATG8 family proteins, SNAP29 and VAMP8. We discovered that Syntaxin17 alone adopts an autoinhibited conformation mediated by a direct interaction between its Habc domain and the Qa-SNARE motif. In addition, we revealed that the Qa-SNARE region of Syntaxin17 contains one LC3-interacting region (LIR) motif, which preferentially binds to GABARAP subfamily members. Importantly, the GABARAP binding of Syntaxin17 can release its autoinhibited state. The determined crystal structure of the Syntaxin17 LIR-GABARAP complex not only provides mechanistic insights into the interaction between Syntaxin17 and GABARAP but also reveals an unconventional LIR motif with a C-terminally extended 310 helix for selectively binding to ATG8 family proteins. Finally, we also elucidated structural arrangements of the autophagic Syntaxin17-SNAP29-VAMP8 SNARE core complex, and uncovered its conserved biochemical and structural characteristics common to all other SNAREs. In all, our findings reveal three distinct states of Syntaxin17, and provide mechanistic insights into the Syntaxin17-mediated autophagosome-lysosome fusion process.


Assuntos
Autofagossomos/fisiologia , Lisossomos/fisiologia , Proteínas Qa-SNARE/metabolismo , Proteínas Qb-SNARE/metabolismo , Proteínas Qc-SNARE/metabolismo , Proteínas R-SNARE/metabolismo , Motivos de Aminoácidos , Proteínas Reguladoras de Apoptose/metabolismo , Família da Proteína 8 Relacionada à Autofagia/metabolismo , Escherichia coli , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo
9.
BMC Complement Med Ther ; 20(1): 206, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32615973

RESUMO

BACKGROUND: Semen Ziziphi spinosae and Radix Polygalae, two herbs commonly used together in Traditional Chinese Medicine for the treatment of insomnia and anxiety. The study aims to study the sedative-hypnotic effect of the active components of the herbal pair, the possible mechanisms of such effect, and related metabolic pathways in vivo. METHODS: The sedative and hypnotic effect of the active components (EI30) of the herbal pair was studied by recording influence on the proportion of sleeping within 30 min, sleep latency and sleep length of pentobarbital sodium-induced sleeping on mice. Possible mechanisms of the sedative-hypnotic effect of the active components were investigated by measuring the content of neurotransmitters in the total protein of mice brain tissue. The main chemical compounds of the herbal pair were identified by Liquid Chromatography-Mass Spectrometry (LC-MS). Serum samples of mice were studied, and related differential metabolites between the normal group and model group, and between model group and treatment group were identified by Gas Chromatography Time-Of-Flight Mass Spectrometry (GC-TOF-MS), Principal Components Analysis (PCA), and Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA). RESULTS: Compared with the control group, high dose EI30 group and the Clonazepam group were with significantly higher proportions of sleep within 30 min (P = 0.027 and 0.005 respectively). Compared with the control group, all of the high, medium and low dose of EI30 groups were with significantly shorter sleep latency (P < 0.01) and prolonged sleeping time (P < 0.01). The herbal pair has good sedative-hypnotic effects, although it is weaker than the effect of Clonazepam. The sedative-hypnotic effect of EI30 is possibly related to the adjustment of neurotransmitters 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) in the total protein of mice brain tissue. There are five metabolic pathways in vivo most related to the sedative-hypnotic effect of EI30, and they are biosynthesis of valine, leucine, and isoleucine, metabolism of glyceride, metabolism of alanine, aspartic acid and glutamic acid, metabolism of phenylalanine, and metabolism of cysteine and methionine. CONCLUSIONS: This study reveals the mechanisms of sedative and hypnotic effects of herbal pair Semen Ziziphi spinosae and Radix Polygalae by using metabolomics methods. This study provides a basis for further development and utilization of this herbal pair.

10.
Neurology ; 95(9): e1236-e1243, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32611640

RESUMO

OBJECTIVE: To assess the prevalence of brain MRI abnormalities in people with epilepsy in rural China and to compare it with that of individuals in the United Kingdom. METHODS: Brain MRI scans were obtained in people with epilepsy who participated in a rural community-based program in China between July 2010 and December 2012. Individual epileptogenic lesion types were reviewed and their associations with seizure control examined. The MRI findings were compared with 2 previous similar studies in the United Kingdom. RESULTS: Among the 597 individuals (58% male, median age 38 years) with MRI scans analyzed, 488 (82%) had active epilepsy. The MRI was abnormal in 389 individuals (65%), with potentially epileptogenic lesion in 224 (38%) and nonspecific abnormalities in 165 (28%), and 108 (18%) were potentially resectable. The potentially epileptogenic lesions were less frequently detected in children (<18 years old, 12 of 68, 18%) than in adults (212 of 529, 40%; p < 0.001). In people with potentially epileptogenic lesions, 67% (150 of 224) had failed ≥2 antiseizure medications. They had higher risk of uncontrolled epilepsy than those with normal MRI (risk ratio [RR] 1.25; p < 0.001) and those with nonspecific abnormality (RR 1.15; p = 0.002) after adjustment for age and sex. The diagnostic yield of MRI was similar to that reported in community- and hospital-based studies in the United Kingdom. CONCLUSIONS: More than one-third of people with chronic epilepsy in rural China have potentially epileptogenic lesions identifiable on brain MRI, with two-thirds fulfilling the definition of pharmacoresistance. These findings highlight the magnitude of the unmet needs for epilepsy surgery in China.


Assuntos
Encefalomalacia/epidemiologia , Epilepsia/epidemiologia , Gliose/epidemiologia , Malformações do Sistema Nervoso/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/epidemiologia , Malformações Vasculares do Sistema Nervoso Central/diagnóstico por imagem , Malformações Vasculares do Sistema Nervoso Central/epidemiologia , Criança , Pré-Escolar , China/epidemiologia , Epilepsia Resistente a Medicamentos , Encefalomalacia/diagnóstico por imagem , Epilepsia/diagnóstico por imagem , Feminino , Gliose/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Malformações do Sistema Nervoso/diagnóstico por imagem , Prevalência , População Rural , Esclerose , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/patologia , Reino Unido/epidemiologia , Adulto Jovem
11.
Nat Commun ; 11(1): 2693, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483345

RESUMO

Our knowledge about the evolution of guarantee network in downturn period is limited due to the lack of comprehensive data of the whole credit system. Here we analyze the dynamic Chinese guarantee network constructed from a comprehensive bank loan dataset that accounts for nearly 80% total loans in China, during 01/2007-03/2012. The results show that, first, during the 2007-2008 global financial crisis, the guarantee network became smaller, less connected and more stable because of many bankruptcies; second, the stimulus program encouraged mutual guarantee behaviors, resulting in highly reciprocal and fragile network structure; third, the following monetary policy adjustment enhanced the resilience of the guarantee network by reducing mutual guarantees. Interestingly, our work reveals that the financial crisis made the network more resilient, and conversely, the government bailout degenerated network resilience. These counterintuitive findings can provide new insight into the resilience of real-world credit system under external shocks or rescues.

12.
Artif Cells Nanomed Biotechnol ; 48(1): 983-996, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32524852

RESUMO

High grade-gliomas are highly invasive and prone to metastasis, leading to poor survival and prognosis. Currently, we urgently need a new treatment strategy to effectively inhibit glioma. In this study, artemether and paclitaxel were used as two agents for tumour suppression. Two functional materials were synthesised and modified on the surface of the micelle as targeting molecules. The addition of two functional materials confers the ability of the micelles to effectively cross the blood-brain barrier (BBB) and then target the glioma cells. Thus, this dual-targeted delivery system allows the drug to play a better role in inhibiting tumour invasion and vasculogenic mimicry (VM) channels. In this paper, the anticancer effects of dual-targeted artemether plus paclitaxel micelles on glioma U87 cells were studied in three aspects: (I) In vitro and in vivo targeting assessment, including the role of penetrating BBB and targeting glioma; (II) In vitro regulation of invasion-associated proteins; (III) Inhibition of VM channels formation and invasion in vitro; (IV) The study of pharmacodynamics in tumour-bearing mice. These results suggest that dual-targeted artemether plus paclitaxel micelle may provide a new strategy to treat glioma via inhibiting invasive and VM channels.

13.
J Orthop Surg Res ; 15(1): 41, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32028972

RESUMO

BACKGROUND: Total knee arthroplasty (TKA) is usually associated with moderate to severe postoperative pain. Peripheral nerve block (PNB) and local infiltration analgesia (LIA) are two major methods for postoperative analgesia. Femoral nerve block (FNB) leads to residual posterior knee pain; thus, currently sciatic nerve block (SNB) and LIA are two major options for supplementing FNB. However, the efficacy and safety of LIA compared with combined femoral and sciatic nerve block still remain controversial. Here, we conducted a study to analyze the postoperative analgesic efficacy of these two methods. METHOD: Two hundred six patients undergoing TKA were enrolled in a retrospective cohort study. The patients received either PNB or LIA. All patients in PNB group were conducted combined femoral and sciatic nerve block. All patients were encouraged to use patient-controlled analgesia (PCA) after surgery. The postoperative visual analog scale (VAS) at rest or with movement during the first 24 h and 48 h was recorded. We analyzed the VAS of 24 h, VAS of 48 h, opioid consumption, and adverse effects between PNB group and LIA group. Chi-square test and nonparametric test were used in this study. RESULTS: There were 82 patients in the PNB group and 124 patients in the LIA group. The patients' characteristics such as age, height, weight, and ASA showed no significant difference (P > 0.05). No significant differences were found (P > 0.05) between the two groups regarding VAS score at rest or with movement. The LIA group had less opioid consumption than the PNB group but without significant difference (P > 0.05). In both groups, the most common side effect was nausea, and the side effects showed no significant differences between groups (P > 0.05). CONCLUSION: Local infiltration analgesia provided a similar analgesic effect and complications compared with combined femoral and sciatic nerve block in the short term. Considering less opioid consumption with local infiltration analgesia though without significant difference and its convenience, local infiltration analgesia provided better postoperative analgesia.


Assuntos
Anestesia Local/métodos , Artroplastia do Joelho/efeitos adversos , Bloqueio Nervoso Autônomo/métodos , Manejo da Dor/métodos , Dor Pós-Operatória/prevenção & controle , Idoso , Artroplastia do Joelho/tendências , Estudos de Coortes , Terapia Combinada/métodos , Feminino , Nervo Femoral/efeitos dos fármacos , Nervo Femoral/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/etiologia , Estudos Retrospectivos , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/fisiologia
14.
Mater Sci Eng C Mater Biol Appl ; 108: 110338, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31923994

RESUMO

Gold nanoparticles (AuNPs) have been reported for their most desirable properties as compared to any other noble metal-based nanoparticles, which wider their applications in various fields including catalysis, bio-imaging, biosensors, medicine, biology, and material chemistry. In this study, the shape-dependent antibacterial activity of AuNPs: nanospheres (AuNSps), nanostars (AuNSts), and nanocubes (AuNCs) were investigated against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus at lower concentrations. The optical, crystallographic and morphological characterization of AuNPs was analyzed by UV-visible spectroscopy, X-ray diffraction spectroscopy, and transmission electron microscopy (TEM). Shape-dependent antibacterial qualitative and quantitative analyses revealed an effective bactericidal activity of AuNCs against the tested bacteria, followed by AuNSps and AuNSts. The study revealed that the AuNCs are effective bactericidal agents with 100% inactivation rate. The visual analysis confirmed the antibacterial activity of AuNCs and AuNSps by showing physical mutilated bacterial cells which involved cell loss, loosening of the cell wall, loss of flagella and cellular matrix. Finally, released nucleic acid was measured for the treated bacterial cells which support the physical mutilation by releasing 38 µg/mL (Pseudomonas aeruginosa) of cellular material after treating with AuNCs. It is concluded from this study that AuNPs showed the significant antibacterial property at lower concentrations. More applications can be explored including anti-infections, decontamination, and food safety.


Assuntos
Antibacterianos , Escherichia coli/crescimento & desenvolvimento , Doenças Transmitidas por Alimentos , Ouro , Nanopartículas Metálicas/química , Pseudomonas aeruginosa/crescimento & desenvolvimento , Staphylococcus aureus/crescimento & desenvolvimento , Antibacterianos/química , Antibacterianos/farmacologia , Doenças Transmitidas por Alimentos/microbiologia , Doenças Transmitidas por Alimentos/prevenção & controle , Ouro/química , Ouro/farmacologia , Humanos
15.
J Control Release ; 316: 22-33, 2019 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-31676386

RESUMO

As the demand for nutrients in malignant proliferation of tumors increases, the L-type amino acid transporter 1(LAT1) and amino acid transporter B0,+ (ATB0,+) of tumor cells are more highly expressed than normal cells which can be used as new targets for active targeting of cancer. However, drug delivery systems often require multi-target design to achieve simultaneous targeting of different receptors or transporters due to the heterogeneity of the tumor. Here we utilized triethylamine-sucrose octasulfate gradient to actively encapsulate irinotecan into the introliposomal aqueous phase. Targeted ability was achieved through inserting different amino acids modified polyethylene glycol monostearate into the liposomes, and found that glutamate-liposomes can be targeted to LAT1, lysine-liposomes can be targeted to ATB0,+, and inspiringly, tyrosine-liposomes can be simultaneously targeted to LAT1 and ATB0,+. The tyrosine-modified liposomes showed the highest cellular uptake in BxPC-3 and MCF-7 cells which were highly expressed both LAT1 and ATB0,+. Moreover, we validated their targeting capabilities and elucidated the transport mechanism of LAT1 and ATB0,+-mediated endocytosis. The tumor inhibition rate of tyrosine-modified liposomes greatly increased from 39% to 87% compared with commercially available liposomes loaded CPT-11(Onivyde®). Overall, it showed a good application prospect for efficient tumor therapy and industrial production.


Assuntos
Antineoplásicos/administração & dosagem , Irinotecano/administração & dosagem , Neoplasias/tratamento farmacológico , Tirosina/química , Sistemas de Transporte de Aminoácidos/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Irinotecano/farmacologia , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Lipossomos , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/patologia
16.
Mol Pharm ; 16(9): 3780-3790, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31398041

RESUMO

A quantitative prediction of human pharmacokinetic (PK) profiles has become an increasing demand for the reduction of the clinical failure of drug formulations. The existing in vitro and in vivo correlation (IVIVC) methodology could achieve this goal, but the development of IVIVC for immediate release (IR) products is challenging. Herein, we report that for certain weakly acidic biopharmaceutical classification system (BCS) class II molecules (piroxicam, PIRO), physiologically based PK (PBPK) modeling could be used as a tool to quantitatively predict PK in beagle dogs and to conduct an interspecies extrapolation to humans. First, robust PBPK models were constructed in beagle dogs under both fasted and fed states. Then, a Z-factor model was integrated to assess the effect of in vitro dissolution rates on the in vivo PK performance, and the results illustrated that PIRO IR products had a much wider dissolution space than was anticipated by bioequivalence. In addition, the parameter sensitivity analysis (PSA) assay showed that good oral absorption was achieved only when the particle size was below 150 µm. Finally, the combined PBPK models were extrapolated to humans to specify a quality control strategy; this extrapolation constituted an extension of a biowaiver for PIRO IR formulations. The results showed that the developed method can be utilized to quantitatively predict human PK, which would be meaningful for future scale-up or postapproval changes.


Assuntos
Química Farmacêutica/métodos , Liberação Controlada de Fármacos/fisiologia , Modelos Biológicos , Piroxicam/química , Piroxicam/farmacocinética , Administração Oral , Adulto , Animais , Estudos Cross-Over , Cães , Composição de Medicamentos , Jejum , Métodos de Alimentação , Feminino , Voluntários Saudáveis , Humanos , Concentração de Íons de Hidrogênio , Cinética , Masculino , Absorção pela Mucosa Oral/fisiologia , Tamanho da Partícula , Piroxicam/administração & dosagem , Piroxicam/sangue , Solubilidade , Equivalência Terapêutica , Adulto Jovem
17.
Nat Commun ; 10(1): 3459, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371777

RESUMO

Myosin VI plays crucial roles in diverse cellular processes. In autophagy, Myosin VI can facilitate the maturation of autophagosomes through interactions with Tom1 and the autophagy receptors, Optineurin, NDP52 and TAX1BP1. Here, we report the high-resolution crystal structure of the C-terminal cargo-binding domain (CBD) of Myosin VI in complex with Tom1, which elucidates the mechanistic basis underpinning the specific interaction between Myosin VI and Tom1, and uncovers that the C-terminal CBD of Myosin VI adopts a unique cargo recognition mode to interact with Tom1 for tethering. Furthermore, we show that Myosin VI can serve as a bridging adaptor to simultaneously interact with Tom1 and autophagy receptors through two distinct interfaces. In all, our findings provide mechanistic insights into the interactions of Myosin VI with Tom1 and relevant autophagy receptors, and are valuable for further understanding the functions of these proteins in autophagy and the cargo recognition modes of Myosin VI.


Assuntos
Citoesqueleto de Actina/metabolismo , Cadeias Pesadas de Miosina/química , Domínios e Motivos de Interação entre Proteínas , Proteínas/química , Autofagossomos/metabolismo , Autofagia/fisiologia , Proteínas de Ciclo Celular , Cristalografia por Raios X , Células HEK293 , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana Transportadoras , Modelos Moleculares , Proteínas de Neoplasias , Proteínas Nucleares , Ligação Proteica , Fator de Transcrição TFIIIA
18.
Nanomedicine ; 21: 102066, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31351237

RESUMO

A single nanodrug delivery system for combined delivery of paclitaxel and doxorubicin that integrates high co-loading efficiency, synchronous co-delivery of combined drugs, controllable drug release, and maintains the drug combination at fixed synergistic ratios has been proven to be challenging. Here, we report a redox dual-responsive prodrug nanosystem consisting of a paclitaxel-doxorubicin heterodimeric prodrug with a thioether bond linkage to effectively co-deliver two therapeutic drugs. The heterodimeric prodrug could self-assemble into uniform nanoaggregates containing DSPE-PEG2K with a precise drug co-loading ratio in water, and possessed a high co-loading content. We demonstrated that this nanosystem provided strong synergistic effects in MCF-7 and 4 T1 cells. In vivo, this nanosystem results in a long blood circulation, high accumulation in the tumor, and significant inhibition of tumor growth in BALB/c mice bearing 4 T1 tumors. Such a simple, safe, and efficient heterodimeric prodrug nanosystem exhibits great potential for clinical translation in future combination chemotherapy treatments.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Nanopartículas , Pró-Fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Asian J Pharm Sci ; 14(3): 321-328, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-32104462

RESUMO

To investigate the impact of particle size on in vitro/vivo performance of praziquantel (PZQ), nanocrystals (NCs) and microcrystals (MCs) of PZQ were prepared using the methods of wet milling and jet milling, respectively. PZQ NCs and MCs were characterized with dynamic light scattering, laser particle size analyzer, transmission electron microscopy, differential scanning calorimetry, X-ray powder diffraction and fourier transform infrared spectroscopy. The average diameters of PZQ NCs and MCs were 364.4 nm and 3.7 µm, respectively. No change in crystalline form was observed. Dissolution tests were performed in two different media, where the cumulative dissolution and dissolution rate of NCs were significantly improved in comparison with those of MCs and KANGQING® in non-sink condition. Similarly, oral bioavailability of PZQ NCs in beagle dogs was 1.68 (P < 0.05) and 1.83 fold (P < 0.01) higher than that of MCs and KANGQING®. Considering the advantages of in vitro/vivo performance and facile preparation, PZQ NCs may have a great application in the treatment of schistosomiasis.

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