Hongzhuan Chen

Renji Hospital, Shanghai, Shanghai Shi, China

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Publications (56)247.63 Total impact

  • Yuan Gong · Xinmin Li · Lei Kang · Ying Xie · Zhengxing Rong · Hao Wang · Hong Qi · Hongzhuan Chen
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    ABSTRACT: The endocannabinoids (eCBs), N-arachidonoylethanolamine (anandamide, AEA) and 2-ararchidonylglycerol (2-AG) have been identified as main endogenous ligands for cannabinoid receptors. Developing a sensitive and robust method to determine AEA and 2-AG has been shown to be essential to understand their effects in stress regulation and the pathogenesis of affective disorders. Since eCBs are endogenous molecules, there is no true blank matrix available to construct calibration curves, thus, it has been a challenge to determine eCBs in plasma and brain matrix. A liquid chromatography tandem mass spectrometry (LC-MS/MS) method is developed to determine the concentrations of AEA and 2-AG in murine plasma and different brain substructures (prefrontal cortex, hippocampus and hypothalamus). To overcome the endogenous interference, a "surrogate analyte" approach was adopted using stable isotope-labeled standards as surrogates of authentic analytes to generate calibration curves in biological matrix. The mobile phase, composed of formic acid 0.1% in water-acetonitrile (40:60, v/v), was optimized to separate 2-AG and its non-bioactive isomer 1-AG. The analytes were extracted with ethyl acetate/n-hexane (9:1, v/v) and separated on an Xbridge C18 (2.1×100mm, 3.5μm) column using N-Oleoylethanolamine-d2 (OEA-d2) as the internal standard. Detection was performed in multiple reaction monitoring (MRM) mode with an electrospray ionization source operated in positive ion mode. The method was applied to assess plasma and brain eCBs in tumor-bearing mice. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of pharmaceutical and biomedical analysis 07/2015; 111. DOI:10.1016/j.jpba.2015.03.017 · 2.83 Impact Factor
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    Fengxiang Yu · Ping Gong · Zhuqin Hu · Yu Qiu · Yongyao Cui · Xiaoling Gao · Hongzhuan Chen · Juan Li
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    ABSTRACT: Aggregated forms of amyloid-β (Aβ) peptides are important triggers for microglial activation, which is an important pathological component in the brains of Alzheimer's patients. Cu(II) ions are reported to be coordinated to monomeric Aβ, drive Aβ aggregation, and potentiate Aβ neurotoxicity. Here we investigated whether Cu(II) binding modulates the effect of Aβ on microglial activation and the subsequent neurotoxicity. Aβ peptides were incubated with Cu(II) at an equimolar ratio to obtain the Cu(II)-Aβ complex. Primary and BV-2 microglial cells were treated with Cu(II)-Aβ, Aβ, or Cu(II). The tumor necrosis factor-α (TNF-α) and nitric oxide levels in the media were determined. Extracellular hydrogen peroxide was quantified by a fluorometric assay with Amplex Red. Mitochondrial superoxide was detected by MitoSOX oxidation. Incubation of Cu(II) with Aβ confers different chemical properties on the resulting complex. At the subneurotoxic concentrations, Cu(II)-Aβ (but not Aβ or Cu(II) alone) treatment induced an activating morphological phenotype of microglia and induced the microglial release of TNF-α and nitric oxide as well as microglia-mediated neuronal damage. Cu(II)-Aβ-triggered microglial activation was blocked by nuclear factor (NF)-κB inhibitors and was accompanied with NF-κB activation. Moreover, Cu(II)-Aβ induced hydrogen peroxide release, which was not affected by NADPH oxidase inhibitors. Mitochondrial superoxide production was increased after Cu(II)-Aβ stimulation. N-acetyl-cysteine, a scavenger of reactive oxygen species (ROS), inhibited Cu(II)-Aβ-elicited microglial release of TNF-α and nitric oxide as well as the microglia-mediated neurotoxic effect. Our observations suggest that Cu(II) enhances the effect of Aβ on microglial activation and the subsequent neurotoxicity. The Cu(II)-Aβ-triggered microglial activation involves NF-κB activation and mitochondrial ROS production.
    Journal of Neuroinflammation 06/2015; 12(1):122. DOI:10.1186/s12974-015-0343-3 · 4.90 Impact Factor
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    ABSTRACT: The multifactorial pathogenesis of Alzheimer's disease (AD) implicates that multi-target-directed ligands (MTDLs) intervention may represent a promising therapy for AD. Amyloid-β (Aβ) aggregation and oxidative stress, two prominent neuropathological hallmarks in patients, play crucial roles in the neurotoxic cascade of this disease. In the present study, a series of novel (-)-meptazinol-melatonin hybrids were designed, synthesized and biologically characterized as potential MTDLs against AD. Among them, hybrids 7-7c displayed higher dual inhibitory potency toward cholinesterases (ChEs) and better oxygen radical absorbance capacity (ORAC) than the parental drugs. Furthermore, compound 7c could effectively inhibit Aβ self-aggregation, showed favorable safety and the blood-brain barrier (BBB) permeability. Therefore, 7c may serve as a valuable candidate that is worthy of further investigations in the treatment of AD. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Bioorganic & Medicinal Chemistry 05/2015; 23(13). DOI:10.1016/j.bmc.2015.04.084 · 2.95 Impact Factor
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    Jianrong Xu · Hengyi Zhao · Zhaoxi Zheng · Yu Wang · Yinyao Niu · Hao Wang · Jun Xu · Yang Lu · Hongzhuan Chen
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    ABSTRACT: Muscarinic acetylcholine receptors (mAChRs) have five subtypes and play crucial roles in various physiological functions and pathophysiological processes. Poor subtype specificity of mAChR modulators has been an obstacle to discover new therapeutic agents. Muscarinic toxin 7 (MT7) is a natural peptide toxin with high selectivity for the M1 receptor. With three to five residues substituted, M3, M4, and M5 receptor mutants could bind to MT7 at nanomolar concentration as the M1 receptor. However, the structural mechanisms explaining MT7-mAChRs binding are still largely unknown. In this study, we constructed 10 complex models of MT7 and each mAChR subtype or its mutant, performed molecular dynamics simulations, and calculated the binding energies to investigate the mechanisms. Our results suggested that the structural determinants for the interactions on mAChRs were composed of some critical residues located separately in the extracellular loops of mAChRs, such as Glu4.56, Leu4.60, Glu/Gln4.63, Tyr4.65, Glu/Asp6.67, and Trp7.35. The subtype specificity of MT7 was attributed to the non-conserved residues at positions 4.56 and 6.67. These structural mechanisms could facilitate the discovery of novel mAChR modulators with high subtype specificity and enhance the understanding of the interactions between ligands and G-protein-coupled receptors. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Journal of Molecular Recognition 02/2015; 28(4). DOI:10.1002/jmr.2438 · 2.34 Impact Factor
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    Xiao Gu · Hongzhuan Chen · Xiaoling Gao
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    ABSTRACT: Alzheimer's disease (AD), the most common form of dementia, is now representing one of the largest unmet medical needs. However, no effective treatment is now available to impede the progression of AD or delay its onset. There are two major challenges for the development of effective therapy for AD. First, the exact cause for AD onset is still unknown. Second, brain drug delivery is significantly hindered by the blood-brain barrier (BBB). In this review, we will summarize the pathological understanding about AD and the related treatments, compare BBB and its effect on brain drug delivery under normal and AD conditions and review the nanotherapeutic strategies that have been developed for AD therapy in recent years.
    Therapeutic delivery 02/2015; 6(2):177-95. DOI:10.4155/tde.14.97
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    ABSTRACT: Neuromuscular blocking agents (NMBAs) are widely used in surgery to achieve skeleton muscles relaxation under light anesthesia status. In this work, we synthesized a series of 3,16-bisquaternary ammonium steroidal NMBAs. Among them, three compounds exhibited higher in vitro activities than the commenced drug rocuronium. In addition, structure-activity relationship was unveiled. We found that the intact acetylcholine-like moiety in D-ring was not necessary for maintaining activity but both the acetyl group and the quaternary nitrogen were very essential. Copyright © 2015. Published by Elsevier Inc.
    Steroids 01/2015; 96. DOI:10.1016/j.steroids.2015.01.008 · 2.72 Impact Factor
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    ABSTRACT: Tumor neovasculature and tumor cells dual-targeting chemotherapy can not only destroy the tumor neovasculature, cut off the supply of nutrition and starve the tumor cells, but also directly kill tumor cells, holding great potential in overcoming the drawbacks of anti-angiogenic therapy only and improving the anti-glioma efficacy. In the present study, by taking advantage of the specific expression of fibronectin extra domain B (EDB) on both glioma neovasculature endothelial cells and glioma cells, we constructed EDB-targeted peptide APTEDB-modified PEG-PLA nanoparticles (APT-NP) for paclitaxel (PTX) loading to enable tumor neovasculature and tumor cells dual-targeting chemotherapy. PTX-loaded APT-NP showed satisfactory encapsulated efficiency, loading capacity and size distribution. In human umbilical vein endothelial cells, APT-NP exhibited significantly elevated cellular accumulation via energy-dependent, caveolae and lipid raft-involved endocytosis, and improved PTX-induced apoptosis therein. Both in vitro tube formation assay and in vivo matrigel angiogenesis analysis confirmed that APT-NP significantly improved the antiangiogenic ability of PTX. In U87MG cells, APT-NP showed elevated cellular internalization and also enhanced the cytotoxicity of the loaded PTX. Following intravenous administration, as shown by both in vivo live animal imaging and tissue distribution analysis, APT-NP achieved a much higher and specific accumulation within the glioma. As a result, APT-NP-PTX exhibited improved anti-glioma efficacy over unmodified nanoparticles and Taxol® in both subcutaneous and intracranial U87MG xenograft models. These findings collectively indicated that APTEDB-modified nanoparticles might serve as a promising nanocarrier for tumor cells and neovasculature dual-targeting chemotherapy and hold great potential in improving the efficacy anti-glioma therapy.
    Biomaterials 09/2014; 35(28):8215–8226. · 8.31 Impact Factor
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    ABSTRACT: Tumor neovasculature and tumor cells dual-targeting chemotherapy can not only destroy the tumor neovasculature, cut off the supply of nutrition and starve the tumor cells, but also directly kill tumor cells, holding great potential in overcoming the drawbacks of anti-angiogenic therapy only and improving the anti-glioma efficacy. In the present study, by taking advantage of the specific expression of fibronectin extra domain B (EDB) on both glioma neovasculature endothelial cells and glioma cells, we constructed EDB-targeted peptide APTEDB-modified PEG-PLA nanoparticles (APT-NP) for paclitaxel (PTX) loading to enable tumor neovasculature and tumor cells dual-targeting chemotherapy. PTX-loaded APT-NP showed satisfactory encapsulated efficiency, loading capacity and size distribution. In human umbilical vein endothelial cells, APT-NP exhibited significantly elevated cellular accumulation via energy-dependent, caveolae and lipid raft-involved endocytosis, and improved PTX-induced apoptosis therein. Both in vitro tube formation assay and in vivo matrigel angiogenesis analysis confirmed that APT-NP significantly improved the antiangiogenic ability of PTX. In U87MG cells, APT-NP showed elevated cellular internalization and also enhanced the cytotoxicity of the loaded PTX. Following intravenous administration, as shown by both in vivo live animal imaging and tissue distribution analysis, APT-NP achieved a much higher and specific accumulation within the glioma. As a result, APT-NP-PTX exhibited improved anti-glioma efficacy over unmodified nanoparticles and Taxol(®) in both subcutaneous and intracranial U87MG xenograft models. These findings collectively indicated that APTEDB-modified nanoparticles might serve as a promising nanocarrier for tumor cells and neovasculature dual-targeting chemotherapy and hold great potential in improving the efficacy anti-glioma therapy.
    Biomaterials 06/2014; 35(28). DOI:10.1016/j.biomaterials.2014.06.022 · 8.31 Impact Factor
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    ABSTRACT: A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of Meserine ((-)-meptazinol phenylcarbamate), a novel potent inhibitor of acetylcholinesterase (AChE), was developed, validated, and applied to a pharmacokinetic study in mice brain. The lower limit of quantification (LLOQ) was 1 ng mL(-1) and the linear range was 1-1,000 ng mL(-1). The analyte was eluted on a Zorbax SB-Aq column (2.1 × 100 mm, 3.5 μm) with the mobile phase composed of methanol and water (70:30, v/v, aqueous phase contained 10 mM ammonium formate and 0.3 % formic acid) using isocratic elution, and monitored by positive electrospray ionization in multiple reaction monitoring (MRM) mode. The flow rate was 0.25 mL min(-1). The injection volume was 5 μL and total run time was 4 min. The relative standard deviation (RSD) of intraday and interday variation was 2.49-7.81 and 3.01-7.67 %, respectively. All analytes were stable after 4 h at room temperature and 6 h in autosampler. The extraction recoveries of Meserine in brain homogenate were over 90 %. The main brain pharmacokinetic parameters obtained after intranasal administration were T max = 0.05 h, C max = 462.0 ± 39.7 ng g(-1), T 1/2 = 0.4 h, and AUC(0-∞) = 283.1 ± 9.1 ng h g(-1). Moreover, Meserine was distributed rapidly and widely into brain, heart, liver, spleen, lung, and kidney tissue. The method is validated and could be applied to the pharmacokinetic and tissue distribution study of Meserine in mice.
    Analytical and Bioanalytical Chemistry 04/2014; 406(14). DOI:10.1007/s00216-014-7779-7 · 3.58 Impact Factor
  • Zhuqin Hu · Fengxiang Yu · Ping Gong · Yu Qiu · Wei Zhou · Yongyao Cui · Juan Li · Hongzhuan Chen
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    ABSTRACT: Microglia-mediated neuroinflammation and the associated neuronal damage play critical roles in the pathogenesis of neurodegenerative disorders. Evidence shows an elevated concentration of extracellular copper(II) in brains of these disorders, which may contribute to neuronal death through direct neurotoxicity. Here we explored whether extracellular copper(II) triggers microglial activation. Primary rat microglia and murine microglial cell line BV-2 cells were cultured and treated with copper(II). The content of tumor necrosis factor-α (TNF-α) and nitric oxide in the medium was determined. Extracellular hydrogen peroxide was quantified by a fluorometric assay with Amplex Red. Mitochondrial superoxide was measured by MitoSOX oxidation. At subneurotoxic concentrations, copper(II) treatment induced dose- and time-dependent release of TNF-α and nitric oxide from microglial cells, and caused an indirect, microglia-mediated neurotoxicity that was blocked by inhibition of both TNF-α and nitric oxide production. Copper(II)-initiated microglial activation was accompanied with reduced IкB-α expression as well as phosphorylation and translocation of nuclear factor-κB (NF-κB) p65 and was blocked by NF-κB inhibitors (BAY11-7082 and SC-514). Moreover, copper(II) treatment evoked a rapid release of hydrogen peroxide from microglial cells, an effect that was not affected by NADPH oxidase inhibitors. N-acetyl-cysteine, a scavenger of reactive oxygen species (ROS), abrogated copper(II)-elicited microglial release of TNF-α and nitric oxide and subsequent neurotoxicity. Importantly, mitochondrial production of superoxide, paralleled to extracellular release of hydrogen peroxide, was induced after copper(II) stimulation. Our findings suggest that extracellular copper(II) at subneurotoxic concentrations could trigger NF-κB-dependent microglial activation and subsequent neurotoxicity. NADPH oxidase-independent, mitochondria-derived ROS may be involved in this activation.
    Toxicology and Applied Pharmacology 04/2014; 276(2). DOI:10.1016/j.taap.2014.01.020 · 3.63 Impact Factor
  • Ying Xie · Pan Jiang · Xinxing Ge · Hao Wang · Biyun Shao · Qiong Xie · Zhuibai Qiu · Hongzhuan Chen
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    ABSTRACT: In this paper a simple and sensitive method for determination of a novel phenylcarbamate AChE inhibitor, meserine, in mouse plasma, brain and rat plasma was evaluated using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Separation was achieved on an Alltech Alltima-C18 column (150mm×2.1mm, 3μm, Deerfield, IL, USA) with isocratic elution at a flow rate of 0.35ml/min. Detection was performed under the multiple reaction monitoring (MRM) mode using an electrospray ionization (ESI) in the positive ion mode. The protein precipitation and liquid-liquid extraction methods were used for the pretreatment of plasma and brain homogenates, respectively. The calibration curves of meserine showed good linearity over the concentration range of 0.5-1000ng/ml for mouse and rat plasma and 0.5-500ng/ml for mouse brain. The intra- and inter-day precision were less than 9.34% and the accuracy was from 95.34% to 107.78% for QC samples. The validated method was successfully applied to a preclinical pharmacokinetic study of meserine in mice and rats after intravenous and subcutaneous administration. The results showed that this novel drug could easily cross the blood-brain barrier to reach the site of drug action. Meserine was rapidly absorbed with a high subcutaneous absolute bioavailability (>90%).
    Journal of pharmaceutical and biomedical analysis 03/2014; 96C:156-161. DOI:10.1016/j.jpba.2014.03.025 · 2.83 Impact Factor
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    Zhihua Yu · Panpan Yu · Hongzhuan Chen · Herbert M. Geller
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    ABSTRACT: Reactive astrogliosis, characterized by cellular hypertrophy and various alterations in gene expression and proliferative phenotypes, is considered to contribute to brain injuries and diseases as diverse as trauma, neurodegeneration, and ischemia. KCa3.1, a potassium channel protein, has been reported to be up-regulated in reactive astrocytes after spinal cord injury in vivo. However, little is known regarding the exact role of KCa3.1 in reactive astrogliosis. To elucidate the role of KCa3.1 in regulating reactive astrogliosis, we investigated the effects of either blocking or knockout of KCa3.1 channels on the production of astrogliosis and astrocytic proliferation in response to transforming growth factor (TGF)-β in primary cultures of mouse astrocytes. We found that TGF-β increased KCa3.1 protein expression in astrocytes, with a concomitant marked increase in the expression of reactive astrogliosis, including glial fibrillary acidic protein (GFAP) and chondroitin sulfate proteoglycans (CSPGs). These changes were significantly attenuated by the KCa3.1 inhibitor TRAM-34. Similarly, the increase in GFAP and CSPGs in response to TGF-β was attenuated in KCa3.1-/- astrocytes. TRAM-34 also suppressed astrocytic proliferation. Additionally, the TGF-β-induced phosphorylation of Smad2 and Smad3 proteins was reduced with either inhibition of KCa3.1 with TRAM-34 or in KCa3.1-/- astrocytes. These findings highlight a novel role for the KCa3.1 channel in reactive astrogliosis phenotypic modulation and provide a potential target for therapeutic intervention for brain injuries. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 03/2014; 130(1). DOI:10.1111/jnc.12710 · 4.24 Impact Factor
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    ABSTRACT: A major cross-cutting problem for glioma therapy is the poor extravasation and penetration of the payload drug in target glioma parenchyma. Here, to overcome these obstacles, a tumor vessel recognizing and tumor penetrating system is developed by functionalizating the poly (ethyleneglycol)-poly (l-lactic-co-glycolic acid) nanoparticles with an iNGR moiety (iNGR-NP). The nanoparticulate formulation is expected to achieve specific deep penetration in the tumor tissue by initially binding to aminopeptidase N, with iNGR proteolytically cleaved to CRNGR, and then bind with neuropilin-1 to mediate deep penetration in the tumor parenchyma. iNGR-NP exhibits significantly enhanced cellular uptake in human umbilical vein endothelial cells, improves the anti-proliferation and anti-tube formation abilities of paclitaxel in vitro. Following intravenous administration, iNGR-NP present favorable pharmacokinetic and tumor homing profiles. Glioma distribution and penetration assays confirm that iNGR-NP achieve the highest accumulation and deepest penetration at the glioma sites. The anti-glioma efficacy of paclitaxel-loaded iNGR-NP is verified by its improved anti-angiogenesis activity and the significantly prolonged survival time in mice bearing intracranial glioma. These evidences highlight the potential of iNGR-decorated nanoparticles in overcoming the leading edge problem in anti-glioma drug delivery.
    Biomaterials 02/2014; 35(14). DOI:10.1016/j.biomaterials.2014.01.082 · 8.31 Impact Factor
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    ABSTRACT: Amyloid-beta (Aβ) accumulation in the brain is believed to play a central role in Alzheimer's disease (AD) pathogenesis, and the common late-onset form of AD is characterized by an overall impairment in Aβ clearance. Therefore, development of nanomedicine that can facilitate Aβ clearance represents a promising strategy for AD intervention. However, previous work of this kind was concentrated at the molecular level, and the disease-modifying effectiveness of such nanomedicine has not been investigated in clinically relevant biological systems. Here, we hypothesized that a biologically-inspired nanostructure - ApoE3-reconstituted high density lipoprotein (ApoE3-rHDL), which presents high binding affinity to Aβ, might serve as a novel nanomedicine for disease modification in AD by accelerating Aβ clearance. Surface plasmon resonance, transmission electron microscopy and co-immunoprecipitation analysis showed that ApoE3-rHDL demonstrated high binding affinity to both Aβ monomer and oligomer. It also accelerated the microglial, astroglial and liver cell degradation of Aβ by facilitating the lysosomal transport. One hour after intravenous administration, about 0.4% ID/g of ApoE3-rHDL got access to the brain. Four-week daily treatment with ApoE3-rHDL decreased Aβ deposition, attenuated microgliosis, ameliorated neurologic changes and rescued memory deficits in an AD animal model. The findings here provided the direct evidence of biomimetic nanostructures crossing the blood-brain barrier, capturing Aβ and facilitating its degradation by glial cells, indicating that ApoE3-rHDL might serve as a novel nanomedicine for disease modification in AD by accelerating Aβ clearance, which also justified the concept that nanostructures with Aβ-binding affinity might provide a novel nanoplatform for AD therapy.
    ACS Nano 02/2014; 8(3). DOI:10.1021/nn4058215 · 12.88 Impact Factor
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    ABSTRACT: Nanotechnology plays a unique instrumental role in the revolutionary development of brain-specific drug delivery, imaging, and diagnosis, but is highly limited by the existence of blood-brain barrier (BBB). In this study, microbubble-enhanced unfocused ultrasound (MEUUS) was developed as an approach to mediate an extensive brain delivery of poly (ethylene glycol) - poly (lactic acid) (PEG-PLA) nanoparticles. Following the MEUUS treatment, the nanoparticles signals were found to penetrate through the vascular walls and distributed deeply into the parenchyma at a significantly higher level (more than 250%) than those of the non-MEUUS treated control. Such effect was reversible and dependent on nanoparticles injection timing, sonication mode and mechanical index. Together with the transmission electron microscopy analysis, the increased brain accumulation of nanoparticles was claimed to be largely mediated by an ultrasound-induced stable cavitation of the microbubble which resulted in mechanical stretching of the vessel wall and consequently induced cellular transcytosis of the nanoparticles. The MEUUS technique was also used to facilitate the brain delivery of PEG-PLA nanoparticles functionalized with amyloid beta-specific antibody 6E10 for enabling the recognition of the hallmarks of Alzheimer's disease that widely distributed in the brain. No erythrocytes extravasation and other visible damages in the brain were detected following the MEUUS treatment. These findings together indicated that unfocused ultrasound with the aid of microbubble could effectively improve the brain delivery of nanoparticles, and this approach might serve as a safe and flexible platform for the potential application of nanoparticles in the diagnosis and therapy of brain diseases.
    Biomaterials 01/2014; 35(10). DOI:10.1016/j.biomaterials.2013.12.043 · 8.31 Impact Factor
  • Ying Xie · Pan Jiang · Xinxing Ge · Hao Wang · Biyun Shao · Qiong Xie · Zhuibai Qiu · Hongzhuan Chen
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    ABSTRACT: A simple, robust and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine the concentration of corticosterone (Cort) which is usually regarded as a stress biomarker in mouse serum. Since Cort is an endogenous hormone, a 'surrogate analyte' strategy was adopted using the stable isotope-deuterated corticosterone as a surrogate of the authentic analyte to generate the calibration curve. With telmisartan as the internal standard, the analytes were extracted with methanol, ethanol and acetone (1:1:1, v/v/v) and separated on a XTerra C18 (2.1 × 50 mm, 3.5 µm) column using a mobile phase consisting of 0.2% formic acid in water-methanol (30:70, v/v). Detection was performed in multiple reaction monitoring mode with an electrospray ionization source operated in positive ion mode. The standard curves were linear (r(2) > 0.999) over the dynamic range of 8.60-430 ng/mL, with a lower limit of quantification of 8.60 ng/mL. The intra- and inter-assay precisions were less than 15.0% of the relative standard deviation. This method was further used for analysis of serum samples from C57B/L tumor-bearing mice before and after the treatment of fluoxetine. Validation of the assay and its application to the analysis demonstrated that the method was applicable to determine meaningful changes in Cort concentrations in serum samples of the tumor-bearing mice for the stress status evaluation. Copyright © 2013 John Wiley & Sons, Ltd.
    Biomedical Chromatography 12/2013; 27(12). DOI:10.1002/bmc.2973 · 1.66 Impact Factor
  • JianRong Xu · Hao Wang · HongZhuan Chen
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    ABSTRACT: Muscarinic acetylcholine receptors (mAChRs) play crucial roles in various physiological functions and pathophysiological processes. Acetylcholine (ACh), as a classical ligand and one of the pivotal neurotransmitters, serves as a prototype for the elucidation of molecular interaction and the development of mimicked and antagonized agents. With the advances in medicinal chemistry and structural biology, more and more mAChRs modulators derived from natural toxins have been identified. Based on the chemical structures and the receptor-ligand interaction modes, these mAChRs modulators can be divided into orthosteric modulators, allosteric modulators and other modulators. Moreover, allosteric modulators can be further divided into three groups: alcuronium-like modulators, staurosporine-like modulators, and phlegmarine-like modulators. In this review, we focus on various mAChRs modulators derived from natural toxins on the basis of the receptor-ligand interaction modes. The understanding of the affinity, the intrinsic efficacy, and the selectivity of mAChRs modulators may lead to the discovery of new drug leads for the treatment of diseases related to mAChRs.
    Science China-Chemistry 10/2013; 56(10):1333-1343. DOI:10.1007/s11426-013-4958-x · 1.52 Impact Factor
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    ABSTRACT: Antiangiogenic therapy shows great advantages in clinical cancer treatment while no overall survival has been achieved. The compromised results were mainly contributed by intrinsic/acquired antiangiogenic drug resistance and increased local invasion or distant metastasis after antiangiogenic therapy. Here we constructed a CGKRK peptide-modified PEG-co-PCL nanoparticulate drug delivery system (DDS), aiming at targeting both tumor angiogenic blood vessels and tumor cells to achieve enhanced anti-tumor activity as well as holding a great potential to overcome the drawbacks of antiangiogenic therapy alone. The obtained CGKRK-functionalized PEG-co-PCL nanoparticles (CGKRK-NP) with a particle size of 117.28±10.42nm and zeta potential of-15.7±3.32mV, exhibited an enhanced accumulation via an energy-dependent, lipid raft/caveolae-mediated endocytosis with the involvement of microtubules in human umbilical vein endothelial cells (HUVEC) and an energy-dependent, lipid raft/caveolae-mediated endocytosis with the participation of Golgi apparatus in human U87MG cells. Using coumarin-6 as the fluorescence probe, invitro U87MG tumor spheroids assays showed that CGKRK-NP effectively penetrated into the tumor spheroids. Selective accumulation and extensive bio-distribution of CGKRK-NP at tumor site was confirmed by invivo imaging and tumor section analysis. After drug loading, CGKRK-NP enhanced cytotoxicity and apoptosis induction activity of the loaded PTX on both HUVEC cells and U87MG cells and improved its inhibition effect on the growth of U87MG tumor spheroids. The smallest tumor volume was achieved by those mice bearing subcutaneous U87MG tumor following the treatment of PTX-loaded CGKRK-NP. The findings here indicated that CGKRK peptide-functionalized nanoparticulate DDS could be used as an effective tumor angiogenic blood vessels and tumor cells dual-targeting DDS and might provide a great promising approach for reducing the disadvantages of antiangiogenic therapy alone.
    Biomaterials 09/2013; 34(37). DOI:10.1016/j.biomaterials.2013.09.001 · 8.31 Impact Factor
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    ABSTRACT: The blood-brain barrier (BBB), which is formed by the brain capillary wall, greatly hinders the development of new drugs for the brain. Over the past decades, among the various receptor-mediated endogenous BBB transport systems, the strategy of using transferrin or anti-transferrin receptor antibodies to facilitate brain drug delivery system is of particular interest. However, the application of large proteins still suffers from the drawbacks including synthesis procedure, stability, and immunological response. Here we explored a B6 peptide discovered by phase display as a substitute for transferrin, and conjugated it to PEG-PLA nanoparticles (NP) with the aim to enhance the delivery of neuroprotective drug across the BBB for the treatment of Alzheimer's disease. B6-modified NP (B6-NP) exhibited significantly higher accumulation in brain capillary endothelial cells via lipid raft-mediated and clathrin-mediated endocytosis. In vivo, fluorescently labeled B6-NP exhibited much higher brain accumulation when compared with NP. Administration of B6-NP encapsulated neuroprotective peptide NAPVSIPQ (NAP) to Alzheimer's disease mouse models showed excellent amelioration in learning impairments, cholinergic disruption and loss of hippocampal neurons even at lower dose. These findings together suggested that B6-NP might serve as a promising DDS for facilitating the brain delivery of neuropeptides.
    Bioconjugate Chemistry 05/2013; 24(6). DOI:10.1021/bc400055h · 4.82 Impact Factor

Publication Stats

777 Citations
247.63 Total Impact Points

Institutions

  • 2011–2015
    • Renji Hospital
      Shanghai, Shanghai Shi, China
  • 2007–2015
    • Shanghai Jiao Tong University
      • • School of Medicine
      • • Laboratories of Pharmacology
      Shanghai, Shanghai Shi, China
  • 2012
    • Ruijin Hospital North
      Shanghai, Shanghai Shi, China
  • 2005–2007
    • Shanghai University
      Shanghai, Shanghai Shi, China
  • 2003
    • Second Military Medical University, Shanghai
      Shanghai, Shanghai Shi, China