Hongzhuan Chen

Renji Hospital, Shanghai, Shanghai Shi, China

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Publications (49)229.73 Total impact

  • [Show abstract] [Hide abstract]
    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; · 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; · 3.66 Impact Factor
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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. · 2.45 Impact Factor
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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; · 3.97 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; · 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; · 12.03 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; · 8.31 Impact Factor
  • Journal of Pharmaceutical and Biomedical Analysis. 01/2014; 96:156–161.
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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 01/2014; · 3.98 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 ± 10.42 nm and zeta potential of -15.7 ± 3.32 mV, 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, in vitro 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 in vivo 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; · 8.31 Impact Factor
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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 06/2013; · 1.95 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; · 4.58 Impact Factor
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    ABSTRACT: By taking advantage of the excessively upregulated expression of neuropilin (NRP) on the surface of both glioma cells and endothelial cells of angiogenic blood vessels, the ligand of NRP with high affinity - tLyp-1 peptide, which also contains a CendR motif ((R/K)XX(R/K)), was functionalized to the surface of PEG-PLA nanoparticles (tLyp-1-NP) to mediate its tumor homing, vascular extravasation and deep penetration into the glioma parenchyma. The tLyp-1-NP was prepared via a maleimide-thiol coupling reaction with uniformly spherical shape under TEM and particle size of 111.30 ± 15.64 nm. tLyp-1-NP exhibited enhanced cellular uptake in both human umbilical vein endothelial cells and Rat C6 glioma cells, increased cytotoxicity of the loaded PTX, and improved penetration and growth inhibition in avascular C6 glioma spheroids. Selective accumulation and deep penetration of tLyp-1-NP at the glioma site was confirmed by in vivo imaging and glioma distribution analysis. The longest survival was achieved by those mice bearing intracranial C6 glioma treated with PTX-loaded tLyp-1-NP. The findings here strongly indicate that tLyp-1 peptide-functionalized nanoparticulate DDS could significantly improve the efficacy of paclitaxel glioma therapy.
    Biomaterials 04/2013; · 8.31 Impact Factor
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    ABSTRACT: Tilorone is an interferon inducer with anticancer activity. Twenty-two novel tilorone analogs were synthesized by improvements of fluorenone skeleton, side chains and amino groups to screen new anticancer agents. In vitro evaluation showed that ten new compounds had better anticancer activities than tilorone. Among them, 2c (IC50 < 7 μM against cancer cell lines and IC50 > 35 μM against non-cancer cell lines) and 5d (IC50 < 10 μM against cancer cell lines and IC50 > 53 μM against non-cancer cell lines) exhibited the best anticancer activities and selectivities. Pharmacophore modeling of highly active compounds was carried out by Molecular Operating Environment (MOE) to generate a visualized model for compound design in future study.
    European Journal of Medicinal Chemistry 04/2013; 64C:432-441. · 3.43 Impact Factor
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    ABSTRACT: Low permeability across the blood-brain tumor barrier (BTB) and poor penetration into the glioma parenchyma represent key obstacles for anti-glioblastoma drug delivery. In this study, MT1-AF7p peptide, which presents high binding affinity to membrane type-1 matrix metalloproteinase (MT1-MMP) that over-expressed on both angiogenic blood vessels and glioma cells, was employed to decorate the paclitaxel-loaded PEG-PLA nanoparticles (MT1-NP-PTX) to mediate glioblastoma targeting. Tumor-homing and penetrating peptide iRGD was co-administrated to further facilitate nanoparticles extravasation from the tumor vessels and penetration into the glioma parenchyma. MT1-NP-PTX showed satisfactory encapsulated efficiency, loading capacity and size distribution. In C6 glioma cells, MT1-NP was found to exhibit significantly enhanced cellular accumulation than that of unmodified NP via both energy-dependent macropinocytosis and lipid raft-mediated endocytosis. The anti-proliferative and apoptosis-induction activity of PTX was significantly enhanced following its encapsulation in MT1-NP. In vivo imaging and glioma distribution together confirmed that MT1-AF7p functionalization and iRGD co-administration significantly improved the nanoparticles extravasation across BTB and accumulation in glioma parenchyma. Furthermore, in vitro C6 glioma spheroid assays evidenced that MT1-NP effectively penetrated into the glioma spheroids and significantly improved the growth inhibitory effects of loaded PTX on glioma spheroids. More importantly, the median survival time of those nude mice bearing intracranial C6 glioma received MT1-NP-PTX and iRGD combination regimen was 60 days, significantly longer than that of other groups. The findings suggested that the BTB/glioma cells dual-targeting DDS co-administrated with iRGD peptide might provide a both practical and feasible solution to highly efficient anti-glioblastoma drug delivery.
    Biomaterials 04/2013; · 8.31 Impact Factor
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    ABSTRACT: Development of effective non-invasive drug delivery systems is of great importance to the treatment of Alzheimer's diseases and has made great progress in recent years. In this work, lactoferrin (Lf), a natural iron binding protein, whose receptor is highly expressed in both respiratory epithelial cells and neurons is here utilized to facilitate the nose-to-brain drug delivery of neuroprotection peptides. The Lf-conjugated PEG-PCL nanoparticle (Lf-NP) was constructed via a maleimide-thiol reaction with the Lf conjugation confirmed by CBQCA Protein Quantitation and XPS analysis. Other important parameters such as particle size distribution, zeta potential and in vitro release of fluorescent probes were also characterized. Compared with unmodified nanoparticles (NP), Lf-NP exhibited a significantly enhanced cellular accumulation in 16HBE14o-cells through both caveolae-/clathrin-mediated endocytosis and direct translocation. Following intranasal administration, Lf-NP facilitated the brain distribution of the coumarin-6 incorporated with the AUC0-8h in rat cerebrum (with hippocampus removed), cerebellum, olfactory tract, olfactory bulb and hippocampus 1.36, 1.53, 1.70, 1.57 and 1.23 times higher than that of coumarin-6 carried by NP, respectively. Using a neuroprotective peptide - NAPVSIPQ (NAP) as the model drug, the neuroprotective and memory improvement effect of Lf-NP was observed even at lower dose than that of NP in a Morris water maze experiment, which was also confirmed by the evaluation of acetylcholinesterase, choline acetyltransferase activity and neuronal degeneration in the mice hippocampus. In conclusion, Lf-NP may serve as a promising nose-to-brain drug delivery carrier especially for peptides and proteins.
    Biomaterials 02/2013; · 8.31 Impact Factor
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    ABSTRACT: Biodegradable polyester nanoparticles have now attracted growing interest as promising drug delivery system. However, a fundamental understanding about its cellular transport as well as the influence by the polymeric architecture is still lack, which remains a significant obstacle to optimal nanocarrier design. In this work, using Caco-2 cell model, we characterized the cellular transport pathway of pegylated polyester nanoparticles and determined the effect of polymer architecture including PEG chain length and core material on its cellular interaction and transcellular transport. The nanoparticles were found to undergo an energy-dependent, lipid raft-mediated, but caveolae-independent endocytosis. PEG chain length (from 2000 to 5000Da) and core material (PLA/PLGA) hardly affected the cellular interaction and the intracellular itinerary of the nanoparticles. However, in the case of transcellular transport, the maximal transcellular transport efficiency for its payload was achieved by the PEG(5000)-PLA(40000) nanoparticles which present higher drug loading capacity and slower drug release. The findings here revealed the cellular interaction mechanism of pegylated polyester nanoparticles and provided evidence for the role of polymer architectures in modulating the transcellular permeability of the agents loaded by the nanoparticles, and would be helpful in improving carrier design to enhance drug delivery.
    International Journal of Pharmaceutics 02/2013; · 3.99 Impact Factor
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    ABSTRACT: Based on the powerful cell-penetrating ability of low molecular weight protamine (LMWP) and the over-expression of matrix metalloproteinases in the tumor sites, we here constructed an activatable low molecular weight protamine (ALMWP) and modified it onto the surface of PEG-PLA nanoparticles to develop a 'smart' drug delivery system with enhanced permeability for facilitating site-specific targeting delivery of anticancer drug. The obtained ALMWP-NP with a particle size of 134.0 ± 4.59 nm and a zeta potential of -34.4 ± 2.7 mV, exhibited an enhanced MMP-dependent accumulation in HT-1080 cells via both energy-independent direct translocation and clathrin-mediated, cytoskeleton-dependent endocytosis. Pharmacokinetic and biodistribution study in HT-1080 tumor-bearing mice showed that ALMWP-NP significantly increased the accumulation of paclitaxel (PTX) in the tumor site but not the non-target tissues. In addition, intra-tumor distribution analysis demonstrated that more ALMWP-NP penetrated deeply into the tumor parenchyma. As a result, PTX loaded by ALMWP-NP exhibited improved anti-tumor efficacy over that by NP and LMWP-NP. The findings suggested that ALMWP-NP could be used as a safe and effective tumor-targeting drug delivery system and opened a new gateway to the application of cell-penetrating peptides for targeted anti-tumor therapy.
    Bioconjugate Chemistry 01/2013; · 4.58 Impact Factor
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    ABSTRACT: In this study, the distribution of a new triazole drug, iodiconazole, in rat dermal interstitial fluid and blood was investigated by double-site microdialysis following dermal administration. It was demonstrated that well-calibrated microdialysis sampling in rats could be used to assess the percutaneous penetration kinetics of iodiconazole cream. Iodiconazole penetrated rapidly and cleared slowly from the dermis. The ratio of area under the concentration-time curve in dermis (AUC(dermis)) to that in blood (AUC(blood)) was close to 20, which meant that the free iodiconazole concentration had a higher distribution in the target tissue. Subsequently, the in vitro antifungal activities of iodiconazole were evaluated and were compared with those of fluconazole, itraconazole, ketoconazole, miconazole and terbinafine. Iodiconazole exhibited broad spectrum and potent activity against 12 kinds of clinically pathogenic fungi. The drug concentration percentage inhibition curves versus time of iodiconazole against the tested fungi elucidated the two-dimensional relationship (concentration-effect) following drug administration, indicating that the percentage inhibition (%) of iodiconazole compared with the drug-free control in dermal dialysate were all >90% in the 900-min sampling time following dermal administration. Moreover, integration of in vivo pharmacokinetic data with the in vitro minimum inhibitory concentration (MIC) provided iodiconazole AUC/MIC ratios in rat dermis and blood of 347.7h and 18.8h, respectively, with an iodiconazole cream (2%) dosage of 0.033g/cm(2) (3cm×5cm). These findings show a reservoir effect in the skin following topical application. Iodiconazole topical cream may be a future alternative for treatment of dermatophytosis in humans.
    International journal of antimicrobial agents 01/2013; · 3.03 Impact Factor

Publication Stats

434 Citations
229.73 Total Impact Points

Institutions

  • 2008–2014
    • Renji Hospital
      Shanghai, Shanghai Shi, China
  • 2005–2014
    • Shanghai Jiao Tong University
      • Laboratories of Pharmacology
      Shanghai, Shanghai Shi, China
  • 2007–2013
    • Fudan University
      • School of Pharmacy
      Shanghai, Shanghai Shi, China
    • Shanghai University
      Shanghai, Shanghai Shi, China
  • 2012
    • Ruijin Hospital North
      Shanghai, Shanghai Shi, China
    • Shanghai Institute of Planned Parenthood Research
      Shanghai, Shanghai Shi, China
  • 2003
    • Second Military Medical University, Shanghai
      Shanghai, Shanghai Shi, China