共查询到20条相似文献,搜索用时 31 毫秒
1.
Fu Chen Zhenshan Jia Kelly C. Rice Richard A. Reinhardt Kenneth W. Bayles Dong Wang 《Pharmaceutical research》2014,31(11):3031-3037
Purpose
The purpose of this study was to develop a novel, drug-free therapy that can reduce the over-accumulation of cariogenic bacteria on dental surfaces.Methods
We designed and synthesized a polyethylene glycol (PEG)-based hydrophilic copolymer functionalized with a pyrophosphate (PPi) tooth-binding anchor using “click” chemistry. The polymer was then evaluated for hydroxyapatite (HA) binding kinetics and capability of reducing bacteria adhesion to artificial tooth surface.Results
The PPi-PEG copolymer can effectively inhibit salivary protein adsorption after rapid binding to an artificial tooth surface. As a result, the in vitro S. mutans adhesion study showed that the PPi-PEG copolymer can inhibit saliva protein-promoted S. mutans adhesion through the creation of a neutral, hydrophilic layer on the artificial tooth surface.Conclusions
The results suggested the potential application of a PPi-PEG copolymer as a drug-free alternative to current antimicrobial therapy for caries prevention. 相似文献2.
Neda Samadi Mies J. van Steenbergen Joep B. van den Dikkenberg Tina Vermonden Cornelus F. van Nostrum Maryam Amidi Wim E. Hennink 《Pharmaceutical research》2014,31(10):2593-2604
Purpose
To investigate the effect of polyethylene glycol (PEG) in nanoparticles based on blends of hydroxylated aliphatic polyester, poly(D,L-lactic-co-glycolic-co-hydroxymethyl glycolic acid) (PLGHMGA) and PEG-PLGHMGA block copolymers on their degradation and release behavior.Methods
Protein-loaded nanoparticles were prepared with blends of varying ratios of PEG-PLGHMGA (molecular weight of PEG 2,000 and 5,000 Da) and PLGHMGA, by a double emulsion method with or without using poly(vinyl alcohol) (PVA) as surfactant. Bovine serum albumin and lysozyme were used as model proteins.Results
PEGylated particles prepared without PVA had a zeta potential ranging from ~ ?3 to ~?35 mV and size ranging from ~200 to ~600 nm that were significantly dependent on the content and type of PEG-block copolymer. The encapsulation efficiency of the two proteins however was very low (<30%) and the particles rapidly released their content in a few days. In contrast, all formulations prepared with PVA showed almost similar particle properties (size: ~250 nm, zeta potential: ~?1 mV), while loading efficiency for both model proteins was rather high (80–90%). Unexpectedly, independent of the type of formulation, the nanoparticles had nearly the same release and degradation characteristics. NMR analysis showed almost a complete removal of PEG in 5 days which explains these marginal differences.Conclusions
Protein release and particle degradation are not substantially influenced by the content of PEG, likely because of the fast shedding of the PEG blocks. These PEG shedding particles are interesting system for intracellular delivery of drugs. 相似文献3.
Suzanne M. D’Addio John Gar Yan Chan Philip Chi Lip Kwok Bryan R. Benson Robert K. Prud’homme Hak-Kim Chan 《Pharmaceutical research》2013,30(11):2891-2901
Purpose
While most examples of nanoparticle therapeutics have involved parenteral or IV administration, pulmonary delivery is an attractive alternative, especially to target and treat local infections and diseases of the lungs. We describe a successful dry powder formulation which is capable of delivering nanoparticles to the lungs with good aerosolization properties, high loadings of nanoparticles, and limited irreversible aggregation.Methods
Aerosolizable mannitol carrier particles that encapsulate nanoparticles with dense PEG coatings were prepared by a combination of ultrasonic atomization and spray freeze drying. This process was contrasted to particle formation by conventional spray drying.Results
Spray freeze drying a solution of nanoparticles and mannitol (2 wt% solids) resulted in particles with an average diameter of 21?±?1.7 μm, regardless of the fraction of nanoparticles loaded (0–50% of total solids). Spray freeze dried (SFD) powders with a 50% nanoparticle loading had a fine particle fraction (FPF) of 60%. After formulation in a mannitol matrix, nanoparticles redispersed in water to < 1 μm with hand agitation and to < 250 nm with the aid of sonication. Powder production by spray drying was less successful, with low powder yields and extensive, irreversible aggregation of nanoparticles evident upon rehydration.Conclusions
This study reveals the unique advantages of processing by ultrasonic spray freeze drying to produce aerosol dry powders with controlled properties for the delivery of therapeutic nanoparticles to the lungs. 相似文献4.
Fumie Yamasaki Shoko Machida Asami Nakata Alfarius Eko Nugroho Yusuke Hirasawa Toshio Kaneda Osamu Shirota Naoyuki Hagane Tadayoshi Sugizaki Hiroshi Morita 《Journal of natural medicines》2013,67(1):212-216
Two new isocoumarin glucosides, haworforbins A (1) and B (2), and a new chromone, haworforbin C (3), have been isolated from Haworthia cymbiformis. Their structures and absolute configurations were elucidated on the basis of NMR and CD data. Haworforbin C (3) exhibited moderate inhibition of nitric oxide production in lipopolysaccharide-stimulated RAW264.7 cell line. 相似文献
5.
Partha Roy Suvadra Das Runa Ghosh Auddy Achintya Saha Arup Mukherjee 《Pharmaceutical research》2013,30(5):1252-1262
Purpose
Paracetamol (acetaminophen, APAP) overdose is often fatal due to progressive and irreversible hepatic necrosis. The aim of this work was to design Andrographolide (AG) loaded nanoparticles to prevent similar hepatic necrosis.Methods
Functionalized AG-loaded PLGA nanoparticles carrying different densities of heparin were prepared following a facile emulsion solvent evaporation technique. Nanoparticle morphology, loading and release kinetics were studied. Hepatic localization of the nanoparticles was investigated in both normal and APAP damaged conditions using FITC fluorescent probe. Different serum parameters and liver histopathology were further examined as indicators of hepatic condition before and after treatment.Result
A collection of heparin functionalized AG-loaded PLGA nanoparticles were designed. Low amount of heparin on the particle surface could rapidly localize the nanoparticles up to the liver. The new functionalized AG nanoparticles affect efficient hepatoprotection in experimental mouse APAP overdose conditions. AG nanoparticle hepatoprotection was due to the rapid regeneration of antioxidant capacity and hepatic GSH store.Conclusions
Engineered nanoparticles loaded with AG provided a fast protection in APAP induced acute liver failure. 相似文献6.
Xihui Gao Jun Qian Shuyan Zheng Ying Xiong Jiahao Man Binxin Cao Lu Wang Shenghong Ju Cong Li 《Pharmaceutical research》2013,30(10):2538-2548
Purpose
To investigate the multivalent effect for up-regulating the intracerebral delivery of nanoparticles via receptor-mediated transcytosis.Methods
Nanoparticles labeled with near-infrared (NIR) fluorophore and different numbers of angiopep-2 peptides that specifically target low-density lipoprotein receptor-related protein (LRP) on the brain capillary endothelial cells were developed. Bio-distribution studies quantified the intracerebral uptakes of these nanoparticles at 2 and 24 h after intravenous injection. In vivo NIR fluorescence imaging, ex vivo autoradiographic imaging and 3D reconstructed NIR fluorescence imaging revealed the nanoparticle distribution pattern in brain. Fluorescence microscopic imaging identified the nanoparticle locations at the cellular level.Results
The multimetirc association between the angiopep-2 peptides labeled on the nanoparticle and the LRP receptors on the brain capillary endothelial cells significantly increased the intracerebral uptake of the nanoparticles. Nanoparticle Den-Angio4 labeled four angiopep-2 peptides achieved the highest BBB traverse efficacy. After penetrating the BBB, Den-Angio4 distributed heterogeneously and mainly located at hippocampus, striatum and cerebellum in the brains.Conclusions
The multivalent effect significantly enhances the BBB permeability of nanoparticles. Den-Angio4 as a nanoparticle prototype provides a two order targeted strategy for diagnosis or treatment of central nerver system diseases by first traversing the BBB via receptor-mediated endocytosis and secondly targeting the leisions with high receptor expression level. 相似文献7.
Pinaki R. Desai Punit P. Shah Patrick Hayden Mandip Singh 《Pharmaceutical research》2013,30(4):1037-1049
Purpose
To investigate the percutaneous permeation pathways of cell penetrating peptide modified lipid nanoparticles and oleic acid modified polymeric nanoparticles.Methods
Confocal microscopy was performed on skin cultures (EpiDermFT?) for modified and un-modified nanoparticles. Differential stripping was performed following in vitro skin permeation of Ibuprofen (Ibu) encapsulated nanoparticles to estimate Ibu levels in different skin layers and receiver compartment. The hair follicles (HF) were blocked and in vitro skin permeation of nanoparticles was then compared with unblocked HF. The surface modified nanoparticles were investigated for response on allergic contact dermatitis (ACD).Results
Surface modified nanoparticles showed a significant higher (p?<?0.05) in fluorescence in EpiDermFT? cultures compared to controls. The HF play less than 5% role in total nanoparticle permeation into the skin. The Ibu levels were significantly high (p?<?0.05) for surface modified nanoparticles compared to controls. The Ibu levels in skin and receiver compartment were not significantly different when HF were open or closed. Modified nanoparticles showed significant improvement in treatment of ACD compared to solution.Conclusions
Our studies demonstrate that increased skin permeation of surface modified nanoparticles is not only dependent on a follicular pathway but also occur through non-follicular pathway(s). 相似文献8.
Purpose
Hedgehog (Hh) and peroxisome proliferator-activated receptor gamma (PPAR-γ) are major signaling pathways involved in the pathogenesis of liver fibrosis. Since Hh inhibitor, vismodegib (GDC) and PPAR-γ agonist, rosiglitazone (RSG) have poor water solubility, our objective was to formulate biodegradable polymeric nanoparticles encapsulating GDC and RSG for treating liver fibrosis.Methods
Methoxy-polyethylene-glycol-b-poly(carbonate-co-lactide) [mPEG-b-p(CB-co-LA)] was synthesized and characterized using 1H NMR. Nanoparticles were prepared using this polymer by emulsification/solvent evaporation method to encapsulate GDC and RSG either alone or in combination. Nanoparticles were characterized for particle size, drug loading, drug release, and anti-fibrotic efficacy after tail vein injection into common bile duct ligated (CBDL) fibrotic rats.Results
mPEG-b-p(CB-co-LA) copolymer has molecular weight of 30,000 Da as determined by 1H NMR. Nanoparticles were monodisperse with a mean particle size of 120–130 nm. Drug loading was 5% and 2% w/w for GDC and RSG, respectively. Nanoparticles carrying both GDC and RSG were formulated at half of their individual drug loading. Systemic administration of drug loaded nanoparticles protected liver injury in CBDL rats by suppressing the activation of hepatic stellate cells, and decreasing inflammatory cytokines.Conclusion
Polymeric nanoparticles for co-delivery of Hh inhibitor and PPAR-γ agonist have the potential to treat liver fibrosis by intervening complex fibrotic cascade. 相似文献9.
Eduardo A. Bender Marcela F. Cavalcante Márcia D. Adorne Letícia M. Colomé Sílvia S. Guterres Dulcinéia S. P. Abdalla Adriana R. Pohlmann 《Pharmaceutical research》2014,31(11):2975-2987
Purpose
In general, the surface functionalization of polymeric nanoparticles is carried out by covalently bounding ligands to the nanoparticle surface. This process can cause a lack or decrease of the ligand specificity to its target receptor, besides the need of purification steps. We proposed a ligand-metal-chitosan-lecithin complex as a new strategy to functionalize the surface of biodegradable nanoparticles.Methods
One pot synthesis of scFv anti-LDL(?)-functionalized nanocapsules was carried out by self-assembly and interfacial reactions. Particle sizing techniques, lipid peroxidation and molecular recognition by enzyme linked immuno sorbent assays were carried out.Results
The selected formulation had unimodal size distribution with mean diameter of about 130 nm. The metals in the complex did not enhance the oxidative stress, and the scFv anti-LDL(?)-functionalized nanocapsules recognized LDL(?) and did not react with native LDL indicating the maintenance of the active site of the fragment.Conclusions
The one pot synthesis, using the ligand-metal-chitosan-lecithin complex to functionalize the surface of the biodegradable nanocapsules, maintained the active site of the antibody fragment making the device interesting for applications in nanomedicine. 相似文献10.
Purpose
We evaluated the controlled release of lysozyme from various poly(D,L-lactic-co-glycolic acid) (PLGA) 50/50-polyethylene glycol (PEG) block copolymers relative to PLGA 50/50.Methods
Lysozyme was encapsulated in cylindrical implants (0.8 mm diameter) by a solvent extrusion method. Release studies were conducted in phosphate buffered saline +0.02% Tween 80 (PBST) at 37°C. Lysozyme activity was measured by a fluorescence-based assay. Implant erosion was evaluated by kinetics of polymer molecular weight decline, water uptake, and mass loss.Results
Lysozyme release from an AB15 di-block copolymer (15% 5 kDa PEG, PLGA 28 kDa) was very fast, whereas an AB10 di-block copolymer (with 10% 5 kDa PEG, PLGA 45 kDa) and ABA10 tri-block copolymer (with 10% 6 kDa PEG, PLGA 27 kDa) showed release profiles similar to PLGA. We achieved continuous lysozyme release for up to 4 weeks from AB10 and ABA10 by lysozyme co-encapsulation with the pore-forming and acid-neutralizing MgCO3, and from AB15 by co-encapsulation of MgCO3 and blending AB15 with PLGA. Lysozyme activity was mostly recovered during 4 weeks.Conclusions
These block co-polymers may have utility either alone or as PLGA blends for the controlled release of proteins. 相似文献11.
12.
Naoki Itoh Eiichi Yamamoto Tomofumi Santa Takashi Funatsu Masaru Kato 《Pharmaceutical research》2016,33(6):1440-1446
Purpose
Nanoparticles have been used in diverse areas, and even broader applications are expected in the future. Since surface modification can influence the configuration and toxicity of nanoparticles, a rapid screening method is important to ensure nanoparticle quality.Methods
We examined the effect of the nanoparticle surface morphology on the HPLC elution profile using two types of 100-nm liposomal nanoparticles (AmBisome? and DOXIL?).Results
These 100-nm-sized nanoparticles eluted before the holdup time (about 4 min), even when a column packed with particles with a relatively large pore size (30 nm) was used. The elution time of the nanoparticles increased with pegylation of the nanoparticles and protein adsorption to the nanoparticles; however, the nanoparticles still eluted before the holdup time.Conclusions
The results of this study indicate that HPLC is a suitable tool for rapid evaluation of the surface of liposomal nanoparticles.13.
Magnetic Targeting of Novel Heparinized Iron Oxide Nanoparticles Evaluated in a 9L-glioma Mouse Model 总被引:1,自引:0,他引:1
Purpose
A novel PEGylated and heparinized magnetic iron oxide nano-platform (DNPH) was synthesized for simultaneous magnetic resonance imaging (MRI) and tumor targeting.Methods
Starch-coated magnetic iron oxide nanoparticles (“D”) were crosslinked, aminated (DN) and then simultaneously PEGylated and heparinized with different feed ratios of PEG and heparin (DNPH1-4). DNPH products were characterized by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and superconducting quantum interference device (SQUID). The magentic targeting of DNPH3, with appropriate amounts of conjugated PEG and heparin, in a mouse 9L-glioma subcutaneous tumor model was confirmed by magnetic resonance imaging (MRI)/electron spin resonance (ESR).Results
DNPH3 showed long circulating properties in vivo (half-life >8 h, more than 60-fold longer than that of parent D) and low reticuloendothelial system (RES) recognition in liver and spleen. Protamine, a model cationic protein, was efficiently loaded onto DNPH3 with a maximum loading content of 26.4 μg/mg Fe. Magnetic capture of DNPH3 in tumor site with optimized conditions (I.D. of 12 mg/kg, targeting time of 45 min) was up to 29.42 μg Fe/g tissue (12.26% I.D./g tissue).Conclusion
DNPH3 showed the potential to be used as a platform for cationic proteins for simultaneous tumor targeting and imaging. 相似文献14.
Kohta Mohri Kengo Nagata Shozo Ohtsuki Shiori Toyama Mao Nonomura Yuki Takahashi Yoshinobu Takakura Makiya Nishikawa Shinji Sakuma 《Pharmaceutical research》2017,34(11):2362-2370
Purpose
We previously demonstrated that the immunostimulatory activity of CpG DNA is increased by the formation of polypod-like structures. The present study was designed to elucidate the mechanism underlying this increase.Methods
Tripodna (three pods) and hexapodna (six pods) were prepared. The cellular uptake of Alexa Fluor 488-labeled DNA samples was examined in several cell lines by measuring the MFI of cells. TNF-α release from RAW264.7 cells was measured after addition of polypodna containing CpG motifs. Dissociation of double stranded DNA was evaluated using FRET.Results
Tripodna and hexapodna were efficiently taken up by macrophage-like RAW264.7 cells and dendritic DC2.4 cells, but not by fibroblast or endothelial cell lines. The uptake by RAW264.7 cells was highest for hexapodna, followed by tripodna, dsDNA, and ssDNA. The release of TNF-α from RAW264.7 cells was also highest for hexapodna. The ratio of TNF-α release to cellular uptake was highest for ssDNA, and lowest for dsDNA. Tripodna and hexapodna were more easily dissociated into single strands after cellular uptake than was dsDNA.Conclusions
The efficient cellular uptake and prompt dissociation into single strands can be directly related to the high immunostimulatory activity of polypod-like structured DNAs containing CpG motifs.15.
Purpose
To evaluate the therapeutic efficacy of dexamethasone (DM) and methotrexate (MTX) entrapped within polysialic acid (PSA)-trimethyl chitosan (TMC) nanoparticles using an in vitro model of rheumatoid arthritis (RA).Methods
The loading capacity of the PSA-TMC nanoparticles was determined. An RA in vitro model was developed by stimulating a synovial cell line with a proinflammatory mediator. Multiplex immunoassay was used to determine changes in the secretion of interleukin-6 (IL-6), interleukin-8 (IL-8), and granulocyte-macrophage colony-stimulating factor (GM-CSF) by the in vitro model following administration of the DM- and MTX-loaded nanoparticles.Results
The loading capacity of the PSA-TMC nanoparticles was approximately 0.1 mg of drug/mg of nanoparticle. When applied to our in vitro model of RA, there were no significant differences in the concentrations of IL-6 and IL-8 when comparing the free drugs and drug-loaded nanoparticles, administered at concentration of 0.1 mg/ml and 1.0 mg/ml, respectively.Conclusions
The present study verified that MTX and DM are able to retain bioactivity when loaded into PSA-TMC nanoparticles. Although in vitro efficacy was not increased, the in vivo efficacy will likely be enhanced by the site-specific targeting conferred by nanoparticle entrapment. 相似文献16.
Purpose
To create poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), where a drug-encapsulating NP core is covered with polyethylene glycol (PEG) in a normal condition but exposes a cell-interactive TAT-modified surface in an environment rich in matrix metalloproteinases (MMPs).Methods
PLGA NPs were modified with TAT peptide (PLGA-pDA-TAT NPs) or dual-modified with TAT peptide and a conjugate of PEG and MMP-substrate peptide (peritumorally activatable NPs, PANPs) via dopamine polymerization. Cellular uptake of fluorescently labeled NPs was observed with or without a pre-treatment of MMP-2 by confocal microscopy and flow cytometry. NPs loaded with paclitaxel (PTX) were tested against SKOV-3 ovarian cancer cells to evaluate the contribution of surface modification to cellular delivery of PTX.Results
While the size and morphology did not significantly change due to the modification, NPs modified with dopamine polymerization were recognized by their dark color. TAT-containing NPs (PLGA-pDA-TAT NPs and PANPs) showed changes in surface charge, indicative of effective conjugation of TAT peptide on the surface. PLGA-pDA-TAT NPs and MMP-2-pre-treated PANPs showed relatively good cellular uptake compared to PLGA NPs, MMP-2-non-treated PANPs, and NPs with non-cleavable PEG. After 3 h treatment with cells, PTX loaded in cell-interactive NPs showed greater toxicity than non-interactive ones as the former could enter cells during the incubation period. However, due to the initial burst drug release, the difference was not as clear as microscopic observation.Conclusions
PEGylated polymeric NPs that could expose cell-interactive surface in response to MMP-2 were successfully created by dual modification of PLGA NPs using dopamine polymerization. 相似文献17.
Rationale
Numerous case reports have suggested that aripiprazole can worsen psychotic symptoms in schizophrenia.Objectives
We reviewed reported cases which have suggested that aripiprazole can worsen psychotic symptoms in schizophrenia and evaluated each regarding quality of the causal relationship.Methods
A systematic literature search was conducted on August 18, 2012, using the PubMed and the EMBASE. Twenty-two cases met the following inclusion criteria: (1) diagnosis of schizophrenia or schizoaffective disorder, (2) worsening of psychotic symptoms associated with aripiprazole, and (3) aripiprazole dose ≤30 mg/day. Information about the causal relationship between aripiprazole and increased psychotic symptoms was extracted. The quality of the causal relationship was evaluated according to the modified guidelines for evaluation of drug-associated events and classified as “questionable,” “moderately suggestive,” or “highly suggestive.”Results
Patients were chronic in at least 15 cases, and prior antipsychotic dose exceeded recommended guidelines in 19 cases. Psychotic symptoms worsened after simply adding aripiprazole to the current regimen in eight cases. Besides psychotic symptoms, increasing agitation (nine cases), aggression (11 cases), and/or activation (seven cases) were reported. Clinical resolution occurred after aripiprazole discontinuation in eight cases. Regarding causal relationship, 11 cases were classified as “highly suggestive,” three as “moderately suggestive,” and eight as “questionable”.Conclusions
Clinicians should be vigilant when adding aripiprazole to patients with chronic schizophrenia also receiving relatively high doses of other antipsychotics, and discontinuation of aripiprazole should be considered if psychotic symptoms and/or agitation/aggression/activation increase. 相似文献18.
Mohammad Ali Amini Mohammad Ali Faramarzi Dariush Mohammadyani Elina Esmaeilzadeh-Gharehdaghi Amir Amani 《Journal of pharmaceutical innovation》2013,8(2):111-120
Purpose
Artificial neural networks (ANNs) are used to optimize a formulation of poly(lactic acid) (PLA) nanoparticles containing hydrophobic drug molecules through a study of the critical parameters affecting nanoparticle size.Methods
We evaluate the effect of input variables, including concentrations of PLA and Tween 80, amplitude of ultrasound wave, and sonication time on the formation of PLA nanoparticles, which were prepared using a solvent evaporation method. Budesonide was used as a model hydrophobic drug. An ANN model was created using training data and evaluated for prediction capability using validation data.Results
The ANN model demonstrated that reducing PLA concentration and increasing Tween 80 concentration provided optimum conditions for the preparation of small particle size. Additionally, the simultaneous use of high sonication time and amplitude has an adverse effect on particle diameter.Conclusion
By defining the effects of each parameter on the size of PLA nanoparticles, this study demonstrated the feasibility of using an ANN model to optimize the conditions for achieving minimum particle size in hydrophobic drug-loaded PLA nanoparticles. 相似文献19.
Michael Morgen David Tung Britton Boras Warren Miller Anne-Marie Malfait Micky Tortorella 《Pharmaceutical research》2013,30(1):257-268
Purpose
To evaluate using cationic polymeric nanoparticles that interact with hyaluronate to form ionically cross-linked hydrogels to increase the intra-articular retention time of osteoarthritis drugs in the synovial cavity.Methods
In vitro tests included nanoparticle release from cross-linked hydrogels using syringe and membrane dissolution tests, viscosity measurement of synovial fluid containing hydrogels, and release-rate measurement for a model active conjugated to a cationically substituted dextran using a hydrolyzable ester linkage in a sink dissolution test. Nanoparticle retention after intra-articular injection into rat knees was measured in vivo using fluorescence molecular tomography.Results
Diffusional and convective transport of cationic nanoparticles from ionically cross-linked hydrogels formed in synovial fluid was slower in vitro than for uncharged nanoparticles. Hydrogels formed after the nanoparticles were mixed with synovial fluid did not appreciably alter the viscosity of the synovial fluid in vitro. In vitro release of a conjugated peptide from the cationic nanoparticles was approximately 20% per week. After intra-articular injection in rat knees, 70% of the nanoparticles were retained in the joint for 1 week.Conclusions
This study demonstrates the feasibility of using cationic polymeric nanoparticles to increase the retention of therapeutic agents in articular joints for indications such as osteoarthritis. 相似文献20.
Xiaoming Luo Guoqing Jia Haixing Song Chaoyu Liu Guannan Wu Xiaohong Li 《Pharmaceutical research》2014,31(1):46-59