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检索条件"任意字段=2014中国药物制剂大会——中国药学会药剂专业委员会年会、第六届亚洲阿登制药技术研讨会暨国际控释协会中国分会年会"

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pH and Redox Dual Responsive Polymeric Micelles for Enhanced Intracellular Drug Release in Cancer Therapy

pH and Redox Dual Responsive Polymeric Micelles for Enhanced...

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2014中国药物制剂大会——中国药学会药剂专业委员会年会、第六届亚洲阿登制药技术研讨会暨国际控释协会中国分会年会

作者： Fengqian Chen Lu Wang Jinming Zhang Yitao Wang Meiwan Chen State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of Macau

To improve the intracellular drug release and anticancer efficacy in cancer therapy,in the present study,a pH and redox dual-sensitive bbdegradable micellar system was devebped for paclitaxel(PTX) delivery based on the self-assembly of D-a-tocopheryl polyethylene glycol 1000-SS-poly(P-amino ester)(TPGS-SS-PBAE)***-SS-PBAE copolymer was first synthesized via Michael addition polymerization of diacrylate and piperazine in the presence of TPGS-SS-diacrylate *** was then baded in the dual-sensitive micelles by solvent evaporation technique with high entrapment efficiency and loading efficiency of89.1±0.3%and 4.5±0.1%,*** average size of these micelles was98.30±0.50 run in PBS(non-GSH,pH 7.4) and would remarkably increase to over1000 nm in simulating tumor microenvironment(10mM GSH,pH 5) during 24 h,making it quite easy for PTX to escape from the core of *** expected,the in vitro release of PTX from micelles in medium to simulating tumor microenvironment was significantly fester than that in either PBS(pH 7.4),acid medium(pH 5.0),or reductive medium(10 mM GSH),demonstrating the synergic effect of pH/redox dualrstimuli ***,the dose-dependent cytotoxicity results by MTT assay revealed that PTX baded TPGS-SS-PBAE micelles had higher anti-cancer activity than pH/redox insensitive controls,with bw IC50 of 3.42 and 2.16 μM on human hepatoma carcinoma HepG2 and SMMC7721 cells,*** addition,blank TPGS-SS-PBAE micelles exhibited non-cytotoxicity up to a concentratbn of 0.1mg/***,the TPGS-SS-PBAE redox and pH dual-responsive micellar system would be an effective intracellular drug delivery carrier for PTX to enhance anticancer efficacy.

关键词： TPGS-SS-PBAE micelles PTX pH and redox dual responsive anticancer

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Enhanced local bioavailability of single or compound drugs delivery to the inner ear through application of PLGA nanoparticles via round window administration

Enhanced local bioavailability of single or compound drugs d...

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2014中国药物制剂大会——中国药学会药剂专业委员会年会、第六届亚洲阿登制药技术研讨会暨国际控释协会中国分会年会

作者： CAI Hui WEN Xingxing LONG Wei CHEN Gang School of Pharmacy Guangdong Pharmaceutical University Department of Clinical pharmacy Guangdong Pharmaceutical University

Objective:Our aim is to examine the potential of poly(D,L-lactide-co-glycolide acid)(PLGA) nanoparticles(NPs) for carrying single or compound drugs traversing the round window membrane(RWM) after round window(RW) administration to guinea ***:Coumarin-6 baded PLGA NPs were prepared by the emulsion/solvent evaporatbn *** NPs loaded with salvianolic acid B(Sal B),tanshinone ⅡA(TS ⅡA) and panax notoginsenoside(PNS)(notoginsenoside R1 and ginsenoside Rg1,Rb1) were prepared by double emulsion/solvent evaporation *** were charactered for entrapment efficiency,morphology,particle size and in vitro *** ofNPs and drug solutbn in guinea pigs were investigated following RW administratioa Results:The mean entrapment efficiency of coumarin-6 NPs was 51.6%.The optimized NPs loaded with compound drugs were displayed the satisfactory entrapment efficiency(91.81%for TS IIA,92.88%for Sal B,37.87%for Rl,44.98%for Rg1,and 93.56%for Rbl,respectively).The copolymers formed spherical shape in a small size(Figs.1-2).The mean diameter of coumarin-6 loaded NPs was about 135 nm with a PDI of0.17(Fig.3).And the average size of the NPs baded with compound drugs had a mean diameter of 154 nm with a PDI of 0.007(Fig.4).Moreover,in vitro drug release behavbr shown that NPs had a good sustained-release characteristics(Fig.5).The pharmacokinetic results showed that NPs applied to the RWM significantly improved drug distributbn within the inner *** AUC0-t of coumarin-6 in the inner ear perilymph(PL) following RW administration of NPs was 4.7-fold higher than that of coumarin-6 solutbn,and the Cmax was 10.9-fold higher(Table 1).Furthermore,the AUC0-t of R1,Rg1 and Rb1 were 4.0-,3.1- and 7.1-fold greater,respectively,after the applicatbn of NPs compared to the compound solutbn,and the Cmax were respectively 14.4-,10.0- and 16.7-fold higher(Table 2).Conclusion:These findings suggested that PLGA NPs with unique properties at nanoscale dimensbns had a powerf

关键词： round window administration nanoparticles inner ear local bioavailability poly(D,L-lactide-co-glycolide acid)

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Construction and anti-tumor mechanism of novel polymeric micelles for targeted intracellular drug delivery based on hyaluronic acid and GSH-response

Construction and anti-tumor mechanism of novel polymeric mic...

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2014中国药物制剂大会——中国药学会药剂专业委员会年会、第六届亚洲阿登制药技术研讨会暨国际控释协会中国分会年会

作者： Shaoping Yin Jue Huai Juan Li Department of Pharmaceutics China Pharmaceutical University

Objective:The aim of our study is to devebp novel polymeric micelles to achieve specific tumor targeting and rapid intracellular drug release at targetMethods:By covalently attaching stearic acid(CI8) to hyaluronic acid(HA) via a linker containing disulfide bond,HA-ss-C18 was *** copolymer HA-C18 was also synthesized for comparison Paclitaxel(PTX) was efficiently baded into *** uptake and intracellular distribution of coumarin-6loaded micelles against B16F10 cells were quantified by flow cytometry and visualized by confocal laser scanning microscopy(CLSM).NIRF imaging was employed to investigate the tumor targeting *** pharmacodynamics of drug loaded micelles were evaluated using subcutaneous tumor bearing ***:The chemical structure of HA-ss-C18 was confirmed by 1H NMR(Fig.1A).Drug loaded HA-ss-C18 micelles presented a redox triggered degradation and drug-release *** fluorescence intensity of HA-ss-C18 micelles was 2.12 folds of that of HA-C18 micelles,indicating that HA-ss-C18 micelles could be well uptaken by *** bright green fluorescence in cytoplasm indicated successful cellular uptake and great release of drugs(Fig.1B).HA receptor competitive inhibition test confirmed that HA-SS-C18 internalized into tumor cells via receptor-mediated *** assay revealed that PTX toaded HA-ss-C18 micelles showed much higher cytotoxic potency than PTX solution and PTX loaded HA-C18(p<0.05).In real-time images,the fluorescence signals in tumors of HA-ss-C18 groups were significant stronger than that of HA-C18 ***,drug toaded HA-ss-C18 showed the strongest tumor inhibition ability(p<0.05) with a tumor inhibition rate(TIR) of 70.97±7.82%.Conclusion:We provided a promising redox-responsive polymeric micelles system for targeted intracellular drug delivery and it will have a tremendous potential in cancer therapy.

关键词： polymeric micelle redox-responsive active tumor targeting HA receptor pharmacodynamics biodistribution

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Eradicating of cancer-associated fibroblasts by liposomal navitoclax to enhance the permeation and anti-tumor effect of liposomal doxorubicin

Eradicating of cancer-associated fibroblasts by liposomal na...

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2014中国药物制剂大会——中国药学会药剂专业委员会年会、第六届亚洲阿登制药技术研讨会暨国际控释协会中国分会年会

作者： Binlong Chen Wenbing Dai Dan Wang Jing Sun Lan Yuan Bing He Hua Zhang Xueqing Wang Qiang Zhang State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking University

The role of the tumor microenvironment is now realized to be of critical importance during the tumor initiation,angiogenesis,progression and ***-associated fibroblasts(CAFs) are abundant in the stroma of solid tumor,which are the main source of collagea Both CAFs and collagen can raise the interstitial fluid pressure(IFP) in tumor,which presents a transport barrier that restricts nanoparticle penetration into the deep of tumor,thereby limiting the efficacy of nano-drug delivery vehicles for cancer ***(ABT-263) is a novel BH3 mimetic,which can induce apoptosis in CAFs but lacks similar effects in normal fibroblasts and most solid cancer *** this study,navitoclax was loaded in sterically stabilized liposomes(SSL-Nav) modified with a peptide FH(FH-SSL-Nav) to kill the fibroblasts in tumor as well as reducing the tumor IFP,making an attempt to deliver more liposomal doxorubicin(SSL-DOX) into tumor *** different multicellular spheroids:mono-Hep G2(S-mono) and co-culture Hep G2 with LX-2(S-co) were used to evaluate the penetration of liposomal coumarin-6(SSL-Cou-6) and the penetration enhancement effect of Nav in *** was verified that the penetration in S-co was much poorer than *** the S-co was treated with Nav,the penetration of SSL-Cou-6 was improved ***,in Hep G2 hepatocellular carcinoma bearing nu/nu mice,intravenous injection of 5mg/kg FH-SSL-Nav,SSL-Nav and oral administration of 5mg/kg free Nav,all could decrease the CAFs in tumor,as well as reducing the tumor ***-SSL-Nav was the most effective one,and was the earliest to play *** vivo imaging also demonstrated that the treatment of FH-SSL-Nav led to a more and longer intratumoral distribution of *** the anti-tumor study,it was proved again that the combination of SSL-Nav and SSL-DOX inhibited tumor growth the most obviously,while either SSL-DOX or SSL-Nav showed poor anti-tumor *** in vitro cell experiment showed that th

关键词： Eradicating of cancer-associated fibroblasts by liposomal navitoclax to enhance the permeation and anti-tumor effect of liposomal doxorubicin

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Charge-conversional PLGA nanoparticle to active deliver chemotherapy drug to tumor

Charge-conversional PLGA nanoparticle to active deliver chem...

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2014中国药物制剂大会——中国药学会药剂专业委员会年会、第六届亚洲阿登制药技术研讨会暨国际控释协会中国分会年会

作者： Jiang-bo Du Dao-zhou Liu Bang-le Zhang Si-yuan Zhou Department of Pharmaceutics School of PharmacyFourth Military Medical University

Poly(lactic-co-glycolic acid)(PLGA) nanoparticles are widely used in tumor targeted drug delivery system owing to its non immunogenicity and biodegradable ***,the naked PLGA nanoparticles not only have low drug loading but also can be rapidly removed from blood circulation by the immune ***,the aim of this study was to focus on the preparation of both active and passive tumor targeting lipid hybrid PLGA nanoparticles(LNPs) to enhance drug loading and drug delivery ***-ARG-HIS-OMe and DSPE-PEG-FA were synthesized and were used to prepare DOX-baded LNPs by emulsion-solvent evaporation *** particle size,drug loading and encapsulation rate of naked PLGA nanoparticles was 162 nm(detected by DLS),2.55%and 22.0%,*** particle size,drug bading and encapsulation rate of LNPs was 191 nm(detected by DLS),10.20%and 86.4%,*** LNPs showed core-shell *** X-ray photoelectric spectrometer analysis indicated that FA and ARG-FflS-OMe were localized on the surface of ***7.4 medium,DOX-baded LNPs showed negatively charged and released DOX *** pH5.0medium,DOX-baded LNPs showed positively charged and released DOX ***-baded LNPs had not effect on the bbod red cell membrane in pH7.4 medium,and it severely destroyed the bbod red cell membrane in pH5.0 *** with free DOX,DOX-baded LNPs delivered more DOX to the nucleus of KB cells and MBA-MD-231/ADR ***-baded LNPs induced more apoptosis on KB cells,A549 cells,MBA-MD-231 cells and MBA-MD-231/ADR cells as compared with free *** with the naked PLGA nanoparticles and free DOX,DOX-baded LNPs significantly inhibited the proliferation of A549 cells,KB cells,MBA-MD-231 cells and MBA-MD-231/ADR ***-baded LNPs showed great cytotoxicity on folate receptor overexpressed tumor *** with 5 mg/kg free DOX,the same dose of the DOX-baded LNPs significantly inhibited the growth of tumor in tumor bearing nude mice(i

关键词： PLGA doxorubicin lipid hybrid nanoparticles folate pH-sensitive

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Synthesis,preparation and potential drug carrier of multifunctional targeted nano-carrier drug delivery system based on CD44 receptor and tumor microenvironment pH condition

Synthesis,preparation and potential drug carrier of multifun...

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2014中国药物制剂大会——中国药学会药剂专业委员会年会、第六届亚洲阿登制药技术研讨会暨国际控释协会中国分会年会

作者： Daquan Chen Kaoxiang Sun Youxin Li Wanhui Liu Fenghua Fu School of Pharmacy Yantai University State Key Laboratory of Long-acting and Targeting Drug Delivery System

Many studies about HA and its derivatives were reported,which can be devided into two *** type was HA-drug conjugates,also called prodrugs,the other type was the micro/nanop articles loading the different *** has been reported that both of the two types of HA can obtain some enhanced tumor targeting and therapeutic ***,some new idea was presented that the native high molecular weight hyaluronan(nHA) and oligosaccharides of hyaluronan(oHA) provoke distinct biological effects upon binding to *** has been reported that nHA binding to CD44 selectively induces CD44 clustering,which could be inhibited by oHA,which is very important and interesting for the future use of HA in drug *** irritated by highly generated HA,CD44 clustering is a unique character which can influence cell *** to the "Coating Saccharide"(CD44 clustering) of tumor surface and the slightly acidic condition of tumor,it is difficult to target the chemotherapeutic drugs to the tumor site and achieve satisfying effect for targeting *** solve this problem,we design a multifunctional oHA-histidine-ketal menthone 1,2-glycerol ketal(oHM)nano-drug delivery system with CD44 receptor as *** shown in the following figure,once oHM nanoparticles meet the CD44 receptor,the coating of CD44 clustering will not *** to the protonation of histidine imidazole group,it is useful for the cellular *** endocytosis,oHM nanoparticles will release the encapsuled drugs under the slightly acidic condition of tumor rapidly with the degration of micellar hydrophobic ketal *** encapsuled drugs will escape from lysosome to cytoplasm with good stability,produce efficacy and reduce side *** synthesis,characterization,and anti-tumor efficacy of oHM nanoparticles(oHMN)were under investigation.

关键词： pH-sensitive oligosaccharides of hyaluronan(oHA) nanoparticles drug delivery

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Incorporation of lapatinib into human serum albumin nanoparticles with enhanced water solubility and anti-tumor effect in breast cancer

Incorporation of lapatinib into human serum albumin nanopart...

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2014中国药物制剂大会——中国药学会药剂专业委员会年会、第六届亚洲阿登制药技术研讨会暨国际控释协会中国分会年会

作者： Xu Wan Xiaoyao Zheng Xiaoying Pang Qizhi Zhang Department of Pharmaceutics School of PharmacyFudan University Key Laboratory of Smart Drug Delivery(Fudan University) Ministry of Education

Purpose:Lapatinib,a dual tyrosine inhibitor of EGFR and HER2,could effectively inhibit the proliferation of HER2 positive breast cancer ***,its poor water solubility restricted its clinical *** made of human serum albumin(HSA) represent promising strategy for improving water solubility of drugs and targeted drug delivery to tumor cells without any serious side ***,lapatinib-loaded HSA nanoparticles(LTNPs) were prepared and the in vitro and in vivo characteristics of the nanoparticle system were evaluated in this ***:LTNPs were prepared by Nab *** nanoparticles' morphology,structure,particle size and the drug encapsulation efficiency were ***,Coumarin-6 was used as a fluorescent probe to evaluate the cellar uptake of *** in vitro cytotoxicity of LTNPs on SKBr3 cells(HER2 overexpressing) and 4T1cells(EGFR overexpressing) were determined by MTT *** penetration and growth inhibitive effects of LTNPs were further evaluated using three-dimensional 4T1 carcinoma *** in vivo distribution of LTNPs in 4T1 tumor-bearing ICR mice was examined using LC/MS/***:HSA nanoparticles markedly elevated the water solubility of lapatinib from 7ng/ml to over 30 mg/*** were mostly spherical with a core-shell structure(Fig.l),and lapatinib was molecularly incorporated in HSA nanoparticles(Fig.2).Its mean diameters were 137.2±20.4 nmand the encapsulation efficiency was 84.9±2.45%.The uptake behavior of LTNPs by 4T1 cells presented a concentration and time-dependent manner(Fig.3).Incorporation of lapatinib in LTNPs did not decrease the cytotoxicity on both breast cancer cells compared with lapatinib solution(LTS,Fig.4).The half maximal inhibitory concentrations(IC50) of LTS and LTNP on SKBr3 cells and 4T1 cells were 9.058 ng/ml and 5.316 ng/ml,6.695 ng/ml and 5.048 ng/ml,*** favored lapatinib penetrating into the carcinoma spheroids and consequently induced more severe inh

关键词： Lapatinib HSA nanoparticles breast cancer

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In Vitro Study of Carbamate-Linked Cationic Lipid-mediated Gene Transfection

In Vitro Study of Carbamate-Linked Cationic Lipid-mediated G...

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2014中国药物制剂大会——中国药学会药剂专业委员会年会、第六届亚洲阿登制药技术研讨会暨国际控释协会中国分会年会

作者： Defu Zhi Shubiao Zhang Yinan Zhao Shaohui Cui Huiying Chen Defeng Zhao State Ethnic Affairs Commission-Ministry of Education Key Laboratory of Biotechnology and Bio-resources Utilization Dalian Nationalities University Zhejiang Jihua Group Co. Ltd.

Gene therapy is a very promising method for the treatment of cancer and genetic diseases by compensating for defective genes or producing beneficial *** vectors that can deliver nucleic acids into cells have much important roles in gene therapy,and broadly fell into viral and non-viral *** vectors are presently the most common method of gene delivery,but non-viral vectors have been increasingly proposed as safer alternatives to viral vectors because of their potential advantages such as ease of synthesis,low immune response against the vector,limited packaging capacity and *** the various non-viral vectors,cationic lipids have attracted increasing attention because they have several advantages including simplicity of method,clinical grade manufacturing,lack of ability to elicit immune response,good repeatability and biodegradability,and efficiency in forming stable injectable complexes even with large *** lipids are comprised of three basic structural domains:a hydrophobic region,a hydrophilic headgroup,and a linker between the two *** structure of cationic lipids is an important property regarding its applicatioa Publications based on cationic lipids have grown tremendously in the last decade with reports on establishment of a structure-function relationship to define the requirements for safe and efficient gene transfer with cationic ***,we described the gene transfection properties of carbamate-linked cationic lipids(N-[l-(2,3-didodecylcarbamoyloxy)propyl]-N,N,N- trimethylammonium iodide(DDCTMA)and N-[l-(2,3-didodecyl carbamoybxy)propyl]-N-ethyl- N,N-dimethylammonium iodide(DDCEDMA)) whose headgroups are different quaternary ammonium headgroups,which have high transfection efficiency in Hela and Hep-2 cells as well as bw *** advance the study of this lipid for gene delivery we investigated the transfection efficiency of the DDCTMA/DOPE/DNA complex in sw480 cells compared with two commercial tra

关键词： Cationic lipids DNA condensation Gene delivery Transefetion efficiency

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Multi-targeting delivery of doxorubicin in tumor cells by saturated fatty acid based pH-sensitive micelle

Multi-targeting delivery of doxorubicin in tumor cells by sa...

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2014中国药物制剂大会——中国药学会药剂专业委员会年会、第六届亚洲阿登制药技术研讨会暨国际控释协会中国分会年会

作者： Han Cui Meng-lei Huan Bang-le Zhang Si-yuan Zhou Department of Pharmaceutics School of PharmacyFourth Military Medical University

Doxorubicin(DOX) is a commonly-used chemotherapy drug for tumor ***,the severe side effect,tow selectivity and multiple drug resistance(MDR) hinder its clinical ***,DOX shows a high affinity to DNA and ***,DNA intercalation is not the only mechanism of the antitumor activity of *** multiple interactions can occur between mitochondria and DOX,which induce the mitochondrial ***,mitochondria specific DOX delivery system can change DOX sub-cellular distribution route and reverse *** was reported that(3-carboxypropyl)triphenyl- phosphonium(TPP) exhibited mitochondrial targeting characteristic due to its high lipophilicity and stable cationic *** theory,DOX can be delivered to mitochondria by conjugating TPP with *** fatty acids are safe and abound of hydrophobic material in *** order to attenuate non selective toxicity and overcome the MDR,a series of saturated fatty acid based pH-sensitive amphiphilic polymer and mitochondria-specific conjugate TPP-DOX was synthesized,and a new pH-sensitive micelle was prepared to deliver DOX to nucleus and mitochondria *** loaded micelle were prepared by emulsion-solvent evaporation *** released from FA-PEG-hyd-PA micelle showed a pH-dependent *** TPP-DOX showed tower cytotoxicity than free DOX on KB cells,A549 cells,Hela cells,HUVEC cells and HEK293 cells,but it showed higher cytotoxicity than free DOX on DOX-resistant MDA-MB-231/ADR ***-DOX/DOX loaded FA-PEG-hyd-PA micelle induced the more apoptosis in KB cells,A549 cells,and MDA-MB-231/ADR cells than DOX loaded FA-PEG-hyd-PA ***-DOX/DOX loaded FA-PEG-hyd-PA micelle showed the higher cytotoxicity against A549 cells,KB cells,Hela cells and MDA-MB-231/ADR cells than DOX loaded FA-PEG-hyd-PA *** microscopy confirmed that TPP-DOX/DOX loaded FA-PEG-hyd-PA micelle respectively delivered TPP-DOX and DOX to the mitochondria and nucleus simultaneo

关键词： doxorubicin multiple drug resistance (3-carboxypropyl)triphenylphosphonium mitochondria pH-sensitive micelle

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A Novel Core-Shell Structural Phospholipid-Functionalized Mesoporous Silica Nanoparticles Modified with Angiopep-2 as Targeting Drug Delivery System for Brain Glioma

A Novel Core-Shell Structural Phospholipid-Functionalized Me...

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2014中国药物制剂大会——中国药学会药剂专业委员会年会、第六届亚洲阿登制药技术研讨会暨国际控释协会中国分会年会

作者： Wang Guowei Guo Manman Xu Junjun Zhang Rongrong Li Fanzhu Zhejiang Chinese Medical University College of Pharmaceutical Science

In order to improve the drug loading coefficient and realize the tagerted delivey of paclitaxel(PTX) to brain glioma,a novel core-shell structural phospholipid-functionalized Mesoporous Silica Nanoparticles(MSN) modified with Angk>pep-2(Ang-MSN-LP) were successfully developed using selfassembly and film hydration *** synthesized by modified-Stober method have ultrahigh surface area with remarkablely high loding ***-2 can specially combine to the bw density lipoprotein receptor-related protein(LRP) receptor overexpressed on the blood-brain barrier(BBB) and brain glioma cells,which can help to overcome the limitations of bw transport of chemotherapeutics across the BBB and poor penetration into tumor *** introducing the innovative preparation process of saturated solution adsorption method,PTX was highly encapsulated(drug loading coefficient up to 11.17%) into MSN by forming crystal anatague complex inside the *** vitro release of PTX solution,MSN-PTX,MSN-LP-PTX and Ang-MSN-LP-PTX in pH 7.4 PBS containing 20%ethanol showed that about 81.5%of PTX released from Ang-MSN-LP-PTX after 50 h and burst release was effectively reduced compared with MSN-PTX,indicating pronounced sustained-release *** bblogical safety of Ang-MSN-LP was evaluated by HBMEC and C6 cell cytotoxicity,which proved Ang-MSN-LP was good bbcompatibility and low *** cooperative targeting to brain glioma by Ang-MSN-LP was evaluated by transwell assay of HBMEC mimicking BBB models,what's more,the anti-ghoma effect of Ang-MSN-LP-PTX was assessed by C6 cell cytotoxicity and median survival time of glioma bearing rats,which showed a better anti-glioma effect than other groups that demonstrated the combinatbn of MSN-LP and angbpep-2 constituted an ideal targetingdrug delivery ***,in vivo pharmacokinetics in rats after tail vein injectbn by using blood and intracerebral microdialysis simultaneously proved that the AUCO-t in brain of Ang-MSN-L

关键词： Mesoporous silica nanoparticles Angiopep-2 Saturated solution adsorption method Blood-brain barrier Brain glioma Blood and intracerebral microdialysis simultaneously

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