CN101382490A - Method for screening high content medicament of cellular level - Google Patents
Method for screening high content medicament of cellular level Download PDFInfo
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- CN101382490A CN101382490A CNA200710012696XA CN200710012696A CN101382490A CN 101382490 A CN101382490 A CN 101382490A CN A200710012696X A CNA200710012696X A CN A200710012696XA CN 200710012696 A CN200710012696 A CN 200710012696A CN 101382490 A CN101382490 A CN 101382490A
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Abstract
The invention discloses a method used for screening high-content drugs at cellular level, which utilizes a special integrated micro-fluidic chip to carry out screening of high-content drugs at cellular level. The invention creatively integrates the sample pretreatment processes of the generation and distribution of drug concentration gradient, and culture, stimulation, washing and marking of chip cell and the like on a large scale on the chip. Compared with the traditional perforated plate technology, the tedious operations of preparing and distributing different drug solution with different concentration are saved, the operation processes of inoculation, simulation, washing and marking of the cells are greatly simplified, the consumption of the cells and a reagent is obviously reduced, and a plurality of drugs can be obtained by running at one time, each drug has a plurality of concentration conditions, and the screening results of a plurality of cell parameters of each concentration condition can be obtained.
Description
Technical field
The present invention relates to the high intension drug screening technology of cellular level, a kind of method of using special-purpose integrated micro-flow control chip to be used for the high intension drug screening of cellular level is provided especially.
Background technology
Drug screening is the committed step of new drug development, and screening model is divided into two kinds of molecular level and cellular levels usually.And the cellular level screening more approaches physiological condition because of it, the accuracy rate height, and disturbing factor is few, has become the main flow means of drug screening.The cellular level screening has multiple mode, and (high content screening HCS) is the core technology of cellular level drug screening in wherein high intension screening.By the influence of physiology courses such as monitoring drug candidate cell growth, propagation, differentiation, apoptosis, metabolism and cell signalling, make every effort in single experiment, obtain to be sieved the multi-C stereo biological effect information that the sample pair cell produces.This screening technique make the researchist toxic action, metabolism that new drug research just can obtain the reactive compound pair cell in early days regulate and cell in the multiple-effect information of different target spot effects, significantly improved the speed of finding reactive compound, and the success ratio of medicine later development, efficient is low, the cycle is long, slow-footed drawback to have overcome conventional medicament screening technique (be screening compound--preliminary drug effect and toxicological evaluation--preclinical study--clinical research).
Although the important value of high intension screening has obtained widespread consensus,, only there are minority scientific research institution and pharmaceuticals to set foot in the research in this field so far in the world because the high technology content of this screening technique itself and enforcement is highly difficult.At present, the major technique approach that HCS adopts is the array microwell plate, carries out cellular incubation on microwell plate, applies medicine irritation, and is aided with automation equipment and high resolving power fluorescence digital image system experimentize operation and data acquisition, analysis.Cellular level drug screening based on this form remains in certain technical matters, operates requiring automatic operating equipment accuracy high as solution evaporation, the micro-example of small volume; Specifically, the pre-treatment of cell sample (as cellular incubation, cell be excited, cell marking, washing etc.) be still off-line and carry out, cause analytic process lengthy and tedious, flux is low; In addition, the bulkiness of instrument and equipment and expensive price make it to be difficult to be generalizable.Therefore, the microminiaturization of HCS technology, robotization and with low costization are the inexorable trends of future development.
By contrast, the micro-fluidic chip laboratory is that the ideal that realizes HCS microminiaturization and robotization is selected.The micro-fluidic chip laboratory claims chip lab (Lab-on-a-Chip) or micro-fluidic chip (Microfluidic) again, refer to specimen preparation, reaction related in chemistry and the field such as biology, separate, basic operation units such as detection, cellular incubation, sorting, cracking are integrated or be integrated into substantially on the chip of more than square centimeters (even littler), form network by the microchannel, run through total system with controlled fluid, in order to a kind of technology of the various functions that replace conventional chemical or biology laboratory.Breadboard essential characteristic of micro-fluidic chip and sharpest edges are that multiple monotechnics flexible combination, scale on the controlled small platform of integral body are integrated.Develop so far, the micro-fluidic chip technology has begun to be applied in the different field of life science, and has become one of important technological platform in the systems biology research.Particularly in recent years, because the multidimensional network feature and the integrated feature of function of micro-fluidic chip, might make that conventional cellular incubation, cell are excited, process integration such as cell marking and detection finish on a very little chip.The scale of various monotechnicss is integrated to make dozens or even hundreds of group to test parallel carrying out, to obtain large number of biological information.The theory of the high intension drug screening of micro-fluidic chip and cellular level is identical, and is expected to become the main flow platform that is used for HCS in quite long one period from now on.
Summary of the invention
The purpose of this invention is to provide a kind of method that is used for the high intension drug screening of cellular level, it is characterized in that: use special-purpose integrated micro-flow control chip to carry out the high intension drug screening of cellular level.
The invention provides a kind of method that is used for the high intension drug screening of cellular level, promptly use special-purpose integrated micro-flow control chip to carry out the high intension drug screening of cellular level;
Described integrated micro-flow control chip is made of 2～99 identical structural units, is connected by a public sample cell between these structural units; Each structural unit contains a concentration gradient maker and an array media to cell culture modules; The top of concentration gradient maker is medicine inlet and nutrient culture media inlet;
Procedure is:
Cell suspension is added the public sample cell that is arranged in chip central authorities, chip places microscopically to observe, when cell flows into cell culture chamber under static pressure drives after, adjust the volume of cell suspension in the sample cell, make it contour with the liquid level of solution of concentration gradient maker inlet, cell is no longer mobile in the chip, parks in cell culture chamber;
The micro-fluidic chip of having inoculated cell is put into cell culture incubator cultivate, then chip is placed the adherent situation of microscopically observation of cell;
Behind the cell attachment, medicine inlet and nutrient culture media inlet to the concentration gradient maker add isopyknic screened medicine and cell culture medium respectively, after treating that the drug concentrations gradient generates, public sample cell connects syringe pump makes liquid in the chip to flow to the array media to cell culture modules from the concentration gradient maker, and chip places cell culture incubator;
After 12～72 hours, disconnect being connected of public sample cell and syringe pump, add wash solution then in public sample cell, under static pressure drove, cleansing solution flowed into the cell culture chamber pair cell and washs;
Add label solution in public sample cell, under static pressure drove, label solution flowed into the cell culture chamber pair cell and carries out mark;
At last, micro-fluidic chip is placed under the fluorescent microscope, carry out the detection of cell the medicine response parameter.
The drug solution that described concentration gradient maker provided by the invention generates acts on the cell in the cell culture chamber in the media to cell culture modules of downstream.
The invention provides a kind of integrated micro-flow control chip, described integrated micro-flow control chip is made of 2～99 identical structural units, is connected by a public sample cell between these structural units; Each structural unit contains a concentration gradient maker and an array media to cell culture modules; The top of concentration gradient maker is medicine inlet and nutrient culture media inlet.
The concentration gradient maker that the invention provides described integrated micro-flow control chip be one tree-shaped, successively increase the structure of branch from top to bottom, the passage of each branch is circuitous broken line shape, and its each outlet is connected with a row cell culture chamber by a long microchannel.
The array media to cell culture modules that the invention provides described integrated micro-flow control chip is connected as row mutually by 2～99 cell culture chambers, 2～99 row forming array formula media to cell culture modules parallel with one another, the outlet of per two row interconnects step by step, finally connect into an exit passageway, the end of this exit passageway is a cell suspension, the inlet of cleansing solution and marking fluid.
The number of each row cell culture chamber of array media to cell culture modules provided by the invention is identical, and per two row cell culture chambers are connected by the microchannel, and per again two of these microchannels are connected to each other, and finally connect into a passage.
The micro-fluidic chip that the present invention uses has eight structural units, therefore can generate eight kinds of drug concentrations gradients simultaneously and act on cell in the cell culture chamber.
The present invention has following advantage:
1. the present invention's solution that only needs two inlets to each concentration gradient maker add respectively to contain the medicine maximum concentration and cellular incubation based sols just can generate this drug concentrations gradient automatically and be automatically assigned in the joining with it cell culture chamber in the exit of concentration gradient maker.
2. the present invention only needs to add respectively cell suspension, wash solution and label solution just can be finished cell in the array media to cell culture modules inoculation, washing and marking operation in public liquid storage tank.
3. creativeness of the present invention is that integrated multiple drug concentrations gradient generates simultaneously, distributes on chip, with the chip cellular incubation, be excited, washing, mark, and be model with clinical common cancer therapy drug inducing apoptosis of tumour cell, drug-induced Apoptosis ability is screened.
4. compare with traditional porous plate technology, the lengthy and tedious operation that the present invention has saved preparation and distributed the variable concentrations solution of multiple medicine has been simplified cell inoculation greatly, has been excited, washing and marking operation process, has reduced the consumption of cell and reagent significantly.
5. the present invention creatively combines the micro-fluidic chip technology with high intension drug screening method, utilizes various functional unit flexible combination on the chip, the integrated feature of scale, produces a large amount of screening conditions simultaneously; Utilize the high intension screening technique feature that the many cells response is analyzed simultaneously in once testing, each screening conditions that chip produces are all carried out the detection and the analysis of a plurality of cellular response parameters, thereby realized micro-fluidic chip cellular level high flux, high intension drug screening first.
Description of drawings
Fig. 1 is the integrated micro-flow control chip platform: (a) be (b) to be the enlarged drawing of one of them structural unit by chip one-piece construction synoptic diagram;
Fig. 2 is that daunomycin (DNR), cis-platinum (DDP), N-acetylcystein (NAC) medicine are induced the apoptotic fluorescent microscope photo of HepG2 at variable concentrations;
Fig. 3 is the The selection result figure of eight kinds of drug-induced HepG2 Apoptosis abilities.
Fig. 4 is actinomycin D (Act D), daunomycin (DNR), N-acetylcystein (NAC) the medicine fluorescent microscope photo that redox state changes in variable concentrations is induced the HepG2 cell;
Fig. 5 is the The selection result figure of redox state changing capability in eight kinds of drug-induced HepG2 cells.
Embodiment
Embodiment 1
(human hepatocellular carcinoma HepG2) is placed on 37 ℃, 5%CO with chip inoculation hepatoma carcinoma cell shown in Figure 1
26h in the incubator, after treating cell attachment, the actinomycin D (Act D) that adds DMEM nutrient culture media (high sugar) and dispose with this nutrient culture media, daunomycin (DNR), epirubicin (IDA), mitomycin (MMC), cis-platinum (DDP), carboplatin (CBP), bleomycin (BLM), eight kinds of medicines of N-acetylcystein (NAC) (concentration is 5 μ M), after treating that the drug concentration gradient generates, syringe pump is connected on the public sample cell, make that liquid flows to media to cell culture modules from the concentration gradient maker in the chip, chip places cell culture incubator 24h, add phosphate buffered saline(PBS) (phosphate buffer saline, PBS) washed cell adds fluorescent dye rhodamine123 (2 μ gmL then
-1) and Hoechst33342 (4 μ gmL
-1) labeled cell 40min, 37 ℃, add the PBS washed cell again, use fluorescent dye propidium iodide (2 μ gmL at last
-1) labeled cell and chip placed under the fluorescent microscope immediately observes.(0 μ M) compares with control group, and along with activity increases, daunomycin (DNR) just causes that at low concentration (1.43 μ M) the cell mitochondrial membrane potential obviously descends, and causes nucleus shrinkage, permeability of cell membrane to increase in high concentration (3.57 μ M); Cis-platinum (DDP) just causes the cell mitochondrial membrane potential to descend in high concentration (3.57 μ M); And contrast medicine N-acetylcystein (NAC) does not have pair cell to produce the obvious (see figure 2) that influences.The fluorescence intensity of above-mentioned three parameters is carried out quantitative Analysis to be shown, increase with drug effect concentration, wherein preceding four kinds of medicines: actinomycin D (Act D), daunomycin (DNR), epirubicin (IDA) and mitomycin (MMC) cause the reduction of cell generation mitochondrial membrane electromotive force, nucleus shrinkage and permeability of cell membrane to increase; And other three kinds of medicines: the reduction of mitochondrial membrane electromotive force has taken place in cis-platinum (DDP), carboplatin (CBP) and bleomycin (BLM) only inducing cell; N-acetylcystein (NAC) does not cause cell generation significant change (see figure 3) as negative control.
(human hepatocellular carcinoma HepG2) is placed on 37 ℃, 5%CO with chip inoculation hepatoma carcinoma cell shown in Figure 1
26h in the incubator, after treating cell attachment, the actinomycin D (Act D) that adds DMEM nutrient culture media (high sugar) and dispose with this nutrient culture media, daunomycin (DNR), epirubicin (IDA), mitomycin (MMC), cis-platinum (DDP), carboplatin (CBP), bleomycin (BLM), eight kinds of medicines of N-acetylcystein (NAC) (concentration is 5 μ M), after treating that the drug concentration gradient generates, syringe pump is connected on the public sample cell, make that liquid flows to media to cell culture modules from the concentration gradient maker in the chip, chip places cell culture incubator 24h, add phosphate buffered saline(PBS) (phosphate buffer saline, PBS) washed cell, add fluorescent dye 2 then, 3-naphthalenedicarboxaldehyde (10 μ M) and dihydroethidium (25 μ M) labeled cell 30min, 37 ℃, chip is placed observation under the fluorescent microscope.(0 μ M) compares with control group, along with activity increases, actinomycin D (Act D) just causes that at low concentration (1.43 μ M) intracellular reactive oxygen class obviously increases and reduced glutathione obviously descends, and causes intracellular reactive oxygen class to reduce in high concentration (3.57 μ M); Daunomycin (DNR) just causes intracellular reactive oxygen class to increase and reduced glutathione decline in high concentration (3.57 μ M); And contrast medicine N-acetylcystein (NAC) does not have pair cell to produce the obvious (see figure 4) that influences.The fluorescence intensity of above-mentioned two parameters is carried out quantitative Analysis to be shown, increase with drug effect concentration, wherein preceding four kinds of medicines: actinomycin D (ActD), daunomycin (DNR), epirubicin (IDA) and mitomycin (MMC) cause taking place in the cell redox state and change; And other three kinds of medicines: cis-platinum (DDP), carboplatin (CBP), bleomycin (BLM) and negative control N-acetylcystein (NAC) do not cause cell generation significant change (see figure 5).
Claims (5)
1, a kind of method that is used for the high intension drug screening of cellular level is characterized in that: use special-purpose integrated micro-flow control chip to carry out the high intension drug screening of cellular level;
Described integrated micro-flow control chip is made of 2～99 identical structural units, is connected by a public sample cell between these structural units; Each structural unit contains a concentration gradient maker and an array media to cell culture modules; The top of concentration gradient maker is medicine inlet and nutrient culture media inlet;
Procedure is:
Cell suspension is added the public sample cell that is arranged in chip central authorities, chip places microscopically to observe, when cell flows into cell culture chamber under static pressure drives after, adjust the volume of cell suspension in the sample cell, make it contour with the liquid level of solution of concentration gradient maker inlet, cell is no longer mobile in the chip, parks in cell culture chamber;
The micro-fluidic chip of having inoculated cell is put into cell culture incubator cultivate, then chip is placed the adherent situation of microscopically observation of cell;
Behind the cell attachment, medicine inlet and nutrient culture media inlet to the concentration gradient maker add isopyknic screened medicine and cell culture medium respectively, after the drug concentrations gradient generates, public sample cell connects syringe pump makes the liquid in the chip flow to the array media to cell culture modules from the concentration gradient maker, and chip places cell culture incubator;
After 12～72 hours, disconnect being connected of public sample cell and syringe pump, add wash solution then in public sample cell, under static pressure drove, cleansing solution flowed into the cell culture chamber pair cell and washs;
Add label solution in public sample cell, under static pressure drove, label solution flowed into the cell culture chamber pair cell and carries out mark;
At last, micro-fluidic chip is placed under the fluorescent microscope, carry out the detection of cell the medicine response parameter.
2, according to the described method that is used for the high intension drug screening of cellular level of claim 1, it is characterized in that: the drug solution that described concentration gradient maker generates acts on the cell in the cell culture chamber in the media to cell culture modules of downstream.
3, the described integrated micro-flow control chip of a kind of claim 1 is characterized in that: described integrated micro-flow control chip is made of 2～99 identical structural units, is connected by a public sample cell between these structural units; Each structural unit contains a concentration gradient maker and an array media to cell culture modules; The top of concentration gradient maker is medicine inlet and nutrient culture media inlet.
4, according to the described integrated micro-flow control chip of claim 3, it is characterized in that: described concentration gradient maker be one tree-shaped, successively increase the structure of branch from top to bottom, the passage of each branch is circuitous broken line shape, and its each outlet is connected with a row cell culture chamber by a long microchannel.
5, according to the described integrated micro-flow control chip of claim 3, it is characterized in that: described array media to cell culture modules is connected as row mutually by 2～99 cell culture chambers, 2～99 row forming array formula media to cell culture modules parallel with one another, the outlet of per two row interconnects step by step, finally connect into an exit passageway, the end of this exit passageway is a cell suspension, the inlet of cleansing solution and marking fluid.
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| CN103257213A (en) * | 2012-02-20 | 2013-08-21 | 中国科学院大连化学物理研究所 | Totally-integrated high-flux cell level micro-fluidic chip medicine evaluating system |
| CN103981085A (en) * | 2014-05-27 | 2014-08-13 | 东南大学 | Self-set concentration gradient drug screening organ chip and preparation method thereof |
| CN104011541A (en) * | 2011-09-13 | 2014-08-27 | 国立大学法人大阪大学 | Method for testing antibacterial-drug sensitivity of bacterium or fungus and system used for same |
| CN104774756A (en) * | 2015-04-23 | 2015-07-15 | 东南大学 | Chip and method for microfluidic drug screening on basis of SERS (surface-enhanced Raman scattering) detection technology |
| CN105713834A (en) * | 2014-12-04 | 2016-06-29 | 中国科学院大连化学物理研究所 | Micro-fluidic chip as well as preparation method and applications thereof |
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| CN115400805A (en) * | 2022-08-26 | 2022-11-29 | 浙江大学 | Mixing chamber-reaction chamber integrated micro-fluidic chip capable of controlling multiple concentration gradients |
| CN116312809A (en) * | 2023-04-10 | 2023-06-23 | 杭州美赛生物医药科技有限公司 | Cell screening method based on antibody coupled magnetic beads |
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| CN104011541A (en) * | 2011-09-13 | 2014-08-27 | 国立大学法人大阪大学 | Method for testing antibacterial-drug sensitivity of bacterium or fungus and system used for same |
| US9399788B2 (en) | 2011-09-13 | 2016-07-26 | Osaka University | Method for inspecting susceptibility of bacteria or fungi to antimicrobial drug and system for use in the same |
| CN104011541B (en) * | 2011-09-13 | 2016-08-24 | 国立大学法人大阪大学 | The inspection method of the Susceptibility to antibiotics of antibacterial or fungus and the system wherein used |
| CN103257213A (en) * | 2012-02-20 | 2013-08-21 | 中国科学院大连化学物理研究所 | Totally-integrated high-flux cell level micro-fluidic chip medicine evaluating system |
| CN103257213B (en) * | 2012-02-20 | 2015-11-18 | 中科信生物科技（大连）有限公司 | A kind of fully integrated high-flux cell horizontal micro-fluidic chip drug evaluation system |
| CN103981085A (en) * | 2014-05-27 | 2014-08-13 | 东南大学 | Self-set concentration gradient drug screening organ chip and preparation method thereof |
| CN105713834A (en) * | 2014-12-04 | 2016-06-29 | 中国科学院大连化学物理研究所 | Micro-fluidic chip as well as preparation method and applications thereof |
| CN105713834B (en) * | 2014-12-04 | 2018-11-09 | 中国科学院大连化学物理研究所 | A kind of micro-fluidic chip and its preparation method and application |
| CN104774756A (en) * | 2015-04-23 | 2015-07-15 | 东南大学 | Chip and method for microfluidic drug screening on basis of SERS (surface-enhanced Raman scattering) detection technology |
| CN105928913A (en) * | 2016-04-14 | 2016-09-07 | 天津中医药大学 | Cell phenotype based high-content multi-index renal toxicity detection method and applications thereof |
| CN108148752A (en) * | 2016-12-06 | 2018-06-12 | 中国科学院大连化学物理研究所 | A kind of integrated drug screening and colouring method based on micro-fluidic chip |
| CN108148752B (en) * | 2016-12-06 | 2023-09-26 | 中国科学院大连化学物理研究所 | Integrated drug screening and dyeing method based on microfluidic chip |
| CN107236668A (en) * | 2017-06-01 | 2017-10-10 | 西北工业大学 | Micro-fluidic chip for breast carcinoma stem cell culture and Pharmaceutical Analysis |
| CN107236668B (en) * | 2017-06-01 | 2020-08-07 | 西北工业大学 | Microfluidic chip for breast cancer stem cell culture and drug analysis |
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| CN115400805A (en) * | 2022-08-26 | 2022-11-29 | 浙江大学 | Mixing chamber-reaction chamber integrated micro-fluidic chip capable of controlling multiple concentration gradients |
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| CN116312809A (en) * | 2023-04-10 | 2023-06-23 | 杭州美赛生物医药科技有限公司 | Cell screening method based on antibody coupled magnetic beads |
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