CN104689340B - A kind of tumour medicine targeting carrier and application - Google Patents
A kind of tumour medicine targeting carrier and application Download PDFInfo
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Abstract
The coupling method of a kind of antitumor drug targeting vector of disclosure of the invention and this carrier and antitumor drug and a kind of antitumor drug formed.This tumour medicine targeting carrier of the present invention is foot and mouth disease virus sample particle.The present invention tumour medicine targeting carrier and anti-tumor medicine object chemical conjugation methods be：With carbodiimide (EDC) and N HOSu NHSs (NHS) chemical coupling reagent activated tumor pharmaceutical carrier, then it is coupled again with other antitumor drugs.The antitumor drug of the present invention can be specifically bound with the integrin receptor of tumor cell surface overexpression, and need not carry out targeting modification to its surface, can improve the targeted therapy effect of anticancer drug.
Description
Technical field
The present invention relates to the coupling of a kind of antitumor drug targeting vector and this carrier and antitumor drug and institute's shapes
Into a kind of antitumor drug.
Background technology
Malignant tumour has become one of current important diseases for threatening human body health, and the whole world increases cancer newly every year
For patient more than 10,000,000, control cancer has become global health strategy emphasis.It is pernicious that chemical therapeutic method is still treatment
One of main means of tumour, traditional chemical therapeutic method is mainly using chemicals, such as antitumor drug adriamycin
（Doxorubicin, DOX）, to inhibit the proliferation of tumour cell and kill tumour cell, but most of chemotherapeutics does not all have
Specificity can also damage normal structure while tumor tissues are inhibited, so, there is very important toxic side effect, such as make
Into immune function decline, bone marrow suppression, heart and hepatotoxicity etc..
It is insufficient existing in terms of in order to overcome chemotherapy, improve the targeting of chemotherapeutic agent --- increase swollen
The drug accumulation of tumor tissue reduces distribution of the drug around normal structure --- be improve antitumous effect effective way it
One.In order to improve the targeting of antitumor drug, currently used method is by antitumor drug and different pharmaceutical carrier phases
With reference to by carrying out appropriate modification to pharmaceutical carrier, to improve the ability of pharmaceutical carrier targeting transport, being controlled so as to reach targeting
The purpose for the treatment of.
Invention content
The present invention provides a kind of tumour medicine targeting carrier, while resists present invention provides this pharmaceutical carrier with other
The mode and the antineoplastic formed is coupled by this carrier and a kind of specific existing antitumor drug that tumour medicine is coupled
Object.
This tumour medicine targeting carrier of the present invention is foot and mouth disease virus sample particle.
The present invention tumour medicine targeting carrier and anti-tumor medicine object chemical conjugation methods be：Use carbodiimide
(EDC) and n-hydroxysuccinimide (NHS) chemical coupling reagent activated tumor pharmaceutical carrier, then again with other antineoplastics
Object is coupled.
Used in the present invention tumour medicine targeting carrier and anti-tumor medicine object chemical conjugation methods be：By aftosa
Virus-like particle is added to the mixing of carbodiimide and n-hydroxysuccinimide dissolved by 2- (N- morpholines) ethanesulfonic acid solution
In object, antitumor drug is added in before the deadline and is coupled, mixture is transferred in assembling buffer solution after coupling,
It assembles buffer solution and carries out dialysis treatment, buffer solution used is pH=8.0, by 40 mM Tris-HCl, 500 mM NaCl and 10
mM CaCl2Composition is coupled the foot and mouth disease virus sample particle residence of upper antitumor drug in bag filter after processing.
The present invention tumour medicine targeting carrier and anti-tumor medicine object a kind of specific chemical conjugation methods be：It prepares
2- (N- morpholines) ethanesulfonic acid solution of 0.2 mol/L MES, 1 mol/L NaCl, pH 6.0；Take the 2- (N- of 0.5 ml
Quinoline) ethanesulfonic acid solution dissolves in 0.4 mg carbodiimides wherein, and separately taking the 2- (N- morpholines) of 0.5 ml, ethanesulfonic acid solution is wherein
0.6 mg n-hydroxysuccinimides are dissolved in, the 2- for dissolving in carbodiimide (N- morpholines) ethanesulfonic acid solution and N- will be dissolved in successively
The foot and mouth disease virus sample particle that 2- (N- morpholines) ethanesulfonic acid solution of HOSu NHS is added to a concentration of 2mg/ml of 1ml is molten
It in liquid, activates 15 minutes at room temperature, then adds in the DOX of a concentration of 5 mg/ml of 30 μ l, adjust pH=8.0, room temperature coupling 15
Minute, then reactant is transferred in the bag filter of 8000 MWCO and is dialysed, the substance not being coupled is removed and obtains object.
In numerous pharmaceutical carriers, virus-like particle（Virus/virus-like particles, VLPs）As one kind
The natural nano grade biomaterial of self assembly, in addition to ensuring the maximization of drugloading rate with larger surface area, sustained release can be passed through
It, can since virus-like particle is same or similar with virion in structure except medicament-carried performance continued treatment effect
Simulation nature virion is combined using specific receptors with host cell, and expression water of these specific receptors in tumour cell
Flat to significantly improve, this provides precondition for targeting advantage of the virus-like particle as tumour medicine carrier, so as to ensure to take
The drug selectivity of band enters cell interior, plays preferable drug effect.
The present invention is using foot and mouth disease virus sample particle as pharmaceutical carrier, by the chemical method of optimization by itself and antineoplastic
Object adriamycin（DOX）Coupling forms foot and mouth disease virus sample particle-adriamycin（FMD VLP-DOX）Conjugate, by means of aftosa
The integrin receptor of RGD motif and tumor cell surface overexpression in virus-like particle VP1 combines, based on tumour cell table
Face receptor target is positioned at tumour cell, can refer to Mehra NK, Mishra V, Jain NK., et al.
Receptor-based targeting of therapeutics. Therapeutic delivery, Mar 2013;4
(3):369-394. reduces toxic side effect of the antitumor drug to normal cell.
In order to improve the effect of the targeted therapy of antitumor drug, for the first time by antitumor drug adriamycin（DOX）And aftosa
Virus-like particle (FMDVLP) is coupled in vitro, using virus-like particle and foot and mouth disease virus particle in structure and biological nature
Similitude, by conservative peptide fragment-RGD of foot and mouth disease virus sample particle surface and the integrin of tumor cell surface overexpression
Receptor（integrin receptors）Specific binding, gives full play to the effect of FMDV-VLP bifunctional molecules --- and it is both medicine
Object delivers function, and has the function of targeting positioning tumor cell.
Secondly the present invention is groped and has been improved to the method for coupling, by improving temperature, shortens coupling time, originally
Half an hour can complete whole coupling reactions at room temperature for invention, and coupling before will could complete coupling overnight at 4 DEG C
Reaction（Referring to Aljabali AA, Shukla S, Lomonossoff GP, Steinmetz NF, Evans DJ
(2013) CPMV-DOX delivers. Mol Pharm 10:3-10 and Ashley CE, Carnes EC, Phillips
GK, Durfee PN, Buley MD, et al. (2011) Cell-specific delivery of diverse
cargos by bacteriophage MS2 virus-like particles. ACS Nano 5: 5729-5745.）.
Using foot and mouth disease virus sample particle as the pharmaceutical carrier of adriamycin, treated available for tumour cell.Integrin receptor
Modified extensively in various tumour medicine carrier surfaces, so as to carry out mediated targeted transport antitumor drug to tumour cell,
Mehra, N.K., Mishra, V., Jain, N.K. can be referred to about application of the integrin receptor in treatment of cancer,
2013. Receptor-based targeting of therapeutics. Therapeutic delivery 4, 369-
394. in the VP1 albumen of assembling foot and mouth disease virus sample particle due to having RGD motif, can be with tumor cell surface overexpression
Integrin receptor specific binding, so as to play the effect of the pharmaceutical carrier of foot and mouth disease virus sample particle, and need not to its surface
Targeting modification is carried out, the targeted therapy that adriamycin is effectively improved with this acts on.In the present invention, foot and mouth disease virus sample particle is utilized
RGD motif contained by itself as the integrin receptor of target recognition of tumor cell surface overexpression, thus only needs
The coupling of one step can be obtained by targeted drug carrier, simplify other drugs carrier elder generation coupling drug again to carrier carry out table
The complex process of face modification, and virus-like particle combines nano material and biological material as a kind of nano grade biological material
The advantage of material can target drug delivery and can play the role of medicament slow release.
Description of the drawings
1 electrophoretogram of attached drawing, wherein：A schemes, and albumen, lane2 cut off the clothing of HIS labels before purification by SDS-PAGE, lane1
Glutelin, lane3 are coupled the capsid protein after DOX, lane4 standard proteins maker.B figures are ultraviolet hypograph, due to coupling
DOX, so having band under ultraviolet.C figure nucleic acid electrophoresis, does not carry out coomassie brilliant blue staining, ultraviolet lower observation, and lane1 is
DOX, lane2 are the virus-like particle before coupling, and lane3 is the virus-like particle after coupling.D figures are coomassie brilliant blue stainings
Afterwards, only lane2 and lane3 have band.After illustrating virus-like particle coupling DOX, molecular weight becomes larger, in nucleic acid electrophoresis and not
Coupling DOX's compares, and is moved behind position.
2 ultraviolet continuous spectrum scanning result curve graph of attached drawing, visible conjugate is at 270nm in figure and 495nm has absorption
Peak.
3 electromicroscopic photograph of attached drawing, after display is coupled DOX, the assembling situation of virus-like particle.
Under the different gradient concentrations of attached drawing 4, the DOX contained in conjugate and DOX is used alone in the cell toxicity test of progress
Concentration it is the same.
5 conjugate of attached drawing enters the fluorescence photo that cell situation carries out tracer, and from 30min to 2h, DAPI is core dyestuff 4',
6- diamidinos -2-phenylindone dyes nucleus, and what is excited at 560nm is the fluorescence of bis- anti-FITC of FMDV-VLP, uses
It is the feux rouges sent out after DOX excitations at tracer foot and mouth disease virus sample particle, 495nm, merge is the feelings after the merging of three
Condition.
6 control group DOX of attached drawing enters the situation of cell.DAPI is core dyestuff 4', 6- diamidino -2-phenylindone to thin
Karyon is dyed, and 495nm is the feux rouges sent out after DOX is excited, and merge is the picture after the two merges.
After 7 conjugate of attached drawing acts on 48h with tumour cell, tumour cell situation photo, DAPI is core dyestuff 4', 6- bis-
Amidino groups -2-phenylindone dyes nucleus, is the feux rouges sent out after DOX is excited at 495nm, merge is the conjunction of three
Situation after and.
Specific embodiment
The present invention is explained with reference to embodiments.
1. the chemical coupling of FMDV-VLP and DOX.
0.4 mg carbodiimides and 0.6 mg n-hydroxysuccinimides are dissolved into each 0.5 ml 2- (N- respectively
Quinoline) in ethanesulfonic acid solution（0.2 mol/L MES, 1 mol/L NaCl, pH 6.0）, it is added sequentially to a concentration of 2mg/ml of 1ml
Foot and mouth disease virus sample particle solution in, activate 15 minutes at room temperature, then add in the DOX of a concentration of 5 mg/ml of 30 μ l, adjust
PH=8.0 are saved, is coupled 15 minutes at room temperature, then mixture is transferred in the bag filter of 8000 MWCO and is dialysed, 4 °C of mistakes
Night simultaneously changes 2-3 dialyzate, removes the substance not being coupled and obtains object.Used elution buffer is：40mM Tris-
HCl, 500mM NaCl, 10mM CaCl2, pH=8.0.
2. the measure of FMDV-VLP-DOX conjugate properties.
Whether conjugate is detected with the Agarose gel electrophoresis of 12% SDS-PAGE and 0.8% respectively
It obtains, is changed with ultraviolet continuous absorption spectrum to detect the absorptance of conjugate, and seen with the form of Electronic Speculum antithesis connection object
It surveys, the results showed that, the capsid protein with His labels is successfully cut off, and capsid protein is successfully coupled after cutting off His labels
Antitumor drug is gone up, by the antitumor drug DOX fluorescence of itself, under ultraviolet light it can be seen that antitumor drug was sent out
Fluorescence is shown in attached drawing 1A and 1B；Conjugate is subjected to agarose electrophoresis simultaneously, after being coupled upper drug, virus-like particle swimming
It is slack-off, see attached drawing 1C and 1D；There are two absorption peaks, see attached drawing 2 in ultraviolet continuous spectrum detection, conjugate；Conjugate is made
Electron microscopic sample is observed it can be seen that after the upper antitumor drug of coupling, and the form of virus-like particle does not change,
See attached drawing 3；The above result shows that foot and mouth disease virus sample particle is coupled really with antitumor drug DOX.
3. conjugate observes the cytotoxicity of tumour cell.
Logarithmic phase tumour cell is collected, adjusts concentration of cell suspension, 200 μ l are added in per hole, bed board makes cell tune to be measured close
It spends to 1000-10000/hole.5% CO2, 37 DEG C are incubated for 24 hours, until cell monolayer is paved with bottom hole（96 hole flat undersides）, add in ladder
Spend the DOX and conjugate of concentration, make the content of DOX in conjugate as individual DOX, for 24 hours after 20 μ l are added in per hole
MTS solution continues to cultivate 1-4h, light absorption value is surveyed at ultraviolet specrophotometer 490nm, MTT experiment is the results show that hoof-and-mouth disease
Malicious sample particle itself does not influence cell activity, does not have toxic side effect to cell, in low concentration, conjugate and individually
DOX antitumor actions are suitable, in high concentration（≥10 µg/ml）When, the antitumor action of conjugate is better than the anti-of individual DOX
Function of tumor, as shown in attached drawing 4.
4. targeting and apoptosis-induced observation of the conjugate to tumour cell.
The conjugate of synthesis and A549 tumour cells are used as experimental group, while be used as with DOX and tumour cell work
For control group.Sample is received in 0.5h, 1h, 2h, experimental group and control group all fix 15min with 0.4% paraformaldehyde solution, and 1%
Triton-100 penetrates 15min, and 1:8000 DAPI carries out nuclear staining 15min, and then experimental group uses I pigs of aftosa Asia respectively
Source primary antibody and ELIAS secondary antibody are incubated 1 hour at 37 DEG C.It is observed under laser confocal microscope, from figure 5 it can be seen that viral
Sample particle is first attached to cell surface, subsequently into cell, releases DOX, and DOX is entered back into core, completes VLP targeting deliveries
The process of antitumor drug.Fig. 6 is the results show that individually DOX is in adherent cell and during entering cell, in disperse point
Cloth without targeting, increases over time, and the DOX concentration of nucleus gradually increases.
Synthetic conjugate is added to culture for 24 hours simultaneously and was replaced in the A549 tumour cells of new culture medium, gently
Jog is even, 5% CO2, 37 DEG C are incubated 48h and receive sample, fix 15 min with 0.4% paraformaldehyde solution, 1% Triton-100 leads to
Saturating 15min, 1:8000 DAPI carries out 15 min of nuclear staining, is observed under laser confocal microscope, it will be seen in fig. 7 that
After conjugate acts on 48 hours with tumour cell, antitumor drug is combined completely into nucleus, and with substance in core, and tumour is thin
The nucleus of born of the same parents is concentrated and is degraded, and these phenomenons are exactly the characteristic variation of Apoptosis, illustrates that conjugate induces
The apoptosis of tumour cell, this is exactly the result to be generated after antitumor drug is had an effect.
The preparation method of the foot and mouth disease virus sample particle of the present invention is as follows：
（1）The structure of small ubiquitin sample modification protein fusion expression carrier pSMA：
A. using saccharomyces cerevisiae genome DNA as template, using smt3F and smt3R as primer amplification smt3 genes, primer sequence
It is as follows：
Sense primer SEQ ID No.1 (smt3F)：
5’ GCCATGGGT CAT CAC CAT CAT CAT CAC GGG TCG GAC TCA GAA GTC AAT CAA
3 ',
Downstream primer SEQ ID No.2 (smt3R)：
5’ GGA TCCGAGACCTTAA GGTCTCAA CCT CCA ATC TGT TCG CGG TG 3 ',
B. smt3 genes are inserted into the pET-28a loads with similary inscribe enzymatic treatment after Nco I and BamH I double digestions
In body, the kalamycin resistance gene of pSMK is replaced with ampicillin resistance, obtains carrier pSMA by resulting vehicle pSMK.
（2）The amplification of Asia I type Foot-and-mouth disease VP0, VP3 and VP1 gene：Pass through reverse transcription polymerase chain
Formula is reacted, using Asia I type foot and mouth disease virus RNA as template, respectively with primer VP0BsmB I and VP0BamH I, VP3BsmB I
VP0, VP3 and VP1 genes are obtained with VP3BamH I and VP1BsmB I and VP1BamH I amplifications.
Primer sequence is as follows：
Sense primer SEQ ID No.3（VP0BsmBI）：
5 ' GTA CTT CGTCTC AAGGT GGA GCC GGG CAA TCC AGT,
Downstream primer SEQ ID No.4（VP0BamH I）：
5 ' GCG AGT GGA TCC TCA CTC TTT CGA GGG CAG TTC,
Sense primer SEQ ID No.5（VP3BsmB I）：
5 ' GGA CTT CGTCTCA AGGT GGG ATA GTT CCT GTG GCG,
Downstream primer SEQ ID No.6（VP3BamH I）：
5’ GCT TAT GGA TCC TCA CTG TTG GCG GGC ATC CAC；
Sense primer SEQ ID No.7（VP1BsmB I）：
5 ' GCA CTT CGTCTCA AGGT ACT ACC ACC ACT GGC GAG,
Downstream primer SEQ ID No.8（VP1BamH I）： 5’GCG CAC GGA TCC TCA CAG AGT CTG TTT
CTC AGG。
（3）The structure of recombinant expression carrier
VP0, VP3 and VP1 after BsmB I and BamH I double digestions is inserted into what is handled through Bsa I digestions respectively
PSMK, pSMA and pSMK obtain recombinant expression carrier pSMK/VP0, pSMA/VP3 and pSMK/VP1.
（4）The structure of double expression recombinant vector
Using pSMK/VP1 as template, obtained by primer amplification of T7BamH I/VP1Xho I containing protokaryons such as T7 promoters
The DNA fragmentation of Expression element and VP1 genes is inserted into the pSMK/VP0 handled with similary digestion after BamH I/Xho I double digestions
In, double expression recombinant vector pSMK/VP0-VP1 is obtained, primer sequence is as follows：
Sense primer SEQ ID No.9（T7BamH I）：5’GCA ATT GGA TCC CGT CCG GCG TAG AGG
ATC GA,
Downstream primer SEQ ID No.10（VP1Xho I）：
5’GCG CAC CTC GAG TCA CAG AGT CTG TTT CTC AGG。
（5）Protein expression and purifying
By pSMA/VP3 and pSMK/VP0-VP1 cotransformations to DE3-RIL plants of bacterium BL21-CodonPlus of expression
Stratagene screens three resistance clones with chloramphenicol, penicillin and kanamycins and carries out Protein expression and purification.
（6）The assembled in vitro of foot and mouth disease virus sample particle：
Protease digestion fusion protein is modified with small ubiquitin sample, removing small ubiquitin sample by HisTrap HP modifies albumen,
The liquid containing VP0, VP1 and VP3 is collected, purpose virus-like particle is assembled into the elution buffer PBS dialysis of pH 7.5.Tool
The way of body is referring also to the related content of Chinese invention patent application 201010251915.1.
<110>Lanzhou Veterinary Inst., Chinese Acedemy of Agaricultural Sciences
<120>A kind of tumour medicine targeting carrier and application
<160> 10
<210> 1
<211> 51
<212> DNA
<213>Artificial sequence（smt3F）
<400>
gccatgggtc atcaccatca tcatcacggg tcggactcag aagtcaatca a 51
<210> 2
<211> 44
<212> DNA
<213>Artificial sequence（smt3R）
<400>
ggatccgaga ccttaaggtc tcaacctcca atctgttcgc ggtg 44
<210> 3
<211> 35
<212> DNA
<213>Artificial sequence（VP0BsmBI）
<400>
gtacttcgtc tcaaggtgga gccgggcaat ccagt 35
<210> 4
<211> 33
<212> DNA
<213>Artificial sequence（VP0BamH I）
<400>
gcgagtggat cctcactctt tcgagggcag ttc 33
<210> 5
<211> 35
<212> DNA
<213>Artificial sequence（VP3BsmB I）
<400>
ggacttcgtc tcaaggtggg atagttcctg tggcg 35
<210> 6
<211> 33
<212> DNA
<213>Artificial sequence（VP3BamH I）
<400>
gcttatggat cctcactgtt ggcgggcatc cac 33
<210> 7
<211> 35
<212> DNA
<213>Artificial sequence（VP1BsmB I）
gcacttcgtc tcaaggtact accaccactg gcgag 35
<210> 8
<211> 33
<212> DNA
<213>Artificial sequence（VP1BamH I）
<400>
gcgcacggat cctcacagag tctgtttctc agg 33
<210> 9
<211> 32
<212> DNA
<213>Artificial sequence（T7BamH I）
<400>
gcaattggat cccgtccggc gtagaggatc ga 32
<210> 10
<211> 33
<212> DNA
<213>Artificial sequence（VP1Xho I）
<400>
gcgcacctcg agtcacagag tctgtttctc agg 33
Claims (4)
1. a kind of tumour medicine targeting that the compound to form inducible apoptosis of tumor cells can be coupled with antitumor drug DOX carries
Body, it is characterised in that this carrier is foot and mouth disease virus sample particle.
2. tumour medicine targeting carrier described in claim 1 and the chemical conjugation methods of anti-tumor medicine object DOX, feature
It is to be coupled with antitumor drug DOX with carbodiimide and n-hydroxysuccinimide chemical coupling reagent.
3. the chemical conjugation methods of tumour medicine targeting carrier according to claim 2 and anti-tumor medicine object, special
Sign is：Foot and mouth disease virus sample particle is added in into the carbodiimide dissolved with 2- (N- morpholines) ethanesulfonic acid and N- hydroxysuccinimidyls acyl Asia
It is activated in the solution of amine, then adds in antitumor drug DOX couplings, mixture is transferred in bag filter after coupling and is dialysed, it is used
Elution buffer be：40mM Tris-HCl, 500mM NaCl, 10mM CaCl2, pH=8.0.
4. the chemical conjugation methods of tumour medicine targeting carrier according to claim 3 and anti-tumor medicine object, special
Sign is：Prepare 2- (N- morpholines) ethanesulfonic acid solution of 0.2 mol/L MES, 1 mol/L NaCl, pH 6.0；Take 0.5 ml
2- (N- morpholines) ethanesulfonic acid solution dissolve in 0.4 mg carbodiimides wherein, 2- (N- morpholines) ethanesulfonic acid for separately taking 0.5 ml is molten
Liquid dissolves in 0.6 mg n-hydroxysuccinimides wherein, 2- (N- morpholines) the ethanesulfonic acid solution that will dissolve in carbodiimide successively
The foot and mouth disease virus of a concentration of 2mg/ml of 1ml is added to 2- (N- morpholines) the ethanesulfonic acid solution for dissolving in n-hydroxysuccinimide
It in sample particle solution, activates 15 minutes at room temperature, then adds in the DOX of a concentration of 5 mg/ml of 30 μ l, adjust pH=8.0, room
Reactant, is then transferred in the bag filter of 8000 MWCO and dialyses by temperature coupling 15 minutes, removes the substance not being coupled and obtains
To object.
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| CN101690822A (en) * | 2009-08-13 | 2010-04-07 | 苏州纳米技术与纳米仿生研究所 | Medicament carrier for targeted medicament delivery on diseases related to macrophage and preparation method thereof |
| CN102895667A (en) * | 2012-10-22 | 2013-01-30 | 苏州百拓生物技术服务有限公司 | Method for preparing lactobionic acid-crosslinked hepatic cell targeted viral vector |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101690822A (en) * | 2009-08-13 | 2010-04-07 | 苏州纳米技术与纳米仿生研究所 | Medicament carrier for targeted medicament delivery on diseases related to macrophage and preparation method thereof |
| CN102895667A (en) * | 2012-10-22 | 2013-01-30 | 苏州百拓生物技术服务有限公司 | Method for preparing lactobionic acid-crosslinked hepatic cell targeted viral vector |
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| 《Self-Assembled Virus-Like Particles from Rotavirus Structural Protein VP6 for Targeted Drug Delivery》;Qinghuan Zhao et al.;《Bioconjugate Chem》;20110221;第22卷;摘要，347页左栏最后一段，scheme 2 * |
| 《Virus-like particle-mediated intracellular delivery of mRNA cap analog with in vivo activity against hepatocellular carcinoma》;Monika Zochowska et al.;《Nanomedicine: Nanotechnology, Biology, and Medicine》;20140804;第11卷;摘要，图1 * |
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