CN105021819B - Fluorescence nanometer magnetic particle-polypeptide substrate complex and preparing method thereof - Google Patents
Fluorescence nanometer magnetic particle-polypeptide substrate complex and preparing method thereof Download PDFInfo
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- CN105021819B CN105021819B CN201410175290.3A CN201410175290A CN105021819B CN 105021819 B CN105021819 B CN 105021819B CN 201410175290 A CN201410175290 A CN 201410175290A CN 105021819 B CN105021819 B CN 105021819B
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6402—Atomic fluorescence; Laser induced fluorescence
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/70—Mechanisms involved in disease identification
- G01N2800/7023—(Hyper)proliferation
- G01N2800/7028—Cancer
Abstract
The invention belongs to the field of biotechnology, and particularly discloses a fluorescence nanometer magnetic particle-polypeptide substrate complex and a preparing method thereof. The complex comprises nanometer magnetic particles, fluorescence molecules and protease polypeptide substrates linked between the nanometer magnetic particles and the fluorescence molecules. The preparing method includes the steps that the nanometer magnetic particles are taken and treated in an activated mode by EDC and NHS, then the fluorescence protease polypeptide substrates and the nanometer magnetic particles are mixed by the ratio that 1.546-3.092 micrograms of fluorescence protease polypeptide substrates is added into per milligram of nanometer magnetic particles and then added into MES, and the mixture is vibrated at the room temperature for 30-60 minutes to obtain the fluorescence nanometer magnetic particle-polypeptide substrate complex; the molar ratio of the nanometer magnetic particles to the EDC to the NHS is 1:1.2:1.2. As the nanotechnology is combined, the fluorescence molecules serve as display molecules, and screening is carried out by detecting the activity of protease, the complex can be used for early cancer screening and provide a basis and guarantee for early cancer treatment, effectively relieves the pain of patients, effectively reduces economical burdens and improves the life quality of patients.
Description
【Technical field】
The invention belongs to biological technical field, more particularly to a kind of fluorescence nano magnetic particle-peptide substrate complex and
Its preparation method.
【Background technology】
One of target that tumor is all the time vast clinical workers and scientific research personnel studies intensively and captures, at present
For most of oncotherapy, only accomplish early diagnosiss, can just accomplish the effectively treatment of tumor.The early stage of tumor examines
Break and depend on the biomarker of specificity.Good biomarker screening method, it may be that wound is little and reproducible, most
Ideally tumor tissues special molecular can detect that by simple blood sample or urine examination.Additionally, triage techniqueses should
This is sensitive enough, both can detect that early-stage cancer, exactly can make a distinction non-cancer stricken person again.The Cancer Biology identified
In label, it was demonstrated that really with clinical meaning such as prostate specific antigen (PSA), carcinoembryonic antigen (CA125) and first shape
Gland globulin, specificity still needs to be further characterized by, and needs with reference to other diagnostic tools ability predictive diseases generations, recurrence, to disease
Feelings are classified and monitoring therapeuticing effect.And those concentration in plasma or serum are the protein of nanomole rank, need
Special putting is exempted from experiment and could detect simultaneously quantitatively.Consequently found that new, more preferable knubble biological labelling, develops simple
Detection method is imperative.
Serum albumin enzyme is a kind of newly discovered tumor markerses, and they are in some precancerous lesions, even in tumor
High-risk group's serum in just there occurs the change of vigor, therefore change the early diagnosis of tumor of design for these enzyme vigor
Method is significant.It has been reported that the protease that there is differential expression in normal population and tumor patients serum have：
Caspase-3, cysteine proteinase 2, GELB, fibrinolysin and serum tissue protease S.For
Protease is the characteristics of vigor changes in normal and cancer patient's serum, with reference to nanotechnology, by the use of fluorescence molecule as display
Molecule, can design early screening of new, the sensitive method used in cancer, and the early treatment for cancer provides foundation and guarantor
Barrier, mitigates as much as possible pain and the financial burden of patient, improves the quality of life of patient, extends its life-span.
【The content of the invention】
The primary and foremost purpose of the present invention is to provide a kind of fluorescence nano magnetic particle-peptide substrate complex.
Another object of the present invention is to provide the preparation side of the fluorescence nano magnetic particle-peptide substrate complex
Method.
The purpose of the present invention is achieved through the following technical solutions：A kind of fluorescence nano magnetic particle-peptide substrate complex,
Including magnetic nanoparticle, fluorescence molecule and the protease polypeptide being linked between the magnetic nanoparticle and fluorescence molecule
Substrate.
The protease polypeptide substrate can be by the protease hydrolyzed in serum.
The peptide substrate is ROX-SGGGDEVDGGGSK.
The magnetic nanoparticle is Fe3O4Magnetic nanoparticle.
The launch wavelength of the fluorescence molecule is more than 600 nanometers.
The fluorescence molecule is Cy5, Cy5.5 or ROX.
The preparation method of the fluorescence nano magnetic particle-peptide substrate complex, comprises the steps：Take nano-magnetic
Particle, Jing after EDC (carbodiimides) and NHS (N- carboxyl sulfosuccinic imines) activation processing, by every milligram of nano-magnetic grain
Son is added and added after the mixing of 1.546-3.092 μ g fluorogenic proteases peptide substrate in MES (MES), and mixing is equal
After even, fluorescence nano magnetic particle-peptide substrate complex is obtained；The mol ratio of the magnetic nanoparticle, EDC and NHS is
1:1.2:1.2。
The magnetic nanoparticle is preferably synthesized using following methods：By the mixing of acetyl acetone ferrum, diphenyl ether and oleyl amine
Uniformly, it is incubated 1-2h after being warming up to 100-120 DEG C under nitrogen protection, then is warming up to 275-295 DEG C, after backflow 1-2h room is cooled to
Temperature, obtains black precipitate；Black precipitate is carried out to add hexamethylene after remove impurity process, supernatant is taken after supersound process, be Fe3O4
The cyclohexane solution of magnetic nanoparticle；Every milliliter of diphenyl ether adds 52.98-88.29mg acetyl acetone ferrum, the hexichol
The volume ratio of ether, oleyl amine and hexamethylene is 1:2:(0.5-1.5)；
The remove impurity is processed and preferably carried out using following methods：Black precipitate is carried out after Magneto separate, to be washed with ethanol
Carry out Magneto separate after washing again, repeat to process three times；
The Magneto separate is preferably magnet adsorption separation；
The time of the supersound process is preferably 30-60min；
The Fe3O4Magnetic nanoparticle is 6-15nm Fe3O4Magnetic nanoparticle, is water-soluble chitosan superparamagnetic water
Dissolubility Fe3O4Nanoparticle.
The MES is preferably pH6.0,25mM MES.
The mix homogeneously is preferably room temperature concussion 30-60min；
The concussion is preferably shakes in 1000-3000rpm rotations.
The fluorescence molecule be preferably under same excitation wavelength, with different emission and launch wavelength spacing
From fluorescence molecule farther out, and different colours are sent after being excited.Such selection helps avoid single fluorescence molecule
Between interfere with each other, can simultaneously detect the change of multiple protein enzyme activity.
The launch wavelength of the fluorescence molecule is preferably greater than 600 nanometers.
The fluorescence molecule is preferably Cy5, Cy5.5 or ROX.
The activation processing preferably carries out at room temperature supersound process；
The supersound process is preferable over 40KHz and carries out supersound process.
The protease polypeptide substrate is preferably screened using following methods：It is thin streaming to be combined using bacteria display technology
The substrate sequence of born of the same parents' technology screening differentially expressed protein enzyme in tumor patient and normal population.It is determined that different substrate polypeptide sequences
Affinity between protease, selective affinity highest polypeptide-proteinase combination is used to build polypeptide nano magnetic particle
Complex.
ROX-SGGGDEVDGGGSK is preferably for the fluorogenic protease peptide substrate sequence of caspase3 protease.
In complex builds, for connecting the peptide chain length between nanoparticle, peptide substrate and fluorescence molecule for 5-
10 aminoacid.
In step (2), can by the fluorescence nano for obtaining magnetic particle-peptide substrate complex be resuspended in 100 μ L,
In the PBS of pH7.4, and situation is coupled in fluorescence microscopy Microscopic observation.
Fluorescence nano magnetic particle-peptide substrate the complex is that the peptide substrate for being applied to early diagnosis of tumor is combined
Body.There is the protease that one or more vigor strengthen or express increase in affinity antibody to SpA；When tested sample or blood
It is middle exist vigor strengthen or express increase protease when, protease can digest the polypeptide being connected with fluorescence molecule so that
Fluorescence molecule splits away off from magnetic nanoparticle, by observing fluorescence signal intensity on magnetic nanoparticle, judges tumor
Whether there is.
The present invention has the following advantages and advantages relative to prior art：The present invention combines nanotechnology, set
The enrichment of magnetic nanoparticle and the display effect of fluorescence molecule, by every milligram of magnetic nanoparticle 1.546- is added
3.092 μ g fluorogenic proteases peptide substrates and build fluorescence nano magnetic particle-multi-functional complex of peptide substrate, by detection
It is right due to the attenuating situation of protease caused fluorescence signal being linked on magnetic nanoparticle to the enzymolysis of peptide substrate
The activity of the protease related to tumor is evaluated in serum, is that the early stage of cancer is controlled so as to be used for the early screening of cancer
Treat and foundation and guarantee are provided, pain and the financial burden of patient is mitigated as much as possible, improve the quality of life of patient.
【Description of the drawings】
Fig. 1 is the scanning electron microscope (SEM) photograph of the magnetic nanoparticle of embodiment 1.
Fig. 2 is the structural representation of the fluorescence nano magnetic particle-peptide substrate complex of embodiment 1.
Fig. 3 is the shows fluorescent microscopy images of the fluorescence nano magnetic particle-peptide substrate complex of embodiment 1；Wherein：A is
The shows fluorescent microscopy images of fluorescence nano magnetic particle-peptide substrate complex；B is that fluorescence nano magnetic particle-peptide substrate is multiple
It is fit not add shows fluorescent microscopy images of the caspase3 after 37 DEG C of water-baths；C is fluorescence nano magnetic particle-peptide substrate complex
Add shows fluorescent microscopy images of the caspase3 after 37 DEG C of water-baths；D is the statistic analysis result figure of B, C.
【Specific embodiment】
With reference to embodiment and accompanying drawing, the present invention is described in further detail, but protection scope of the present invention is not
It is limited to this.
Embodiment 1
(1) synthesis of magnetic nanoparticle
Prepare water-soluble chitosan superparamagnetic water solublity Fe3O4Nanoparticle：Acetyl acetone is added toward 100ml reaction bulbs
Ferrum 0.7063g, diphenyl ether 10mL, oleyl amine 20mL stirring mixing, under nitrogen protection 110 DEG C are warming up to, and are incubated 2h, exclude system water
Point；285 DEG C are then heated to, after backflow 1h room temperature is cooled to, obtain black precipitate；By the black precipitate Jing magnet adsorptions for obtaining
After separation, again Jing magnet adsorptions are separated after being washed with ethanol, repeat to process three times, are precipitated thing；Add toward precipitate
Enter 10mL hexamethylene, 10000rpm supersound process 30min takes supernatant, is 10nm Fe3O4The hexamethylene of magnetic nanoparticle is molten
Liquid；
(2) screening of protease polypeptide substrate sequence
Using bacteria display technology Flow Cytometry is combined respectively to caspase3 protease (Sino Biological
Inc., 10050-H08E), cysteine proteinase 2 (Pierce, MA121303), GELB (Sino
Biological Inc., 10327-HNAH), fibrinolysin (Haematologic Technologies Inc., HCPM-0140)
Screened with serum tissue protease S (Sino Biological Inc., 10487-H08H), it is determined that different substrate polypeptide sequences
Affinity between row and protease, even if the side of the proteinase substrate sequence reference CLiPs obtained using bacteria display screening
Method (PNAS103 (20):7583-7588 (2006)), selective affinity highest caspase3 protease is received for building polypeptide
Rice magnetic particle complex.
(3) structure of the selection of fluorescein and fluorescence nano magnetic particle-peptide substrate complex
The magnetic nanoparticle of step (1) is taken, Jing after EDC and NHS supersound process (frequency is 40KHz), per milligram of nanometer
Magnetic particle adds 2.78 μ g for the substrate polypeptide (ROX-SGGGDEVDGGGSK) of caspase3, is dissolved in pH value 6.0,25mM
MES in, room temperature rotation concussion 1h；After magnetic frame adsorbs, supernatant discarded is removing uncombined polypeptide.It is coupled with polypeptide
Magnetic nanoparticle be resuspended in 100 μ L pH7.4PBS, and fluorescence microscopy Microscopic observation be coupled situation, as a result see in Fig. 3
A；A from Fig. 3 can be seen that the present embodiment and successfully construct fluorescence nano magnetic particle-peptide substrate complex.
The principle that fluorescein is selected is to select as far as possible under same excitation wavelength, with different emission, and transmitted wave
Distant fluorescence molecule between length (launch wavelength need to be more than 600 nanometers, such as Cy5, Cy5.5), and after being excited
Send different colours.Such selection helps avoid interfering with each other between single fluorescence molecule, can simultaneously detect various
The change of prolease activity.In complex builds, for connecting the peptide chain between nanoparticle, peptide substrate and fluorescence molecule
Length need to be between 5 to 10 aminoacid.
Effect example：Cysteine aspartase 3 (caspase3) vigour changes are detected
By the fluorescence nano magnetic particle-peptide substrate complex of 20 μ L embodiments 1,0.5U caspase3,10 μ L10
It is placed in 37 DEG C of water-baths after × buffer and the mixing of 70 μ L sterilized water, lucifuge 4h；Matched group is only added and receiving that polypeptide is coupled
Rice magnetic particle and sterilized water, are placed in fluorescence microscopy Microscopic observation, as a result as shown in Figure 3 after the same terms process.Can be with from Fig. 3
Find out, add the experimental group of caspase3, the fluorescence signal of magnetic nanoparticle substantially weakens (see the C in Fig. 3), and only adds water
Matched group fluorescence signal then without any impact (see the B in Fig. 3), its statistical data is consistent with the result of fluorescence microscope
(see the D in Fig. 3).
The specific embodiment of present invention described above, does not constitute limiting the scope of the present invention.Any basis
Various other corresponding change and deformation done by the technology design of the present invention, should be included in the guarantor of the claims in the present invention
In the range of shield.
Claims (8)
1. a kind of fluorescence nano magnetic particle-peptide substrate complex, it is characterised in that including magnetic nanoparticle, fluorescence point
Son and the protease polypeptide substrate being linked between the magnetic nanoparticle and fluorescence molecule；The peptide substrate is ROX-
SGGGDEVDGGGSK。
2. fluorescence nano magnetic particle-peptide substrate complex according to claim 1, it is characterised in that the nanometer
Magnetic particle is Fe3O4Magnetic nanoparticle.
3. fluorescence nano magnetic particle-peptide substrate complex according to claim 1, it is characterised in that the fluorescence
The launch wavelength of molecule is more than 600 nanometers.
4. fluorescence nano magnetic particle-peptide substrate complex according to claim 3, it is characterised in that the fluorescence
Molecule is Cy5, Cy5.5 or ROX.
5. the preparation method of the arbitrary described fluorescence nano magnetic particle-peptide substrate complex of Claims 1-4, its feature
It is to comprise the steps：Magnetic nanoparticle is taken, Jing after EDC and NHS activation processing, is added by every milligram of magnetic nanoparticle
Enter and added in MES after the mixing of 1.546-3.092 μ g fluorogenic proteases peptide substrate, after mix homogeneously, obtain fluorescence nano magnetic
Particle-peptide substrate complex；The mol ratio of the magnetic nanoparticle, EDC and NHS is 1:1.2:1.2.
6. the preparation method of fluorescence nano magnetic particle-peptide substrate complex according to claim 5, its feature exists
In the magnetic nanoparticle is synthesized using following methods：By acetyl acetone ferrum, diphenyl ether and oleyl amine mix homogeneously, nitrogen
It is incubated 1-2h after being warming up to 100-120 DEG C under protection, then is warming up to 275-295 DEG C, after backflow 1-2h room temperature is cooled to, obtains black
Color is precipitated；Black precipitate is carried out to add hexamethylene after remove impurity process, supernatant is taken after supersound process, be Fe3O4Nano-magnetic grain
The cyclohexane solution of son；Every milliliter of diphenyl ether adds 52.98-88.29mg acetyl acetone ferrum, the diphenyl ether, oleyl amine and ring
The volume ratio of hexane is 1:2:(0.5-1.5).
7. the preparation method of fluorescence nano magnetic particle-peptide substrate complex according to claim 5, its feature exists
In the MES is pH 6.0,25mM MES.
8. the preparation method of fluorescence nano magnetic particle-peptide substrate complex according to claim 6, its feature exists
In the time of the supersound process is 30-60min.
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| JP2006507004A (en) * | 2002-11-22 | 2006-03-02 | マーリゲン、バイオサイエンシーズ、インコーポレーテッド | Protease enzyme detection |
| CA2445420A1 (en) * | 2003-07-29 | 2005-01-29 | Invitrogen Corporation | Kinase and phosphatase assays |
| US20050036947A1 (en) * | 2003-08-12 | 2005-02-17 | General Electric Company | Target-specific activatable polymeric imaging agents |
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| EP2019587B1 (en) * | 2006-05-03 | 2010-08-25 | The Regents of the University of California | Detection of protease and protease activity using a single nanocrescent sers probe |
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