CN106349331A - Bispyrene-based pH (Potential of Hydrogen)-response self-assembly polypeptide nano material, and preparation method and application thereof - Google Patents
Bispyrene-based pH (Potential of Hydrogen)-response self-assembly polypeptide nano material, and preparation method and application thereof Download PDFInfo
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- 239000002086 nanomaterial Substances 0.000 title claims abstract description 100
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 100
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 100
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 238000001338 self-assembly Methods 0.000 title claims abstract description 21
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- 229910052739 hydrogen Inorganic materials 0.000 title claims abstract description 4
- 239000001257 hydrogen Substances 0.000 title claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 12
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000872 buffer Substances 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 10
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 9
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
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- 239000003960 organic solvent Substances 0.000 claims description 4
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- 150000001413 amino acids Chemical class 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
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- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
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- 101100298998 Caenorhabditis elegans pbs-3 gene Proteins 0.000 description 2
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- 208000035126 Facies Diseases 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
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- NERFNHBZJXXFGY-UHFFFAOYSA-N [4-[(4-methylphenyl)methoxy]phenyl]methanol Chemical compound C1=CC(C)=CC=C1COC1=CC=C(CO)C=C1 NERFNHBZJXXFGY-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0056—Peptides, proteins, polyamino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nanotechnology (AREA)
- Veterinary Medicine (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
- Organic Chemistry (AREA)
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- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Genetics & Genomics (AREA)
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- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
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- Optics & Photonics (AREA)
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Abstract
The invention provides a bispyrene-based pH (Potential of Hydrogen)-response self-assembly polypeptide nano material, and a preparation method and application thereof. The bispyrene-based pH-response self-assembly polypeptide nano material has a structure as shown in formulas I to IV. The bispyrene-based pH-response self-assembly polypeptide nano material has pH response, can be self-assembled into nano fiber under the environment that the pH is greater than or equal to 1.0 and smaller than 8.0 and can be assembled into nanospheres under the environment that the pH is greater than or equal to 8.0, and a hydrophobic micromolecular imaging agent and medicine can be recruited, so that the utilization rate of the micromolecular imaging agent and treatment medicine can be greatly increased; the bispyrene-based pH-response self-assembly polypeptide nano material can be converted into fiber in positions of ill tissues or cells in situ, is capable of greatly prolonging the retention time, can be used for biological imaging and treating, is capable of providing a reliable diagnosis and targeted therapy method for disease treatment, and has a wide application prospect.
Description
Technical field
The invention belongs to technical field of nano material, it is related to a kind of polypeptide nano material and its preparation method and application, especially
It is related to a kind of ph based on double pyrenes and responds polypeptide nano material of self assembly and its preparation method and application.
Background technology
In recent years, nano material receives great attention in the diagnosis of clinical disease and the application for the treatment of.Polypeptide is from group
Dress nano material, due to its good bio-compatibility and Chemical Diversity, is widely used in bio-imaging and treatment.And it is different
The nano material of size and pattern has strong influence for bio-imaging and treatment.As nano-particle, correlational study shows,
When nanoparticle size is in 10-100nm, nano-particle circulation time in vivo can be increased;And work as nano-scale in 15-
During 350nm, nano-particle can gather myocardial infarction, tumor and other inflammation part by targeting;But such nano-particle meeting
It is targeted the quick removing of tissue.And inherently one metastable state of the structure of nano-particle, can over time and other factorses
The change of (enzyme, temperature, ph etc.) and there is topographical transition.Secondly, compared to nano-particle, nanofiber has preferably stable
Property and be not easy in vivo to be eliminated, the holdup time of material can be extended.Using this property of nanofiber, permissible
For the long-acting imaging of biology and treatment.On the other hand, small molecule preparation and medicine have certain hydrophobicity, limit
Its biologic applications.Using method for small molecule preparation and medicine is with polymer nano material, it to be carried out at present
Sealing, this method is released and is had certain challenge for the realizing controlled-release of small molecule preparation and medicine.Therefore open up a kind of new
Strategy be used for tumor detection and treatment very necessary.
Therefore, in the art it is desired to be able to combine the stability of nanofiber and the hydrophobicity of small-molecule drug, design
A kind of polypeptide nano material that can form fiber with converted in-situ, for recruiting hydrophobic small molecule material and being used for biological one-tenth
Picture and treatment, the potential new diagnosis and treatment strategy of this tool, there is widely studied meaning.
Content of the invention
For the deficiencies in the prior art, it is an object of the invention to provide a kind of polypeptide nano material based on double pyrenes and its
Preparation method and application, particularly provide a kind of ph based on double pyrenes to respond polypeptide nano material of self assembly and preparation method thereof
And application.
For reaching this goal of the invention, the present invention employs the following technical solutions:
On the one hand, the present invention provides a kind of polypeptide nano material based on double pyrenes, and described nano material has as following formula i-
Structure shown in iv:
Wherein r1For having the peptide sequence of intramolecular multiple hydrogen bonding, r2For the peptide sequence of histidine composition, r3For hydrophilic
The polyglycol chain of property, r1、r2And r3Between be connected by amido link.
The polypeptide nano material of structure of the present invention has ph response, can form fiber with converted in-situ, for recruiting
The small molecule preparation raising hydrophobic and medicine, greatly improve the utilization rate of small molecule preparation and medicine.
Preferably, the described donor based on pyrene compound groups double in the polypeptide nano material of double pyrenes is to have shown in formula v
Double pyrene compounds of structure:
Double pyrenes in the polypeptide nano material based on double pyrenes
Compound group and r1Or r2Form amido link and link together.
Preferably, r1For:
WhereinRepresent group connection site.I.e. in the present invention, r1Donor constructions be:
(can be represented with klvff) or(can be represented with lpffd).
Preferably, r2Donor be the polypeptide being made up of 4-10 histidine, such as r2Donor be by 4,5,6,7,8,9
Or the polypeptide that 10 histidine are constituted, the hexapeptide being preferably made up of 6 histidine.
Preferably, r3Donor be carboxy blocking Polyethylene Glycol, its weight average molecular weight be 300-2000, such as 300,
400th, 500,600,700,800,900,1000,1200,1400,1600,1800 or 2000.
On the other hand, the invention provides the preparation method of the described polypeptide nano material based on double pyrenes, methods described with
Resin is carrier, using pyrene compounds double shown in formula v and aminoacid as raw material, prepares described base using solid phase synthesis process
Polypeptide nano material in double pyrenes.
On the other hand, the invention provides the ph response self-assembling method of the described polypeptide nano material based on double pyrenes,
The method comprising the steps of:
(1) the polypeptide nano material based on double pyrenes is dissolved in organic solvent, obtains polypeptide nano material solution;
(2) the polypeptide nano material solution that step (1) obtains is added in buffer solution, in the buffering of 1.0≤ph < 8.0
In liquid, described polypeptide nano material self assembles are nanofiber;In the buffer of ph >=8.0, described polypeptide nano material is certainly
It is assembled into nanosphere.
Preferably, the described organic solvent of step (1) be in dmso, dmf or Isosorbide-5-Nitrae-dioxane any one or at least
Two kinds of combination, preferably dmso.
Preferably, the concentration of the described polypeptide nano material solution of step (1) is 10-4-10-2M, such as 1 × 10-4m、3×
10-4m、5×10-4m、8×10-4m、1×10-3m、3×10-3m、5×10-3m、8×10-3M or 1 × 10-2m.
Preferably, the described self assembly of step (2) is carried out under ultrasonic, and the described ultrasonic time is 1-10min, for example
1min, 2min, 3min, 4min, 5min, 6min, 7min, 8min, 9min or 10min.
Preferably, step (2) described ultrasonic after 20-40 DEG C (such as 22 DEG C, 25 DEG C, 28 DEG C, 30 DEG C, 32 DEG C, 35 DEG C or
38 DEG C) keep 0.5-12h (such as 0.8h, 1h, 3h, 5h, 8h, 10h, 11h or 12h).
The present invention has ph response based on the polypeptide nano material of double pyrenes, can be self-assembled into not under different ph values
Same form, nanofiber or nanosphere that the present invention prepares, with respect to nano-particle, there is more preferable stability,
Biology is not easy to be eliminated in vivo, has the longer holdup time in vivo, and have good bio-compatibility,
Epr effect, good ph sensitivity and the ability that hydrophobic small-molecule drug is recruited.
On the other hand, the invention provides the described polypeptide nano material based on double pyrenes preparation cancer treatment drugs and
Application in bio-imaging agent.
Ph response polypeptide nano material provided by the present invention, based on its good sensitivity to ph, can be with in-situ transesterification
Change and form fiber, for recruiting hydrophobic small molecule preparation and medicine, greatly improve small molecule preparation and medicine
Utilization rate, is with a wide range of applications.
With respect to prior art, the method have the advantages that
The present invention has ph response based on the polypeptide nano material of double pyrenes, from group in the environment of 1.0≤ph < 8.0
Dress forms nanofiber, is assembled into nanosphere, can recruit hydrophobic small molecule preparation and medicine in the environment of ph >=8.0
Thing, greatly improves the utilization rate of small molecule preparation and medicine, and this nano material can be former in diseased tissue or cell area
Position is converted into fiber, can greatly prolong the holdup time, can be used for bio-imaging and treatment, is disease (especially cancer) treatment
Reliable diagnosis and targeted therapies are provided, are with a wide range of applications.
Brief description
Fig. 1 is the mass spectrum of the polypeptide nano material based on double pyrenes of embodiment 1 preparation;
Fig. 2 is the fluorescence intensity being obtained based on the polypeptide nano material self assembles aptitude tests of double pyrenes of embodiment 1 preparation
Curve chart;
Fig. 3 is the buffering in ultra-pure water (a figure) and ph=6.0 for the polypeptide nano material based on double pyrenes of embodiment 1 preparation
Transmission electron microscope picture after self assembly in liquid (b figure), the scale of a figure and b in figure is 100nm;
Fig. 4 is to carry out common incubation with Nile red to cell using the polypeptide nano material based on double pyrenes of embodiment 1 preparation
Single-photon laser copolymerization Jiao's photo afterwards, wherein a figure are light field under the conditions of 405nm laser excitation for cell ball focusing results altogether
Figure, b figure is result figure when collecting 450-550nm under the conditions of cell ball 405nm laser excitation in double pyrene green glows, and c figure is cell
The result figure in Nile red HONGGUANG during 550-700nm is collected under the conditions of ball 405nm laser excitation;
Fig. 5 is that the polypeptide nano material based on double pyrenes of embodiment 1 preparation occurs original position pattern to turn in cancer cell surface
The stereoscan photograph changed, wherein b figure is the enlarged drawing of a in figure selected location, and a icon chi is 50 μm, and b icon chi is 5 μm;
Fig. 6 is that the polypeptide nano material based on double pyrenes of embodiment 1 preparation is used for recruiting the petty action of fluorescent dye Nile red
Thing imaging experiment result figure;Wherein a figure is that the polypeptide nano material based on double pyrenes for the intravenous injection is tied with the imaging after Nile red 4h
Fruit is schemed, and b figure is the imaging results figure after the polypeptide nano material based on double pyrenes for the intravenous injection and Nile red 96h;
Fig. 7 is the mass spectrum of the polypeptide nano material based on double pyrenes of embodiment 6 preparation;
Fig. 8 is the fluorescence intensity being obtained based on the polypeptide nano material self assembles aptitude tests of double pyrenes of embodiment 6 preparation
Curve chart;
Fig. 9 is the buffer (b figure) in (a figure) and ph=6.0 for the polypeptide nano material based on double pyrenes of embodiment 6 preparation
Transmission electron microscope picture after middle self assembly, the scale of a figure and b in figure is 100nm;
Figure 10 is that the polypeptide nano material based on double pyrenes of embodiment 6 preparation is carried out to cell after common incubation with Nile red
Single-photon laser copolymerization Jiao's photo, a figure is light field under the conditions of 405nm laser excitation for cell ball focusing results figure altogether, and b figure is
The result figure in double pyrene green glows during 450-550nm is collected, c figure is that cell ball 405nm swashs under the conditions of cell ball 405nm laser excitation
The result figure in Nile red HONGGUANG during 550-700nm is collected under photo-excitation conditions;
Figure 11 is that the polypeptide nano material based on double pyrenes in embodiment 6 occurs the conversion of original position pattern in cancer cell surface
Stereoscan photograph, wherein b figure is the enlarged drawing of a in figure selected location, a icon chi be 50 μm, b icon chi be 5 μm;
Figure 12 is that the polypeptide nano material based on double pyrenes of embodiment 6 preparation is used for recruiting the petty action of fluorescent dye Nile red
Thing imaging experiment result figure, wherein a figure are that the polypeptide nano material based on double pyrenes for the intravenous injection is tied with the imaging after Nile red 4h
Fruit is schemed, and b figure is the imaging results figure after the polypeptide nano material based on double pyrenes for the intravenous injection and Nile red 96h.
Specific embodiment
To further illustrate technical scheme below by specific embodiment.Those skilled in the art should be bright
, described embodiment is only to aid in understanding the present invention, is not construed as the concrete restriction to the present invention.
Embodiment 1
In the present embodiment, the structure of the polypeptide nano material based on double pyrenes is as follows:
I.e. in formula ii provided by the present invention, r1Donor be klvff, r2Donor be six being made up of 6 histidine
Peptide, r3Donor be carboxy blocking Polyethylene Glycol, its molecular weight be 1000g mol-1.
Described synthesized with the solid phase synthesis process of polypeptide based on the polypeptide nano material of double pyrenes, using Wang resin, press
According to polypeptide sequence, it is coupled by coupling agent (N-methyl morpholine: dmf=5:95, volume ratio), wherein carried the peg of carboxyl
And double pyrene compound is similarly reacted according to the coupling method of aminoacid, after pure through trifluoroacetic acid cracking, revolving, ether
Change and obtain.
Based on the polypeptide nano material of double pyrenes, mass spectral characteristi is carried out to the present embodiment synthesis, result is as shown in figure 1, by this
Figure understands, the quasi-molecular ions appeared in figure meets the characteristic peak of the molecular weight of material molecule, and peak shape complies fully with peg polymerization
The characteristic peak of chain.
Embodiment 2
In the present embodiment embodiment 1 is prepared carries out self assembly based on the polypeptide nano material of double pyrenes, investigates
The ph response of this material.
First, the self assembly ability of the polypeptide nano material based on double pyrenes for the test, by embodiment 1 prepare based on double
The polypeptide nano material of pyrene is dissolved in dmso, tests its fluorescence intensity, then adds water and carries out group assembling, often plus after a certain amount of water
Water is made to be sufficiently mixed with organic faciess, standing tests its fluorescence intensity in one minute afterwards, and test result is as shown in Figure 2.
From figure 2 it can be seen that adding h in the dmso solution to the polypeptide nano material based on double pyrenes2During o, fluorescence increases
By force, show that material is changed into state of aggregation from single dispersing.
The ph response self-assembling method of the described polypeptide nano material based on double pyrenes is as follows:
Weigh and be dissolved in 10ml dmso solvent based on the polypeptide nano material 5mg of double pyrenes, by this solution with syringe respectively
Fast injection, in the ultra-pure water of 90ml and in the buffer of ph=6.0, ultrasonic 30 minutes, stands two hours, respectively obtains glimmering
Light nano-particle and nanofiber dispersion liquid.
Fig. 3 is the buffer in ultra-pure water and ph=6.0 for the polypeptide nano material based on double pyrenes for preparing of embodiment 1
Transmission electron microscope picture after middle self assembly, from the figure 3, it may be seen that have ph response based on the polypeptide nano material of double pyrenes, in ph gradually
It is changed under acid condition, pattern can be changed into threadiness from nano-particle.
Embodiment 3
What embodiment 1 was prepared carries out the burnt test of cell copolymerization based on the polypeptide nano material of double pyrenes, investigates it right
The recruitment situation of medicine or preparation, method is as follows:
Prepare cell suspending liquid, each copolymerization Jiao culture dish 1ml, overnight incubation.Take out culture medium, add based on double pyrenes
Culture medium 1ml that 20 μm of polypeptide nano material concentration, overnight;Replace medicine with 20 μm of nile red (Nile red), culture 2 is little
When, cleaned with pbs 3 times, carry out co-focusing imaging experiment, using 405nm laser channeling, collect green light band 450-550nm, red
Optical band 550-700nm.
Result as shown in figure 4, cell ball is incubated altogether with material, Nile red, single photon confocal experiments, excite in 405nm
When, when gathering 450-550nm scope, in the green glow of double pyrenes;When gathering 550-700nm scope, the HONGGUANG in Nile red, that is,
There is fret (Fluorescence Resonance Energy transfer) it was demonstrated that material can be assembled in a large number in cell surface, effectively recruit Nile red fluorescence dye
Material.
Embodiment 4
The polypeptide nano material based on double pyrenes that investigation embodiment 1 prepares in this embodiment is in cancer cell surface
Conversion situation, method is as follows:
Prepare 1% agarose gel solution (0.1g agarose is dissolved in 10ml water), be heated to seething with excitement, be transferred quickly to surpass
Net platform, the every hole of 96 orifice plates adds 100 μ l agarose solutions.Then open ultra violet lamp 30min.Get out mcf-7 cell to hang
The every hole of supernatant liquid adds 2000 cells, every hole 200 μ l.Culture 7 days, takes out culture medium, and each hole adds the polypeptide based on double pyrenes
Nano material concentration is 20 μm of culture medium, and volume is 200 μ l, cultivates 24h.Take out cell ball, 20% glutaraldehyde solution (penta 2
Aldehyde: pbs buffer=1:4) solidification 2-3h, then the ethanol of 30%, 50%, 70%, 90%, 100% having been diluted with pbs successively
Solution dehydrates are processed, each concentration dehydration three times, 10 minutes every time.Then replace water outlet and ethanol with t-butanol solution, replace 3
Secondary, 10 minutes every time.Finally the cell mass handled well experiment is added drop-wise to silicon chip, is dried, scanning.
Result is as shown in Figure 5 it is seen that the polypeptide nano material based on double pyrenes for preparing of embodiment 1 is in cancer cell surfaces
There is converted in-situ, form fiber.
Embodiment 5
The polypeptide nano material based on double pyrenes that investigation embodiment 1 prepares in the present embodiment is in toy body
Imaging contexts, method is as follows:
Mouse subcutaneous injection about 106Individual mcf-7 cell, sets up mouse models for tumour growth.When mouse tumor length extremely
Diameter about 5.0mm about when, start for imaging experiment.First, intravenous injection 200 μ l medicine, concentration is 200 μm;8 hours
Afterwards, the nile red solution 200 μ l of 20 μm of intravenous injection, carries out small animal imaging experiment immediately, collects wave band 550-600nm.
Result is as shown in fig. 6, this chart is bright: after intravenous injection medicine, then injects Nile red, 4h can detect Nile red
Signal, shows that material can have the ability recruiting fluorescence molecule;After 96h, Nile red can also be detected at mouse tumor position
Signal, show material tumor locus can ultra-long time be detained, and can recruit fluorescence molecule for cancer detection.
Embodiment 6
In the present embodiment, the structure of the polypeptide nano material based on double pyrenes is as follows:
I.e. in formula iv provided by the present invention, r1Donor be klvff, r2Donor be six being made up of 6 histidine
Peptide, r3Donor be carboxy blocking Polyethylene Glycol, its molecular weight be 1000g mol-1.
The solid phase synthesis process of the described polypeptide nano material use based on double pyrenes polypeptide as described in example 1 above closes
Become.
Based on the polypeptide nano material of double pyrenes, mass spectral characteristi is carried out to the present embodiment synthesis, result is as shown in fig. 7, by this
Figure understands, the quasi-molecular ions appeared in figure meets the characteristic peak of the molecular weight of material molecule, and peak shape complies fully with peg polymerization
The characteristic peak of chain.
Embodiment 7
In the present embodiment embodiment 6 is prepared carries out self assembly based on the polypeptide nano material of double pyrenes, investigates
The self assembly ability of this material and ph response.
First, the self assembly ability of the polypeptide nano material based on double pyrenes for the test, by embodiment 6 prepare based on double
The polypeptide nano material of pyrene is dissolved in dmso, tests its fluorescence intensity, then adds water and carries out group assembling, often plus after a certain amount of water
Water is made to be sufficiently mixed with organic faciess, standing tests its fluorescence intensity in one minute afterwards, and test result is as shown in Figure 8.
As can be seen from Figure 8, the dmso solution to the polypeptide nano material based on double pyrenes adds h2During o, fluorescence increases
By force, show that material is changed into state of aggregation from single dispersing.
The ph response self-assembling method of the described polypeptide nano material based on double pyrenes is as follows:
Weigh Compound 5mg is dissolved in 10ml dmso solvent, and by this solution, with syringe, respectively fast injection arrives 90ml to surpassing
In pure water and in the buffer of ph=6.0, ultrasonic 30 minutes, stand two hours, respectively obtain fluorescent nano particle and Nanowire
Dimension dispersion liquid.
Fig. 9 is the buffer in ultra-pure water and ph=6.0 for the polypeptide nano material based on double pyrenes for preparing of embodiment 6
Transmission electron microscope picture after middle self assembly, as shown in Figure 9, has ph response based on the polypeptide nano material of double pyrenes, in ph gradually
It is changed under acid condition, pattern can be changed into threadiness from nano-particle.
Embodiment 8
What embodiment 6 was prepared carries out the burnt test of cell copolymerization based on the polypeptide nano material of double pyrenes, investigates it right
The recruitment situation of medicine or preparation, method is as follows:
Prepare cell suspending liquid, each copolymerization Jiao culture dish 1ml, overnight incubation.Take out culture medium, add based on double pyrenes
Culture medium 1ml that 20 μm of polypeptide nano material concentration, overnight;Replace medicine with 20 μm of nile red (Nile red), culture 2 is little
When, cleaned with pbs 3 times, carry out co-focusing imaging experiment, using 405nm laser channeling, collect green light band 450-550nm, red
Optical band 550-700nm.
As shown in Figure 10, cell ball is incubated altogether result with material, Nile red, single photon confocal experiments, excites in 405nm
When, when gathering 450-550nm scope, in the green glow of double pyrenes;When gathering 550-700nm scope, the HONGGUANG in Nile red, that is,
There is fret (Fluorescence Resonance Energy transfer) it was demonstrated that material can be assembled in a large number in cell surface, effectively recruit Nile red fluorescence dye
Material.
Embodiment 9
The polypeptide nano material based on double pyrenes that investigation embodiment 6 prepares in this embodiment is in cancer cell surface
Conversion situation, method is as follows:
The agarose gel solution (0.1g agarose is dissolved in 10ml water) of configuration 1%, is heated to seething with excitement, is transferred quickly to surpass
Net platform, the every hole of 96 orifice plates adds 100 μ l agarose solutions.Then open ultra violet lamp 30min.Get out mcf-7 cell to hang
The every hole of supernatant liquid adds 2000 cells, every hole 200 μ l.Culture 7 days, takes out culture medium, and each hole adds drug concentration to be 20 μm
Culture medium, volume is 200 μ l, cultivates 24h.Take out cell ball, 20% glutaraldehyde solution (glutaraldehyde: pbs buffer=1:4)
Solidification 2-3h, then the ethanol solution processed of 30%, 50%, 70%, 90%, 100% having been diluted with pbs successively, each
Concentration dehydration three times, 10 minutes every time.Then with t-butanol solution displacement water outlet and ethanol, displacement 3 times, 10 minutes every time.?
Afterwards the cell mass handled well experiment is added drop-wise to silicon chip, is dried, scanning.
Result is as shown in figure 11 it is seen that the polypeptide nano material based on double pyrenes for preparing of embodiment 6 is in cancerous cell table
There is converted in-situ in face, form fiber.
Embodiment 10
The polypeptide nano material based on double pyrenes that investigation embodiment 6 prepares in the present embodiment is in toy body
Imaging contexts, method is as follows:
Mouse subcutaneous injection about 106Individual mcf-7 cell, sets up mouse models for tumour growth.When mouse tumor length extremely
Diameter about 5.0mm about when, start for imaging experiment.First, intravenous injection 200 μ l medicine, concentration is 200 μm;8 hours
Afterwards, the nile red solution 200 μ l of 20 μm of intravenous injection, carries out small animal imaging experiment immediately, collects wave band 550-600nm.
As shown in figure 12, this chart is bright: after intravenous injection medicine, then injects Nile red, 4h can detect Buddhist nun sieve for result
Red signal, shows that material can have the ability recruiting fluorescence molecule;After 96h, Buddhist nun sieve can also be detected at mouse tumor position
Red signal, shows that material can ultra-long time be detained in tumor locus, and can recruit fluorescence molecule for the detection of cancer.
Applicant states, the present invention illustrates that by above-described embodiment the ph based on double pyrenes of the present invention responds self assembly
Polypeptide nano material and its preparation method and application, but the invention is not limited in above-described embodiment, that is, do not mean that the present invention
Have to rely on above-described embodiment could implement.Person of ordinary skill in the field it will be clearly understood that any improvement in the present invention,
The interpolation of the equivalence replacement to raw material selected by the present invention and auxiliary element, selection of concrete mode etc., all fall within the present invention's
Within the scope of protection domain and disclosure.
Claims (10)
1. a kind of polypeptide nano material based on double pyrenes is it is characterised in that described polypeptide nano material has as following formula i-iv institute
Show structure:
Wherein r1For having the peptide sequence of intramolecular multiple hydrogen bonding, r2For the peptide sequence of histidine composition, r3For hydrophilic
Polyglycol chain, r1、r2And r3Between be connected by amido link.
2. the polypeptide nano material based on double pyrenes according to claim 1 is it is characterised in that the described polypeptide based on double pyrenes
In nano material, the donor of double pyrene compound groups is double pyrene compounds with structure shown in formula v:
Preferably, r1For:
WhereinRepresent group connection site.
3. the polypeptide nano material based on double pyrenes according to claim 1 and 2 is it is characterised in that r2Donor be by 4-10
The polypeptide that individual histidine is constituted, the hexapeptide being preferably made up of 6 histidine.
4. the polypeptide nano material based on double pyrenes according to any one of claim 1-3 is it is characterised in that r3Donor
For the Polyethylene Glycol of carboxy blocking, its weight average molecular weight is 300-2000.
5. the preparation method of the polypeptide nano material based on double pyrenes according to any one of claim 1-4, its feature exists
In with resin as carrier, using pyrene compounds double shown in formula v and aminoacid as raw material, being prepared using solid phase synthesis process
The described polypeptide nano material based on double pyrenes.
6. the ph response self assembly side of the polypeptide nano material based on double pyrenes according to any one of claim 1-4
Method, the method comprising the steps of:
(1) the polypeptide nano material based on double pyrenes is dissolved in organic solvent, obtains polypeptide nano material solution;
(2) the polypeptide nano material solution that step (1) obtains is added in buffer solution, in the buffer of 1.0≤ph < 8.0
In, described polypeptide nano material self assembles are nanofiber;In the buffer of ph >=8.0, described polypeptide nano material is from group
Fill as nanosphere.
7. method according to claim 6 it is characterised in that the described organic solvent of step (1) be dmso, dmf or Isosorbide-5-Nitrae-
In dioxane any one or at least two combination, preferably dmso.
8. the method according to claim 6 or 7 is it is characterised in that the concentration of the described polypeptide nano material solution of step (1)
For 10-4-10-2m.
9. the method according to any one of claim 6-8 is it is characterised in that the described self assembly of step (2) is under ultrasonic
Carry out, the described ultrasonic time is 1-10min;
Preferably, step (2) described ultrasonic after 20-40 DEG C keep 0.5-12h.
10. the polypeptide nano material based on double pyrenes according to any one of claim 1-4 is in preparation cancer treatment drugs
And the application in bio-imaging agent.
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