CN110101684A - A kind of cellular membrane biomimetic nano particle and its preparation method and application of bio-orthogonal targeting - Google Patents
A kind of cellular membrane biomimetic nano particle and its preparation method and application of bio-orthogonal targeting Download PDFInfo
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- CN110101684A CN110101684A CN201910400977.5A CN201910400977A CN110101684A CN 110101684 A CN110101684 A CN 110101684A CN 201910400977 A CN201910400977 A CN 201910400977A CN 110101684 A CN110101684 A CN 110101684A
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- Medicinal Preparation (AREA)
Abstract
A kind of cellular membrane biomimetic nano particle of bio-orthogonal targeting, which is characterized in that it includes the nanometer core that high polymer and active constituent are constituted, and is wrapped in the cell membrane of nanometer core external；Basic metabolism object embedded with the functional group for having modified bio-orthogonal in the cell membrane.The basic metabolism object of the functional group with bio-orthogonal is modified with the basic metabolism object of the functional group of bio-orthogonal by being added in cell culture, and by metabolism, and the basic metabolism object for being modified with the functional group of bio-orthogonal is embedded in cell membrane.
Description
Technical field
The present invention provides a kind of cellular membrane biomimetic nanometers with bio-orthogonal targeting and tumor thermal therapy effect
The technology of preparing of grain (BINPs), core are to wrap up the friendship of polyglycolide third of indocyanine green (Indocyanine green, ICG)
Ester copolymer (Poly (lactic-co-glycolic acid), PLGA), surface cover chemistry report group (- N3/-BCN/-
Tz/- alkynyl etc.) functionalization cell membrane, and there is good optical imagery and tumor thermal therapy effect.Cell membrane surface
Covalent bond occurs for the pairing group of reporter group and tumor cell surface, effectively improves interior tumor cell to immunocyte
The targets identification and intake ability of film bionic nano particle, enhance BINPs to the photo-thermal therapy effect of tumour cell, and have day
The bioactive functions and good biocompatibility of right cell membrane.
Background technique
With riseing year by year for Incidence and the death rate, cancer has become the important threat of human health.Although
The means such as traditional operation, radiotherapy, chemotherapy and targeted therapy have tremendous development, but its toxic side effect is big, easy to recur, to patient
Survival state have no and significantly improve.Therefore, develop safe and effective antineoplaston mode to improve life in patients,
It is most important to cure tumour.Photo-thermal therapy (Photothermal Therapy, PTT) the oncotherapy plan outstanding as one
Slightly, have efficiently, Noninvasive, do not injure the characteristics of normal tissue, have in the research of oncotherapy well application before
Scape.
Photo-thermal therapy is that one kind is efficient, and the ideas of cancer therapy of Noninvasive, treatment principle utilizes photosensitizer
Photothermal conversion performance converts light energy into thermal energy under the irradiation of laser to kill tumour.However, the light that nano material mediates
Cumulant of the heat cure largely by Nano medication in tumor locus is influenced.In general, nano particle relies primarily on
The accumulation of the long retention effect of Thief zone (Enhanced permeability and retention effect, EPR) effect is swollen
Tumor position, this accumulation are limited, although the amount for improving drug can increase its enrichment in tumour, are improved and are treated
Effect, but a series of toxic side effect can many times be brought by improving dosage.Therefore, in the tumor thermal therapy of Nano medication
In the process, the targeted delivery and enhancing photo-thermal nano particle for how realizing Nano medication are in solution in the accumulation of tumor locus
State the key of problem.
In order to improve the bioavailability of nano particle, increases it in the enrichment of tumor locus, target is carried out to nano particle
It is an effective method to modification.Cellular membrane biomimetic nano particle is by wrapping up natural cell membrane to nano particle table
Face imparts the biological property of nano particle Yu derived cell identity function.Biological cell as a kind of functional activity cell,
It can be by the specific receptor tumor cell above cell membrane, however, the immunologic escape of tumour significantly reduces cell
Immune identification action needs to add thus the identification and interaction of additional artificial targeting enhancing cells against tumor.Biology is just
Hand over targeting as one kind can in vivo carry out efficient, special chemical reaction, can be used for tumour imaging label with
Target administration.Based on the above reasons, the present invention devises a kind of cellular membrane biomimetic nano particle of bio-orthogonal targeting, particle
Core is to contain the PLGA nanometer core of ICG, and outside coats the cell membrane of bio-orthogonal reporter group, this to have artificial bio-membrane
Orthogonal targeting passes through the immune identification action of bio-orthogonal reaction and cell membrane with the bionic nano particle of cell membrane characteristics, realizes
To the efficiently concentrating of tumour, enhance photo-thermal therapy effect.
The fast development of nanotechnology is so that the targeted therapy and in-vivo diagnostic of tumour have the development of a leap.Nanometer
The stability of drug can be improved as pharmaceutical carrier in material, reduces the toxic side effect of drug, makes drug/photosensitizer in tumour
Position accurately discharges or achievees the effect that sustained release and control release, overcomes conventional medicament bioavilability low, adverse reaction is tight
The disadvantages of weight.The excellent characteristics such as nano particle is preferable nanometer medicine-carried system, has carrying drug ratio high, and surface is easily modified, make
Extensive research and application have been obtained for the emerging strategy of tumor thermal therapy.Number of the nano particle in tumor locus cumulant
Directly related with the photo-thermal therapy effect of tumour, conventional nano particle can accumulate in tumor locus by the passive target of EPR, but
It is to be limited by drug of the EPR effect accumulation in tumour, will limit the treatment effect of anti-tumor drug to a certain extent
Fruit, while increasing drug dose and can bring serious biosafety issues to patient.It is tired in tumour in order to improve drug
Product, the usually ligand molecular in nano grain surface modification active targeting, such as antibody, polypeptide, aptamers etc. pass through ligand-
The connection of receptor realizes that anti-tumor drug in the highly enriched of tumor locus, reduces toxic side effect.By in nano grain surface
Modification targeting group etc. is accumulated to increase particle in the targeting of tumour, and having developed for this technology is more mature.However, this
Kind not only increases the complexity of preparation process to the functional modification of nano particle, while can also give the biology of nano particle
Medical application brings potential uncontrollable factor, it is difficult to popularization and promotion.
In recent years, cellular membrane biomimetic nano particle has obtained the extensive pass of scientists as a kind of cancer target strategy
Note, this nano particle make nano particle not only contain size by the way that natural cell membrane is coated to nano grain surface
Size can remain the complicated ingredient of cell membrane surface with the nanometer core of function point analysis.Cell membrane nano particle is as one
Kind of bionic nano particle, can replicate the sophisticated functions of n cell, the long circulating function including red blood cell, cancer cell it is homologous
Target function, the inflammation targeted function of macrophage can make to receive by the way that natural cell membrane is coated to nano grain surface
Rice grain has the similar biological property of n cell.However, being caused due to the antigenic mutation and immunologic escape of tumour cell
Stating heterologous cells film bionic nano particle, there are targets identification effect deficiencies, or there are potential biosafety issues.For
These technical bottlenecks are now badly in need of developing a kind of natural, safe and effective tumour nano target treatment technology, cell are overcome to control
" undershooting-effect " during treatment improves the photo-thermal therapy effect of tumour.
Summary of the invention
The present invention reports a kind of cellular membrane biomimetic nano particle of bio-orthogonal targeting, which is characterized in that it includes high
The nanometer core that polymers and active constituent are constituted, and be wrapped in the cell membrane of nanometer core external；
Basic metabolism object embedded with the functional group for having modified bio-orthogonal in the cell membrane；
In the basic metabolism object of the functional group for having modified bio-orthogonal, the functional group of bio-orthogonal is nitrine
Base, alkynyl, octynyl, diphenyl cyclooctyne base, tetrazine base, dibenzo cyclooctyne (DBCO), dibenzocyclooctadiene (DIBO), two
It is fluorinated cyclooctyne (DIFO), double aryl cyclohexanone (BARAC) or BCN ((1R, 8S, 9r)-bicyclic [6.1.0] nonyl- 4- alkynyl -9-
Base methanol)；The basic metabolism object is amino acid, protein, sugar or lipid；The functional group and base of the bio-orthogonal
Plinth metabolin is coupled by chemical bond.Preferably, the sugar is monosaccharide or monosaccharide derivatives；The lipid be choline or
Choline derivative.
In the inventive solutions, the monosaccharide derivatives include mannosamine hydrochloride, glucosamine HCL
Or galactosamine hydrochloride, four acetyl mannose (Ac4Man), four acetyl galactose (Ac4Gal), acetylsalicylic acid (Neu5Ac),
Four acetyl glucosamine (Ac4Glc)；
In the inventive solutions, the monosaccharide be selected from mannose, glucose, galactolipin, deoxyribose, fructose,
Ribose, xylose, arabinose.
In the inventive solutions, the cholinomimetic includes dimethylethanolamine.
In the inventive solutions, the amino acid derivativges be selected from glycine, alanine, valine, leucine,
Isoleucine, phenylalanine, proline, tryptophan, serine, tyrosine, cysteine, methionine, asparagine, glutamy
Amine, threonine, aspartic acid, glutamic acid, lysine, arginine and histidine.
In the inventive solutions, the basic metabolism object of the functional group for being modified with bio-orthogonal is selected from tetrem
Acyl group-N- n-heptylacetylene-acetylmannosamine Ac4ManNBCN, tetra-acetylated-N- nitrine acetylmannosamine Ac4ManNAz,
Ac4ManNAz, Neu5AcBCN, tetra-acetylated-N- alkynyl-acetylgalactosamine Ac4GalNAl, tetra-acetylated-N- alkynyl-second
Acyl mannosamine Ac4ManNAl, azidoethyl choline AE-Cho, nitrine propyl choline AP-Cho, alkynyl cholesterol Alkyne
Cholesterol, nitrine phenylalanine Az-Phe, nitrine methionine AHA, alkynes alanine HPG, tetra-acetylated-N- nitrine
Acetylgalactosamine Ac4GalNAz, tetra-acetylated-N- nitrine acetylglucosamine Ac4GlcNAz, Neu5AcBCN n-heptylacetylene-N- second
Acyl neuraminic acid.
The basic metabolism object of the functional group with bio-orthogonal is modified with biology by being added in cell culture
The basic metabolism object of orthogonal functional group, and by metabolism, and the basis of the functional group of bio-orthogonal will be modified with
Metabolin is embedded in cell membrane；
The cell membrane is the cell membrane of normal cell；The normal cell is preferably T cell, tumour cell, red blood cell.
In the inventive solutions, constitute nanometer core high polymer be Vicryl Rapide, calcium phosphate,
Mesoporous silicon.
In the inventive solutions, the active constituent refers to the medicative compound of tool, specifically includes
There are drug, the enhancing photosensitizer, detection reagent, anti-tumor drug of chemotherapeutic activity, albumen；Preferably, the enhancing photosensitizer choosing
From ICG or Ce6.
Another aspect of the invention provides the preparation method of the cellular membrane biomimetic nano particle of bio-orthogonal targeting comprising
Following steps:
1) preparation is modified with the basic metabolism object of the functional group of bio-orthogonal；
2) natural activity cell and the basic metabolism object for the functional group for being modified with bio-orthogonal are incubated for altogether, until obtaining thin
Cellular surface is embedded in the modification living cells of the functional group with bio-orthogonal；
3) cell membrane that cell surface is embedded in the modification of the functional group with bio-orthogonal is obtained by physical method；
And Cell membrane vesicles are obtained by physical impact；
4) the nanometer core for containing active constituent is prepared using high molecular polymer as carrier；
5) by step 3) Cell membrane vesicles be wrapped in step 4) obtain nanometer core surfaces, obtain bio-orthogonal target
To cellular membrane biomimetic nano particle.
In the inventive solutions, normal cell is subjected to culture in step 2) and is added after the activation that stimulates proliferation
It is incubated for altogether with the basic metabolism object for the functional group for being modified with bio-orthogonal, is modified with the basic generation of the functional group of bio-orthogonal
Thanking to object concentration is 2-100 μM.
In the inventive solutions, the method that cell membrane is obtained in step 3) is that centrifugation obtains cell precipitation, then
It is cracked the hypotonic lysis liquid containing protease inhibitors is wherein added, sonicated cells, obtains cell membrane.
In the inventive solutions, also include purifying cells film the step of, is obtained after cell membrane in step 3), it is described
The method that purifying cells film step passes through differential centrifugation, it is preferable that first to take supernatant after 3200 × g centrifugation；Supernatant, then with 1-
20000 × g high speed centrifugation, takes supernatant；Supernatant takes precipitating to get arriving finally with 50000-200000 × g high speed centrifugation
The cell membrane of purifying.
In the inventive solutions, the method squeezed in step 3) is the polycarbonate that cell membrane is passed through 220nm
Film squeezes, or is squeezed after cell membrane is mixed with phosphatide or phospholipid derivative by the polycarbonate membrane of 220nm, obtains cell membrane
Vesica.
In the inventive solutions, the phospholipid derivative is distearoylphosphatidylethanolamine-polyethylene glycol, two
Stearyl phosphatidyl ethanol amine.
In the inventive solutions, step 5) is the poly- carbonic acid that Cell membrane vesicles and nanometer core are passed through to 220nm
Ester film squeezes, and obtains the cellular membrane biomimetic nano particle of bio-orthogonal targeting.
In the inventive solutions, step 4) is that macromolecule polymer solution is added gradually to active ingredient solution
In, form nanometer core granule.
The cellular membrane biomimetic nano particle that another aspect of the present invention provides bio-orthogonal targeting treats tumour in preparation
Drug in purposes.
The cellular membrane biomimetic nano particle of another aspect offer bio-orthogonal targeting of the present invention is preparing photo-thermal therapy
Purposes in reagent.
The cellular membrane biomimetic nano particle of another aspect offer bio-orthogonal targeting of the present invention is preparing cancer target
Purposes in detection reagent.
In the present invention, " basic metabolism object " is that can be digested, be absorbed in vivo, operated, decomposed etc. and life
The substance for managing related chemical process, without limitation to the type of basic metabolism substance, the substance that all organisms can be metabolized
It can be used as basic metabolism object.
In the present invention, " bio-orthogonal " refers to biology itself can not interfered biochemical in active somatic cell or tissue
The chemical reaction that can be carried out under reaction condition.
This bionic nano particle with the orthogonal targeting of artificial bio-membrane passes through the immune of bio-orthogonal reaction and cell membrane
Recognition reaction promotes tumour cell sticking and be enriched with to nano particle, enhances the photo-thermal therapy effect of photosensitizer ICG.
The invention discloses a kind of natural fine after birth bionic nanos with bio-orthogonal targeting and photo-thermal therapy effect
Grain technology of preparing.The technology is embedded in bio-orthogonal reporter group (- N by cell glucose metabolism in living cells film3/-BCN/-
Tz/- alkynyl etc.), the n cell membrane structure of chemistry report base group modification is obtained, and to wrap up indocyanine green (Indocyanine
Green, ICG) poly (glycolide-co-lactide) copolymer (Poly (lactic-co-glycolic acid), PLGA) be granular core
The heart covers chemistry report group (- N on its surface3/-BCN/-Tz/- alkynyl etc.) functionalization cell membrane, prepare artificial bio-membrane
The cellular membrane biomimetic nano particle of orthogonal targeting.Utilize the immune knowledge of efficient, special bio-orthogonal targeting and cell membrane itself
It does not act on, the targeting absorption and accumulation of the tumour cell that enhancing natural fine after birth bionic nano particle modifies complementation group, into
And realize safe and efficient tumor thermal therapy effect (principle such as Fig. 1).The present invention provides one kind to have bio-orthogonal targeting
With the technology of preparing of the natural fine after birth bionic nano particle (BINPs) of tumor thermal therapy effect, core is package indoles
Poly (glycolide-co-lactide) copolymer (Poly (the lactic-co- of the photosensitizers such as cyanines green (Indocyanine green, ICG)
Glycolic acid), PLGA), surface covers bio-orthogonal reporter group (- N3/-BCN/-Tz etc.) functionalization n cell
Film, and there is good optical imagery and tumor thermal therapy effect.The reporter group and tumor cell surface of cell membrane surface
Pairing group covalent bond occurs, effectively improve interior tumor cell to the targets identification of cellular membrane biomimetic nano particle with
Intake ability, enhancing BINPs to the photo-thermal therapy effect of tumour cell, and have the function of the Immune discrimination of n cell with well
Biocompatibility.
The metabolic derivative of the natural activity cell membrane marker, it is characterized in that a kind of carrying chemistry report group (-
N3/-BCN/-Tz/- alkynyl etc.) the functional group for being modified with bio-orthogonal basic metabolism object.It will be chemical using chemical synthesis
Reporter group is introduced into the metabolites such as monosaccharide, lipid and amino acid, formed can carry out cell metabolism be modified with biology just
The basic metabolism object of the functional group of friendship.Competent cell can be by cell metabolism engineering by the above-mentioned function of being modified with bio-orthogonal
In the basic metabolism object insertion cell membrane of group, the natural fine after birth that the functional group modification of bio-orthogonal is capable of on surface is obtained.
The PLGA nanometer core that ICG or Ce6 is contained using ultrasonic method synthesis, the natural fine after birth that above-mentioned chemistry report group marks is led to
Physical impact method package is crossed to nanometer core surfaces, obtains the natural fine after birth nano particle BINPs of chemistry report base group modification.
BINPs nano particle can target the immune identification action with itself by bio-orthogonal, promote nano particle thin in tumor target
Enrichment in born of the same parents, thus photo-thermal therapy effect of the enhancing to tumour.
The basic metabolism object for being modified with the functional group of bio-orthogonal specifically includes that the function of being wherein modified with bio-orthogonal
Group monosaccharide analog derivative has Ac4ManNBCN、Ac4GalNAz、Ac4ManNAz、Neu5AcBCN、Ac4GalNAl、Ac4ManNAl
Deng；The functional group lipid derivant for being modified with bio-orthogonal has AE-Cho, AP-Cho, Alkyne Cholesterol etc.；It repairs
The functional group amino acid derivativges for being decorated with bio-orthogonal have Az-Phe, AHA, HPG etc., their structural formula is as follows.
Main sugar/rouge/amino acid metabolism derivant structure formula
The present invention also provides a kind of targetings of external photo-thermal killing tumor cell of natural fine after birth photo-thermal nano particle to control
Treatment technology.The technology passes through-N3,-BCN, the bio-orthogonal coupling reaction between the chemical groups such as-Tz and-alkynyl, by chemistry report
The complementation group of group metabolism modification to cell bionic nano particle surface and the tumor cell surface after metabolism modification occurs high
Effect, special bio-orthogonal reaction improve ICG, Ce6 nanometers to enhance absorption and intake of the tumour target cell to nano particle
Photo-thermal therapy effect of the particle to tumour cell.It is characterized in that the described method comprises the following steps:
(1) the cellular membrane biomimetic nano particle (BINPs) of bio-orthogonal targeting is prepared: natural activity cell is by chemical base
Sugar/rouge/amino acid derivatives of group's modification are incubated for 48h altogether, will be upper by n cell sugar, rouge and amino acid metabolism engineering
Chemistry report group insertion n cell film surface is stated, is modified reporter group using the method for ultrasonication and physical impact
Natural fine after birth is wrapped in PLGA-ICG/Ce6 core surfaces, is prepared into the cellular membrane biomimetic nano particle of bio-orthogonal targeting；
(2) tumour cell/tissue chemical group is modified: by the metabolism of the base group modifications such as-BCN/-Tz/-DBCO/- alkynyl
Analog derivative handles tumour cell (being incubated for 48h altogether), and by cell glucose metabolism engineering, above-mentioned reporter group is embedded in tumour cell
Surface, to obtain the tumour cell of chemical group modification；
(3) the BINPs particle photo-thermal therapy of the orthogonal targeting of external biological: in vitro in photo-thermal therapy model, chemical group
The tumour target cell of (- BCN/-Tz/-DBCO etc.) modification and BINPs nano particle are incubated for 45min altogether, are targeted by bio-orthogonal
With the immune identification action of natural fine after birth itself, tumour cell is promoted to adsorb and absorb nano particle.Cell is by different
After wave band of laser treatment with irradiation, significantly increased using the photo-thermal effect of the photosensitizer (ICG/Ce6 etc.) of accumulation to tumour cell
Lethal effect.
Beneficial effect
(1) by the immune identification action of artificial bio-membrane's orthogonal targeting and natural fine after birth itself, chemistry report base is carried
The cell membrane nano particle of group can form covalent bond with tumor cell membrane surface complementarity pairing group rapidly, thus effectively
Nano particle is improved in the targeting of tumor locus and richness product.
(2) during can effectively overcoming photo-thermal therapy using the orthogonal targeting technology of this efficient, special vivo biodistribution
Tumour miss target phenomenon and immunologic escape, improve photo-thermal curative effect.
(3) metabolism modification is carried out to cell by cell metabolism engineering, high effect nontoxic can avoid direct chemical coupling to thin
The influence of cellular surface bioactive molecule, the immunologic function activity of effective protection natural fine after birth.
Detailed description of the invention
Fig. 1 is the preparation principle of the cell bionic nano particle of bio-orthogonal targeting.
Fig. 2 is confocal fluorescent imaging and flow cytometry Ac4Metabolic marker of the GalNAz sugar derivatives to T cell.
Fig. 3 is transmission electricity and dynamic scattering analysis N3The pattern and particle diameter distribution of-TINPs nano particle.
Fig. 4 is functional protein and the change of PAGE gel electrophoresis and Western blot analysis T cell film nano particle
Learn the integrality of group.Wherein, I is T cell lysate；II is T cell membrane vesicle；III is N3-TINPs；IV is TINPs.
Fig. 5 is that confocal fluorescent is imaged from flow cytometry Raji cell to the target of free ICG and different nano particles
It is evaluated to intake situation.
Fig. 6 is the T cell film bionic nano particle (N of bio-orthogonal targeting3- TINPs) to the photo-thermal of Raji tumour cell
Treatment evaluation.
Fig. 7 is T cell film bionic nano particle (N3- TINPs) in the intracorporal tumor-targeting of mouse and bio distribution.
Specific embodiment
This technology invention is described further with example below, but does not limit the contents of the present invention
Example 1: the rouge of chemistry report base group modification/amino acid/carbohydrate derivative synthesis
The synthesis of lipid derivant: referring especially to document Analytical Chemistry 2,013 85 (10), 5263-
Method synthesis disclosed in 5270.Specifically the preparation method is as follows: a certain amount of glycol dibromide and sodium azide are dissolved
In DMF, 80 DEG C are reacted 20 hours, and ice water and sodium chloride solution are added after reaction, intermediate 2 '-bromine nitrine second is obtained by extraction
Alkane.The 2 ' of acquisition-bromine nitrine ethane are dissolved in tetrahydrofuran, argon gas protection is lower to be added dimethyl methyl hydramine, anti-at 0 DEG C
6h is answered, is precipitated to obtain target product azidoethyl choline AE-Cho with ether.The synthetic route of choline derivative as follows.Its
Azido group can be modified into the membranous system of cell by cell lipid metabolism after middle cholinomimetic acetylation.
The synthetic route of choline derivative
Amino acid/carbohydrate derivative synthesis: using Boc-homoserine, Neu5Ac molecule as raw material, by a series of
Chemical reaction, prepares carry-N respectively3Or amino acid, the carbohydate metabolism modifier of-BCN point chemical group:
Azidohomoalanine (AHA) and Neu5Ac-N3, Neu5Ac-BCN (amino acid metabolism modifier as follows
Azidohomoalanine (AHA) synthetic line and monosaccharide metabolic modifiers N3/ BCN-Sugar synthetic line).Wherein nitrine
Bio-orthogonal reaction occurs for the fluorescent marker that group can be modified with alkynyl compounds, and-BCN can be with nitrine/tetrazine (- N3/-Tz)
The fluorescent marker hair click chemistry reaction of modification.The amino acid of synthesis, carbohydate metabolism modifier are subjected to nuclear-magnetism, mass spectrum simultaneously
Identification and characterization.
Amino acid metabolism modifier Azidohomoalanine (AHA) synthetic line
Monosaccharide metabolic modifiers N3/ BCN-Sugar synthetic line
Example 2: the preparation of azide functionalities group metabolic marker T cell
Source of people T cell (1 × 10 obtained will be expanded7It is a) it is incubated at containing interleukin-22 (interleukin-2, IL-
2) and in the AIM-V culture medium of 2% fetal calf serum (FBS), CD3/CD28 antibody magnetic bead, which is added, stimulates T cell Proliferative Activated,
The carbohydrate derivative Ac that nitrine is modified is added after co-culturing 72h4GalNAz (50 μM), then washed carefully after incubation 48h with PBS altogether
Born of the same parents 2 times, i.e. acquisition nitrine (- N3) functional group label activating T cell (N3- T cell), and use streaming and co-focusing imaging
It is analyzed and identified, as shown in Fig. 2, Ac4488 fluorescence signal of Fluor of GalNAz sugar-modified T cell surface display green,
Without being nearly no detectable fluorescence signal by sugar-modified T cell surface；Equally, flow cytometric analysis results are shown
Ac4GalNAz sugar-modified T cell detects more fluorescence signals, consistent with the result of co-focusing imaging.These results card
It is bright ,-N3The surface of T cell has been arrived by successful modification.
Example 3: the T cell film bionic nano particle (N of bio-orthogonal targeting3- TINPs) synthesis
2 × 10 are taken respectively7A N31000 turns of centrifugation 4min of T cell and T cell, are added hypotonic in obtained cell precipitation
Lysate (contains protease inhibitors), is placed in and cracks on ice, subsequent further sonicated cells.For the cell purified
Film, we use differential centrifugation: first under the conditions of 4 DEG C, taking supernatant after 3200 × g is centrifuged 5min；Supernatant, then with 1-
20000 × g high speed centrifugation 20min (4 DEG C), takes supernatant.Supernatant, finally with 50000-200000 × g high speed centrifugation 50min
(4 DEG C) take precipitating to get the N of purifying is arrived3T cell film and T cell film.Respectively by N3Add after T cell film, the dissolution of T cell film
Enter the distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG of 90 μ g2000), it is squeezed by the polycarbonate membrane of 220nm
10 times or so, obtain N3T cell membrane vesicle, T cell membrane vesicle.
The ICG of 1mg is taken to be dissolved in 4% ethanol solution, using VCX130 Ultrasonic Cell Disruptor ultrasound 5min, during which dropwise
The PLGA acetonitrile solution (4mg/mL) of 0.5mL is added, obtains the PLGA nanometer core (ICG-PLGA) comprising ICG.By previous step
Obtained N3T cell membrane vesicle mixed with ICG-PLGA nanometers of cores (10:1, mass ratio, i.e. cell membrane with respect to nanometer core and
Speech is excessive), it is squeezed 10 times with the polycarbonate membrane of 220nm, obtains-the N for containing ICG3The T cell film bionic nano particle of modification
(N3- TINPs), to remove free drug and organic solvent, by obtained particle in the super filter tube of 100kDa centrifugal ultrafiltration.
The T cell film bionic nano particle (TINPs) for containing ICG is made in the same way；Equally, cell is substituted with soybean lecithin
Membrane vesicle preparation includes the phospholipid polyalcohol nano particle (INPs) of ICG.
We are characterized and have been identified to nano particle, as shown in figure 3, N3- TINPs transmission electron microscope picture shows typical case
Nucleocapsid structure, dynamic light scattering testing result surface partial size shows N between 50-60nm3The T cell film success of functionalization
Package to ICG-PLGA nanometers of core surfaces, meet Electronic Speculum result.Meanwhile SDS-PAGE the result shows that, N3- TINPs and
The protein graphical spectrum of TINPs has similar with T cell lysate and cell membrane；And Western blot is as the result is shown in N3- TINPs and
A large amount of TCR, N can be detected in TINPs3A large amount of-N also can be detected in-TINPs3Group (Fig. 4), these results prove cell membrane
The successful preparation of nano particle, N3- TINPs can use the memebrane protein and-N of preservation3Group realize T cell Immune discrimination and
Bio-orthogonal targeting.
Example 4: bio-orthogonal reaction enhances tumour cell to T cell film bionic nano particle (N3- TINPs) it targets and takes the photograph
It takes
By 1 × 105The Raji cell kind of the BCN modification of a culture keeps it slightly adherent into 8 well culture plates, will be above-mentioned
BCN-Raji cell respectively with ICG, INPs, TINPs, N3- TINPs (ICG concentration is 20 μ g/mL) is incubated under the conditions of 4 DEG C
45min is washed three times with PBS.15min then is fixed with 4% paraformaldehyde, nucleus is contaminated with Hoechst 33258
Color, and the intake situation with flow cytometry Raji cell to variable grain is imaged with confocal fluorescent.
As shown in Figure 5A, N3The Raji cell of-TINPs particle disposal shows bright ICG red fluorescence, hence it is evident that is better than
The Raji cell of free ICG, INPs or TINPs processing.Flow cytometry shows compared with other particle groups, N3-TINPs
The Raji cell of incubation can detect stronger fluorescence signal and more positive cell numbers (Fig. 5 B-C), with co-focusing imaging knot
Fruit is consistent.The above results prove that Raji cell is to N3The intake of-TINPs is more, this is because N3- TINPs has double targetings
Ability, i.e. the Immune discrimination targeting of T cell film and bio-orthogonal target ability, enable it to preferably by Raji cellular uptake.
Example 5:T cellular membrane biomimetic nano particle (N3- TINPs) tumour cell photo-thermal is killed and is studied
By 105In a BCN-Raji cell inoculation to 96 orifice plates, respectively by concentration be 0-50 μ g/mL ICG, INPs,
TINPs、N3- TINPs is added in cell and is incubated for 45min.With the laser irradiation Raji cell 5min (0.8W/cm of 808nm2), then
With the survival rate of CCK-8 detection Raji cell, records data and calculate the versus cell survival rate in each hole.Meanwhile in 50 μ g/mL
ICG concentration under, the Raji cell after illumination is subjected to live/dead cell with calcein/propidium iodide (Calcein-AM/PI)
Dyeing, then carries out imaging analysis to the Raji cell after dyeing with fluorescence inverted microscope.
Such as Fig. 6 A, when ICG concentration is 50 μ g/mL, the survival for the ICG group and INPs group Raji cell of dissociating after laser irradiation
Rate is respectively 62% and 53%, and TINPs and N3The survival rate that-TINPs organizes Raji cell is lower than 20%, especially N3-TINPs
The survival rate of group Raji cell is minimum.Meanwhile calcein/propidium iodide (Calcein-AM/PI) cell dyeing the results show that
N3There is a large amount of red fluorescence in the Raji cell of-TINPs group, shows the mortality of Raji cell (Fig. 6 B).
Example 6:T cellular membrane biomimetic nano particle (N3- TINPs) in-vivo tumour targeting Journal of Sex Research
When the gross tumor volume of NOD/SCID tumor-bearing mice reaches 100-200mm3When, mouse is divided into three groups, it is quiet by tail
INPs, TINPs, the N for injecting 150 μ L respectively is administered in arteries and veins3- TINPs (ICG concentration is 400 μ g/mL) injects N3- TINPs's is small
Mouse shifts to an earlier date intratumor injection Ac4ManN-BCN makes mouse tumor mark BCN group.It is small to being administered with small animal living body imaging system
Mouse carries out fluorescence imaging, and the excitation wavelength of ICG is 710nm, launch wavelength 800nm.After handling 48h, by its major organs
(heart, liver, spleen, lung, kidney) and tumour are taken out, and carry out fluorescence imaging with small animal living body imaging system.By the major organs of taking-up
It being homogenized in the dimethyl sulfoxide (DMSO) of 6mL with tumor tissues, 9000rpm is centrifuged the ICG in 15min extraction tissue,
The content of ICG is measured by Fluorescence Spectrometer.
By Fig. 7 A as it can be seen that the mouse tumor position ICG fluorescence of INPs administration group is weaker, TINPs group after administration 48 hours
There is stronger ICG fluorescence in mouse tumor, however, N3The mouse tumor position of-TINPs administration group shows that strongest ICG is glimmering
Light wants high more than other two groups, this is attributed to N3The T cell film Immune discrimination targeting of-TINPs and bio-orthogonal target dual
Targeting ability.In addition, the major organs (heart, liver, spleen, lung, kidney) and tumor tissues of mouse to be carried out to fluorescence imaging (figure afterwards in vitro
7B), as a result, it has been found that, N3The tumour ICG fluorescence of-TINPs group is most strong, hence it is evident that is higher than INPs group and TINP group, ICG is in the tired of tumour
Product highest.Meanwhile the bio distribution of internal ICG is the results show that N3The content of ICG is obvious in the mouse tumor of-TINPs administration group
Higher than other two groups, about doubles (Fig. 7 C) than INPs group and TINPs group, show N3- TINPs has outstanding swell in vivo
Tumor targets ability.
Claims (10)
1. a kind of cellular membrane biomimetic nano particle of bio-orthogonal targeting, which is characterized in that it includes high polymer and active constituent
The nanometer core of composition, and be wrapped in the cell membrane of nanometer core external；
Basic metabolism object embedded with the functional group for having modified bio-orthogonal in the cell membrane；
In the basic metabolism object of the functional group for having modified bio-orthogonal, the functional group of bio-orthogonal is azido, alkynes
Base, octynyl, diphenyl cyclooctyne base, tetrazine base, DBCO, DIBO, bifluoride cyclooctyne (DIFO), BARAC
(biarylazacyclooctynone) or BCN ((1R, 8S, 9r)-bicyclic [6.1.0] nonyl- 4- alkynyl -9- base methanol)；It is described
Basic metabolism object be amino acid, protein, sugar or lipid；The functional group and basic metabolism object of the bio-orthogonal pass through
Chemical bond coupling；
Preferably, the cell membrane is the cell membrane of normal cell.
2. the cellular membrane biomimetic nano particle of bio-orthogonal targeting according to claim 1, the sugar are monosaccharide or list
Sugar derivatives；The lipid is choline or choline derivative；
Preferably, the monosaccharide derivatives include mannosamine hydrochloride, glucosamine HCL or galactosamine hydrochloride, four
Acetylated mannan sugar (Ac4Man), four acetyl galactose (Ac4Gal), acetylsalicylic acid (Neu5Ac), four acetyl glucosamines
(Ac4Glc)；
The monosaccharide is selected from mannose, glucose, galactolipin, deoxyribose, fructose, ribose, xylose, arabinose；
The cholinomimetic includes dimethylethanolamine；
The amino acid derivativges be selected from glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline,
Tryptophan, serine, tyrosine, cysteine, methionine, asparagine, glutamine, threonine, aspartic acid, paddy ammonia
Acid, lysine, arginine and histidine；
It is highly preferred that the basic metabolism object of the functional group for being modified with bio-orthogonal is selected from Ac4ManNBCN、Ac4GalNAz、
Ac4ManNAz、Neu5AcBCN、Ac4GalNAl、Ac4GalNAz、Ac4ManNAl、AE-Cho、AP-Cho、Alkyne
Cholesterol、Az-Phe、AHA、HPG。
3. the cellular membrane biomimetic nano particle of bio-orthogonal targeting according to claim 1 or claim 2, has the function of bio-orthogonal
The basic metabolism object of group is modified with the basic metabolism object of the functional group of bio-orthogonal by being added in cell culture, and leads to
Metabolism is crossed, and the basic metabolism object for being modified with the functional group of bio-orthogonal is embedded in cell membrane.
4. the cellular membrane biomimetic nano particle of any one of -3 bio-orthogonal targetings according to claim 1, constitutes nanometer core
High polymer be Vicryl Rapide.
5. the cellular membrane biomimetic nano particle of any one of -4 bio-orthogonals targetings according to claim 1, the activity at
Divide and refer to have medicative compound, specifically includes the drug with chemotherapeutic activity, enhancing photosensitizer, detection reagent, resists and swell
Tumor medicine；Preferably, the enhancing photosensitizer is selected from ICG or Ce6.
6. the preparation method of the cellular membrane biomimetic nano particle of bio-orthogonal targeting according to claim 1-5,
Itself the following steps are included:
1) preparation is modified with the basic metabolism object of the functional group of bio-orthogonal；
2) natural activity cell and the basic metabolism object for the functional group for being modified with bio-orthogonal are incubated for altogether, until obtaining cell table
Face is embedded in the modification living cells of the functional group with bio-orthogonal；
3) cell membrane that cell surface is embedded in the modification of the functional group with bio-orthogonal is obtained by physical method；And lead to
It crosses physical impact and obtains Cell membrane vesicles；
4) the nanometer core for containing active constituent is prepared using high molecular polymer as carrier；
5) by step 3) Cell membrane vesicles be wrapped in step 4) obtain nanometer core surfaces, obtain bio-orthogonal targeting
Cellular membrane biomimetic nano particle.
7. preparation method according to claim 6, wherein the method for obtaining cell membrane in step 3) is that centrifugation obtains cell
Then precipitating is cracked the hypotonic lysis liquid containing protease inhibitors is wherein added, sonicated cells, cell is obtained
Film.
8. preparation method according to claim 6 or 7, wherein also comprising purifying cells after acquisition cell membrane in step 3)
The step of film, the method that the purifying cells film step passes through differential centrifugation, it is preferable that first to take supernatant after 3200 × g centrifugation；
Supernatant, then with 1-20000 × g high speed centrifugation, take supernatant；Supernatant, finally with 50000-200000 × g high speed centrifugation,
Precipitating is taken to get the cell membrane of purifying is arrived.
9. according to the described in any item preparation methods of claim 6-8, wherein the method squeezed in step 3) is to lead to cell membrane
The polycarbonate membrane for crossing 220nm squeezes, or passes through the polycarbonate of 220nm after cell membrane is mixed with phosphatide or phospholipid derivative
Film squeezes, and obtains Cell membrane vesicles；
Preferably, the phospholipid derivative is distearoylphosphatidylethanolamine-polyethylene glycol, distearoylphosphatidyl ethyl alcohol
Amine.
10. the cellular membrane biomimetic nano particle of bio-orthogonal targeting according to claim 1-5 is treated in preparation
Purposes in the drug of tumour, photo-thermal therapy reagent or cancer target detection reagent.
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