CN104815341A - Targeted polymer micelle magnetic nanoparticle, and preparation method and application thereof - Google Patents
Targeted polymer micelle magnetic nanoparticle, and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a polymer micelle magnetic nanoparticle having a selective specific targeting function on pancreas cancer. A preparation method of the polymer micelle magnetic nanoparticle comprises the following steps: carrying out an amide reaction on a carboxyl group on a CKAAKN polypeptide and an amino group on the carboxyl group on polyethylene glycol-polylactic acid-glycolic acid, coupling the CKAAKN polypeptide to prepare a CKAAKN-PEG-PLGA graft product, and carrying out an aqueous solvent diffusion technology with a Fe3O4 magnetic nanoparticle as a targeting marker material to prepare the polymer micelle magnetic nanoparticle. The preparation method has the advantages of reasonable design, convenient operation and low cost. The polymer micelle magnetic nanoparticle provided by the invention has high magnetic Fe3O4 nanoparticle wrapping ability, has the advantages of good stability and dispersibility, small particle size and uniform dispersion, can enhance the targeted uptake ability of the pancreas cancer to improve the uptake rate, and can be used as a pancreas cancer targeted magnetic resonance specific contrast agent to realize safe and rapid pancreas cancer targeted molecule image imaging.
Description
Technical field
The invention belongs to compounds process for production thereof, relate to the synthetic method of polymer micelle magnetic nano particle, particularly relate to a kind of target polymer micelle magnetic nano particle, can be used as the application of mr contrast agent in biomedical sector of nanoscale special target cancer of pancreas.
Background technology
The diagnostic means of current cancer of pancreas mainly comprises detection and the imaging diagnosis of tumor marker.Sugar antigen CA19-9 be current clinical middle use the most extensively and the tumor marker to diagnosis of pancreatic cancer approved most, but it also can be positive in the diseases such as chronic pancreatitis, lacks enough Sensitivity and Specificity.The conventional Image detection means of diagnosis of pancreatic cancer comprise computer tomography (CT), nuclear magnetic resonance (MRI), ultrasonic endoscope (EUS) and Positron emission computed tomography (PET) etc.But these Imaging Methods are also difficult to diagnose diameter to be less than the pancreas tumor of 2cm.Therefore, in order to the accuracy rate of diagnosis of Early pancreatic carcinoma can be improved, find high sensitivity, high specific and the targeted molecular probe of the low toxic and side effects of tool seems particularly important.
Polymer micelle is a kind of Performances of Novel Nano-Porous grain of rice transmission system developed in recent years, formed by amphipathic copolymer self assembly, self assembly can form a kind of special nucleocapsid structure with hydrophobic cores and hydrophilic shell in aqueous, be a kind of extremely promising Performances of Novel Nano-Porous meter level drug administration carrier.Polymer micelle can by " strengthening infiltration and retention effect " (enhanced permeability and retention effect, EPR) make macromolecule carrier system passive target to tumor locus, improve image contrast agent in the concentration of tumor locus, also reduce Normocellular toxic and side effects simultaneously.Polymer micelle has hydrophilic top layer and comparatively small particle diameter, to be difficult to identify by reticuloendothelial system and absorb, extend circulation time in vivo, entrained image contrast agent can be made more effectively to arrive target spot, improve the utilization rate of contrast medium.
Polyethylene Glycol (Polyethylene glycol, PEG) be the polymer of oxirane hydrolyzate, nontoxic, nonirritant, and with gas chromatography component, there is good biocompatibility, the picked-up of reticuloendothelial system can be hidden, thus extend carrier circulation time in blood, increase target organ further to the picked-up of nanoparticle; Poly(D,L-lactide-co-glycolide (poly (lactic-co-glycolic acid), PLGA), be polymerized at random by two kinds of monomer-lactic acid and hydroxyacetic acid, there is good biocompatibility, nontoxic, good encystation and filming performance, be widely used in pharmacy, medical engineering Material Field.
Targeting peptide is the amino acid polypeptide with the stronger affinity of specific antigen obtained by phage library display technique, having that molecular weight is little, to be easy to synthetic, hypotoxicity, reduced immunogenicity and vivo degradation product be the features such as endogenous material, is think the carrier of more satisfactory a kind of diagnosing tumor at present.Tumor targeting peptide has been applied in the diagnosis research to tumor in conjunction with different image contrast agent by image detection equipment, and it has been expanded cancer target diagnosis dramatically and has become the targeted probes of a kind of new and effective specific transmission image contrast agent to tumor locus.CKAAKN polypeptide is linear amino target polypeptide pancreatic cancer cell and tumor neogenetic blood vessels thereof while phage library display technique filters out to selectivity specific bond ability, and to normal pancreatic tissue almost without specific binding capacity.
Summary of the invention
First object of the present invention is to provide target polymer micelle magnetic nano particle cancer of pancreas to the effect of selectivity special target, and this magnetic nano particle is made up of (wherein the percentage ratio of each composition is volume ratio) materials such as F-68 solution (94%), CKAAKN polypeptide-polyethylene glycol-polylactic acid-hydroxyacetic acid grafting (4%), ferriferrous oxide nano solution (1%) and oleic acid ethanol (1%).
Plan the polymer micelle after CKAAKN is peptide modified as cancer of pancreas site-specific contrast medium carrier, build the cancer of pancreas site-specific contrast medium through USPIO labelling, may greatly improve contrast medium targeting, and being expected to reduce contrast medium injection dosage, final realization reduces contrast medium to the object of whole body toxic and side effects.
Second object of the present invention is to provide the preparation method of the special target polymer micelle magnetic nano particle of cancer of pancreas, is realized by following scheme:
(1) synthesis of CKAAKN-PEG-PLGA grafting
Get commercially available poly lactic-co-glycolic acid (PLGA, Mw:8000) a certain amount of DMSO (DMSO is dissolved in, Mw:78.13) in solution, add a certain amount of N respectively, N'-dicyclohexylcarbodiimide (DCC, and N-hydroxy-succinamide (NHS Mw:206.18), Mw:115.09), after under argon shield, room temperature magnetic agitation reacts 24 h, slowly drip containing a certain amount of Polyethylene Glycol (PEG, Mw:1500) DMSO solution, after continuing reaction 6 h, through dialysis, centrifugal, dissolve with acetone (concentration is 20mg/mL) after lyophilization, redissolve with deionized water again, PEG-PLGA copolymer is obtained after lyophilization.Getting appropriate PEG-PLGA copolymer, CKAAKN polypeptide and DCC is respectively dissolved in a certain amount of DMSO solution, after room temperature lower magnetic force stirring reaction 8 h, mix with a certain amount of deionized water, and dialyse, centrifugal, dry, namely obtain CKAAKN-PEG-PLGA grafting; Grafting is dissolved in D
2in O, concentration is 20 mg/ml, with nuclear magnetic resonance analyser by hydrogen compose nuclear magnetic resonance, NMR (
1h NMR) carry out detecting and recording proton nmr spectra, structural analysis is carried out to its characteristic peak, confirmation structure.
(2) preparation of cancer of pancreas special target polymer micelle magnetic nano particle
CKAAKN-PEG-PLGA-USPIO is prepared with solvent diffusion method and dialysis.Concrete grammar is: weigh a certain amount of above-mentioned CKAAKN-PEG-PLGA and be dissolved in appropriate deionized water, under ultrasonic agitation condition, adds a certain amount of oil-soluble Fe
3o
4the magnetic nano particle solution that (particle diameter is 5 nm, and concentration is 5 mg/ml) is core, after ultrasonic agitation 10 min, steams at 60 DEG C of water bath condition backspins, obtains polymer micelle magnetic nano particle (CKAAKN-PEG-PLGA-USPIO).
Described polymer micelle magnetic nano particle has in an aqueous medium by diffusion property, and the polymer micelle magnetic nano particle solution of 100 μ g/ml can form that particle diameter is 80 ~ 110nm, Zeta potential is the nanoparticle of-24 ~-31mV.
Polymer micelle nanoparticle has higher coated magnetic Fe
3o
4nano-particle ability, and there is good dispersibility.
3rd object of the present invention is to provide described polymer micelle magnetic nano particle and in preparation cancer of pancreas is had to application in the mr contrast agent of selectivity special target effect.The polymer micelle magnetic nano particle formed, has by the quick capture functions of human pancreatic cancer cell.
The present invention is on the research work basis in our early stage, adopt the peptide modified polyethylene glycol-polylactic acid-co-glycolic acid of CKAAKN, on this basis, solvent diffusion method preparation is adopted cancer of pancreas to be had to the polymer micelle magnetic nano particle of selectivity special target function.The appearance of this material and through further carrier applied research, will promote the special target mr contrast agent development of cancer of pancreas greatly.The invention provides the method for this polymer micelle magnetic nano particle of preparation, not only simple operation but also with low cost, there is extremely strong feasibility, be suitable for commercial application.
Polymer micelle magnetic nano particle provided by the present invention is a kind of Novel magnetic resonance contrast medium cancer of pancreas to selectivity special target function, can be applicable to biomedical sector.Utilize this contrast medium, be expected to realize safety, fast cancer of pancreas targeted molecular video imaging; Improve the capability of independent innovation of China's mr contrast agent research and development; For the research and development of the novel contrast medium of developing China's magnetic resonance, provide Theory and technology basis.
Accompanying drawing explanation
figure 1: be the syntheti c route figure of cancer of pancreas special target polymer micelle magnetic nano particle of the present invention.
figure 2: grafting
1h nuclear magnetic resonance map.
figure 3: the transmission electron microscope figure of polymer micelle magnetic nano particle.
figure 4: the cytotoxicity of polymer micelle magnetic nano particle.
figure 5: BxPC-3 cell is at the laser confocal microscope figure of different time points picked-up magnetic nano particle.
figure 6: the magnetic resonance image (MRI) of the polymer micelle magnetic nano particle of different whole concentration of iron.
Detailed description of the invention
The present invention is further described in conjunction with the accompanying drawings and embodiments.
embodiment one:the synthesis of CKAAKN-PEG-PLGA grafting
Get commercially available poly lactic-co-glycolic acid (PLGA, Mw:8000) a certain amount of DMSO (DMSO is dissolved in, Mw:78.13) in solution, add a certain amount of N respectively, N'-dicyclohexylcarbodiimide (DCC, and N-hydroxy-succinamide (NHS Mw:206.18), Mw:115.09), after under argon shield, room temperature magnetic agitation reacts 24 h, slowly drip containing a certain amount of Polyethylene Glycol (PEG, Mw:1500) DMSO solution, after continuing reaction 6 h, through dialysis, centrifugal, dissolve with acetone (concentration is 20mg/mL) after lyophilization, redissolve with deionized water again, PEG-PLGA copolymer is obtained after lyophilization.Getting appropriate PEG-PLGA copolymer, CKAAKN polypeptide and DCC is respectively dissolved in a certain amount of DMSO solution, after room temperature lower magnetic force stirring reaction 8 h, mix with a certain amount of deionized water, and dialyse, centrifugal, dry, namely obtain CKAAKN-PEG-PLGA grafting.Grafting is dissolved in D
2in O, concentration is 20 mg/ml, is undertaken detecting and recording proton nmr spectra, carry out structural analysis to its characteristic peak by nuclear magnetic resonance analyser.
See Fig. 2, result shows, and occurred a sharp-pointed unimodal signal at chemical shift 3.01-3.17 ppm place, this peak can belong to CKAAKN polypeptide cysteine – CH2 proton peak; Occurred a bimodal signal at chemical shift 3.36-3.58 ppm place, this peak belongs to the-CH2 proton peak signal on NH2-PEG-NH2; At chemical shift 7.96-8.31 ppm place, there is-NH proton peak the signal of amido link.Result shows, the CKAAKN-PEG-PLGA grafting that CKAAKN target polypeptide is modified successfully is synthesized in this research.
embodiment two:
1, the preparation of polymer micelle magnetic nano particle and physical and chemical property determining
CKAAKN-PEG-PLGA-USPIO is prepared with solvent diffusion method and dialysis.Concrete grammar is: by a certain amount of oil-soluble Fe
3o
4(particle diameter is 5 nm, concentration is 5 mg/ml) for the magnetic nano particle solution ultrasonic disperse of core is in F-68 solution (Poloxamer 188,0.1 %, w/v) in, probe continual ultrasonic 30 min(600 w, work 2 s, interval 3 s) after, add the oleic acid alcoholic solution of 10 mg/ml, Probe Ultrasonic Searching 5 min, to obtain Fe
3o
4nanoparticle dispersion liquid.Weighing a certain amount of CKAAKN-PEG-PLGA is dissolved in appropriate deionized water; Under ultrasonic agitation condition, add a certain amount of Fe
3o
4nanoparticle dispersion liquid, after continual ultrasonic 10 min, steams at 60 DEG C of water bath condition backspins, finally obtains cancer of pancreas special target polymer micelle magnetic nano particle (CKAAKN-PEG-PLGA-USPIO).
Get polymer micelle magnetic nano particle solution appropriate, dilute with a certain amount of deionized water, measure the particle diameter of nanoparticle, surface potential and polydispersity index respectively by 3000 HS granularities and surface potential analyser.
By certain density polymer micelle magnetic nano particle sample drop on the copper mesh (300 order) being coated with carbon film, after sucking unnecessary liquid with filter paper, use 2 %(w/v) phosphotungstic acid carries out dyeing 1 min, its form of transmission electron microscope observing and size after dry.
After measured, the particle diameter of polymer micelle magnetic nano particle, polydispersity index and surface potential are in table 1.
See Fig. 3, result shows, and polymer micelle magnetic nano particle has good particle size distribution, and outward appearance is spherical in shape or oval, and size is unanimously near uniform, the black Fe of visible parcel in it
3o
4nano-particle.
2, polymer micelle magnetic nano particle Study of cytotoxicity
This research adopts the cytotoxicity of tetramethyl azo azoles salt trace enzyme reaction colorimetry (MTT Assay) to the polymer micelle magnetic nano particle of preparation to evaluate.Taking the logarithm people's Normal Pancreas ductal epithelial cell HPDE6-C7 cell of trophophase, after trypsinization, is 5 × 10 with the cell culture fluid adjustment cell density containing 10% hyclone
4individual/ml, is then inoculated in 96 porocyte culture plates, every hole 0.2 ml, 37 DEG C, 5% CO
2hatch 24 h in cell culture incubator, after the complete adherent growth of cell, add the polymer micelle magnetic nano particle solution of variable concentrations, with untreated blanc cell for contrast, every hole establishes 3 parallel group.After continuing cultivation 48 h, every hole adds the MTT solution (concentration is 5.0 mg/ml) of 20 μ l, continues to hatch 4 h in cell culture incubator, abandoning supernatant, every hole adds 100 μ l dimethyl sulfoxide, constant temperature oscillation 20 min, measure 570 nm place absorbances by microplate reader, calculate cell survival rate.
See Fig. 4, result shows, in HPDE6-C7 cell culture fluid, respectively add different Fe
3o
4the polymer micelle magnetic nano particle of content (Cmax 100 μ g/ml) after hatching 48 h, the survival rate of HPDE6-C7 cell is all higher than 80%, result shows that polymer micelle magnetic nano particle prepared by this institute has hypotoxicity, and its application will have benefited from the clinical safety accepting magnetic resonance radiography inspection patient.
3, polymer micelle magnetic nano particle cellular uptake
Get appropriate fluorescein isothiocyanate (fitc) (FITC) to be dissolved in the dehydrated alcohol of 10 ml, add a certain amount of CKAAKN-PEG-PLGA grafting, lucifuge stirring reaction 24 h under room temperature.Then add the deionized water of 100 ml, precipitate filtered on buchner funnel, natural drying under room temperature, to obtain the grafting powder of fluorescein isothiocyanate (fitc) labelling, keep in Dark Place for subsequent use.
By a certain amount of oil-soluble Fe
3o
4(particle diameter is 5 nm, concentration is 5 mg/ml) for the magnetic nano particle solution ultrasonic disperse of core is in F-68 solution (Poloxamer 188,0.1 %, w/v) in, probe continual ultrasonic 30 min(600 w, work 2 s, interval 3 s) after, add the oleic acid alcoholic solution of 10 mg/ml, Probe Ultrasonic Searching 5 min, to obtain Fe
3o
4nanoparticle dispersion liquid.Get the grafting of appropriate fluorescein isothiocyanate (fitc) labelling, and be dissolved in a certain amount of deionized water, under ultrasound condition, the grafting of fluorescein isothiocyanate (fitc) labelling is injected into Fe
3o
4in nanoparticle dispersion liquid, after continual ultrasonic 5 min, finally obtain thiocyanogen fluorescein-labeled polymer micelle magnetic nano particle solution.
With human pancreatic cancer cell BxPC-3 cell for model cell, at 37 DEG C, 5% CO
2under condition, cultured cell is to being logarithmic growth after date, and collected by centrifugation, by every hole 1 × 10
5the density of individual cell inoculates 24 well culture plates, preculture 24 hours in incubator.The polymer micelle magnetic nano particle solution adding fluorescein isothiocyanate (fitc) labelling in culture fluid is hatched.After cultivating certain hour, use confocal laser scanning microscope.Result show, polymer micelle magnetic nano particle can fast absorb by cell.Fig. 5 is the laser confocal microscope photo after polymer micelle magnetic nano particle and BxPC-3 cell are hatched altogether.As shown in Figure 5, along with the prolongation of time, viewed green fluorescence intensity strengthens gradually, prolongation along with the time is described, the picked-up of BxPC-3 cell to polymer micelle magnetic nano particle increases gradually, and namely the picked-up of polymer micelle magnetic nano particle in BxPC-3 cell line has time dependence.
embodiment three:polymer micelle magnetic nano particle its magnetic resonance scans
The magnetic susceptibility of polymer micelle magnetic nano particle is weighed by the change in the T2* relaxation time measuring magnetic resonance imaging.The polymer micelle magnetic nano particle suspension of the variable concentrations prepared (0,1,10,15,25,50,75,100 μ g/ml) is respectively charged in the Eppendorf pipe of 2.0 ml, be placed on and fill in the test tube case of water, scan with eight channel head coils under the magnetic resonance of GE 3.0T whole body.
See Fig. 6, result shows, along with the increase of whole concentration of iron in polymer micelle magnetic nano particle suspension on ESWAN image, T2* signal intensity lowers gradually, illustrate that the polymer micelle magnetic nano particle prepared by this experiment has negative reinforcement effect, namely within finite concentration scope, polymer micelle magnetic nano particle concentration is higher, and its negative reinforcement effect is more obvious.Result is pointed out, and the present invention can be used as mr contrast agent and has the feasibility being applied to inside and outside imaging.
Without the need to elaborating further, believe content disclosed before employing, those skilled in the art can apply the present invention to greatest extent.Therefore, embodiment is above interpreted as only illustrating, and not limits range of application of the present invention by any way.So substantial scope of the present invention will be determined by appended claims and equivalents thereof.
Claims (6)
1. a target polymer micelle magnetic nano particle, it is characterized in that, this magnetic nano particle is made up of 94%F-68 solution, 4%CKAAKN polypeptide-polyethylene glycol-polylactic acid-hydroxyacetic acid grafting, 1% ferriferrous oxide nano solution and 1% oleic acid ethanol, wherein the percentage ratio of each composition is volume ratio, and targeting wherein refers to have selectivity special target to cancer of pancreas.
2. the preparation method of target polymer micelle magnetic nano particle according to claim 1, be is characterized in that, realized by following scheme:
(1) synthesis of CKAAKN-PEG-PLGA
Getting commercially available poly lactic-co-glycolic acid is dissolved in DMSO solution, add N respectively, N'-dicyclohexylcarbodiimide and N-hydroxy-succinamide, after under argon shield, room temperature magnetic agitation reacts 24 h, slowly drip the DMSO solution containing Polyethylene Glycol, after continuing reaction 6 h, through dialysis, centrifugal, with acetone solution after lyophilization, redissolve with deionized water again, PEG-PLGA copolymer is obtained after lyophilization, get PEG-PLGA copolymer, CKAAKN polypeptide and N, N'-dicyclohexylcarbodiimide is dissolved in DMSO solution, after room temperature lower magnetic force stirring reaction 8 h, mix with deionized water, and dialyse, centrifugal, dry, namely CKAAKN-PEG-PLGA grafting is obtained, its structure is confirmed by hydrogen spectrum nuclear magnetic resonance, NMR,
(2) preparation of cancer of pancreas special target polymer micelle magnetic nano particle
Weighing CKAAKN-PEG-PLGA grafting is dissolved in deionized water, under ultrasonic agitation condition, adds oil-soluble Fe
3o
4for the magnetic nano particle solution of core, after ultrasonic agitation 10 min, steam at 60 DEG C of water bath condition backspins, obtain polymer micelle magnetic nano particle: CKAAKN-PEG-PLGA-USPIO.
3. the preparation method of target polymer micelle magnetic nano particle according to claim 2, is characterized in that, in step (1), acetone concentration is 20mg/mL.
4. the preparation method of target polymer micelle magnetic nano particle according to claim 2, is characterized in that, the Fe of step (2) oil-soluble
3o
4particle diameter be 5 nm, concentration is 5 mg/ml.
5. the preparation method of target polymer micelle magnetic nano particle according to claim 2, it is characterized in that, described polymer micelle magnetic nano particle has in an aqueous medium by diffusion property, and the polymer micelle magnetic nano particle solution of 100 μ g/ml can form that particle diameter is 80 ~ 110nm, Zeta potential is the nanoparticle of-24 ~-31mV.
6. polymer micelle magnetic nano particle according to claim 1 to have the application in the mr contrast agent of selectivity special target effect to cancer of pancreas in preparation.
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Cited By (5)
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| CN109395102A (en) * | 2018-11-13 | 2019-03-01 | 贵阳中医学院 | A kind of cancer of pancreas double-target polymer magnetic nano particle and its preparation method and application |
| CN109675064A (en) * | 2018-12-10 | 2019-04-26 | 中国药科大学 | For the integrated iron of diagnosis and treatment-gallic acid coordination polymer and its preparation method and application |
| CN110339373A (en) * | 2018-04-04 | 2019-10-18 | 中国科学院宁波材料技术与工程研究所 | A kind of nano combined micella and its preparation method and application |
| CN110787306A (en) * | 2018-08-02 | 2020-02-14 | 武汉凯德维斯生物技术有限公司 | Preparation and application of nano micelle developer for cervical cancer sentinel lymph node |
| CN111973762A (en) * | 2020-08-04 | 2020-11-24 | 新乡医学院 | Medicine-carrying multifunctional magnetic nano-bubble and preparation method and application thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110339373A (en) * | 2018-04-04 | 2019-10-18 | 中国科学院宁波材料技术与工程研究所 | A kind of nano combined micella and its preparation method and application |
| CN110787306A (en) * | 2018-08-02 | 2020-02-14 | 武汉凯德维斯生物技术有限公司 | Preparation and application of nano micelle developer for cervical cancer sentinel lymph node |
| CN110787306B (en) * | 2018-08-02 | 2022-09-13 | 武汉凯德维斯生物技术有限公司 | Preparation and application of nano micelle developer for cervical cancer sentinel lymph node |
| CN109395102A (en) * | 2018-11-13 | 2019-03-01 | 贵阳中医学院 | A kind of cancer of pancreas double-target polymer magnetic nano particle and its preparation method and application |
| CN109395102B (en) * | 2018-11-13 | 2021-08-17 | 贵州中医药大学 | Pancreatic cancer double-targeting polymer magnetic nanoparticle and preparation method and application thereof |
| CN109675064A (en) * | 2018-12-10 | 2019-04-26 | 中国药科大学 | For the integrated iron of diagnosis and treatment-gallic acid coordination polymer and its preparation method and application |
| CN109675064B (en) * | 2018-12-10 | 2021-09-28 | 中国药科大学 | Iron-gallic acid coordination polymer for diagnosis and treatment integration and preparation method and application thereof |
| CN111973762A (en) * | 2020-08-04 | 2020-11-24 | 新乡医学院 | Medicine-carrying multifunctional magnetic nano-bubble and preparation method and application thereof |
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