CN104004196A - Preparation method and application of degradable hyperbranched polyamidoamine - Google Patents
Preparation method and application of degradable hyperbranched polyamidoamine Download PDFInfo
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- CN104004196A CN104004196A CN201410184171.4A CN201410184171A CN104004196A CN 104004196 A CN104004196 A CN 104004196A CN 201410184171 A CN201410184171 A CN 201410184171A CN 104004196 A CN104004196 A CN 104004196A
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- 229920000962 poly(amidoamine) Polymers 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims abstract description 60
- 239000000178 monomer Substances 0.000 claims abstract description 52
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims abstract description 30
- 229960000304 folic acid Drugs 0.000 claims abstract description 30
- 235000019152 folic acid Nutrition 0.000 claims abstract description 30
- 239000011724 folic acid Substances 0.000 claims abstract description 30
- 230000001588 bifunctional effect Effects 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 32
- 239000000047 product Substances 0.000 claims description 31
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 30
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 28
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 19
- 238000006845 Michael addition reaction Methods 0.000 claims description 18
- 238000013019 agitation Methods 0.000 claims description 18
- 238000001291 vacuum drying Methods 0.000 claims description 14
- 238000007306 functionalization reaction Methods 0.000 claims description 11
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims description 8
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 8
- 229950007687 macrogol ester Drugs 0.000 claims description 8
- 239000007795 chemical reaction product Substances 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 7
- DJVKJGIZQFBFGS-UHFFFAOYSA-N n-[2-[2-(prop-2-enoylamino)ethyldisulfanyl]ethyl]prop-2-enamide Chemical group C=CC(=O)NCCSSCCNC(=O)C=C DJVKJGIZQFBFGS-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 4
- 238000007599 discharging Methods 0.000 claims description 3
- 229920000642 polymer Polymers 0.000 abstract description 13
- 238000000034 method Methods 0.000 abstract description 12
- 210000004881 tumor cell Anatomy 0.000 abstract description 9
- 230000008685 targeting Effects 0.000 abstract description 6
- 239000012876 carrier material Substances 0.000 abstract description 3
- 230000008878 coupling Effects 0.000 abstract description 3
- 238000010168 coupling process Methods 0.000 abstract description 3
- 238000005859 coupling reaction Methods 0.000 abstract description 3
- 239000002202 Polyethylene glycol Substances 0.000 abstract 3
- 229920001223 polyethylene glycol Polymers 0.000 abstract 3
- IMUDHTPIFIBORV-UHFFFAOYSA-N aminoethylpiperazine Chemical compound NCCN1CCNCC1 IMUDHTPIFIBORV-UHFFFAOYSA-N 0.000 abstract 2
- 239000002994 raw material Substances 0.000 abstract 2
- 125000000524 functional group Chemical group 0.000 abstract 1
- 238000012701 michael addition polymerization Methods 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 108090000623 proteins and genes Proteins 0.000 description 13
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 239000000843 powder Substances 0.000 description 8
- 238000001556 precipitation Methods 0.000 description 8
- 238000004062 sedimentation Methods 0.000 description 8
- 239000003937 drug carrier Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- OOTFVKOQINZBBF-UHFFFAOYSA-N cystamine Chemical compound CCSSCCN OOTFVKOQINZBBF-UHFFFAOYSA-N 0.000 description 6
- 229940099500 cystamine Drugs 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 229960003180 glutathione Drugs 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 229920000587 hyperbranched polymer Polymers 0.000 description 4
- 230000005311 nuclear magnetism Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000002861 polymer material Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- -1 polyoxyethylene Polymers 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004043 responsiveness Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 229920003656 Daiamid® Polymers 0.000 description 1
- 241000555268 Dendroides Species 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 238000001237 Raman spectrum Methods 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000003916 acid precipitation Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940088623 biologically active substance Drugs 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229920006317 cationic polymer Polymers 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 208000002925 dental caries Diseases 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 210000001163 endosome Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000003929 folic acid group Chemical group 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
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- 230000002132 lysosomal effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
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- 230000002018 overexpression Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
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- 229940067626 phosphatidylinositols Drugs 0.000 description 1
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Landscapes
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a preparation method and application of degradable hyperbranched polyamidoamine. Degradable hyperbranched polyamidoamine is prepared by taking a bifunctional monomer containing a disulfide bond or a ketal bond and an amino-containing trifunctional monomer N-aminoethylpiperazine (AEPZ) or diethylenetriamine (DETA) as main raw materials and employing a one-pot method to perform Michael addition polymerization reaction. By coupling polyethylene glycol (PEG) and folic acid (FA) with degradable hyperbranched polyamidoamine, folic-acid-targeted PEGylated degradable hyperbranched polyamidoamine is obtained. The raw materials are easily available, the preparation method is simple, and the prepared polymer medicine carrier has the advantages of hyperbranched polyamidoamine, such as three-dimension branching structure, a lot of cavities at the interior of molecules, low viscosity, a lot of functional groups, simple preparation method, biodegradability, and the like. Additionally, the water solubility and the stability of the carrier material are improved by grafting a PEG chain segment to the terminal, and the carrier is endowed with active targeting property on tumor cells through coupling of FA.
Description
Technical field
The invention belongs to technical field of polymer materials, be specifically related to a kind of preparation method and application thereof of the degradable over-branched polyamidoamine discharging for medicine control.
Background technology
Over-branched polyamidoamine, not only has the structure and characteristics similar to dendroid daiamid, and preparation easily, without careful separating-purifying, can obtain required polymkeric substance by monomer is synthetic by single stage method, be therefore subject to numerous researchists' favor.Over-branched polyamidoamine inside has cavity, can packaging medicine molecule, as gene, antitumor drug etc.; The performance that a large amount of end group of its molecular surface not only can improve material itself by various modifications can also connect the biologically active substance such as gene and antibody, and this is just for design slowly-releasing and targeting preparation provide a great convenience.
Over-branched polyamidoamine cationic polymers end group is modified and can be changed its chemical attribute, even affect its physical properties, as electric charge, wetting ability, solubleness etc.Polyoxyethylene glycol (PEG) is most widely used microparticle surfaces decorative material, hydrophilic PEG chain can form sterically hindered make particle stability increase and difficult gathering, can shield the absorption of the materials such as protein in blood and the picked-up of hiding reticuloendothelial system simultaneously, extend carrier cycling time in vivo, improved the bioavailability of medicine.
Desirable drug carrier material should be nontoxic, biocompatible, not only can protect the activity of medicine, can also degradation in vivo be small-molecule substance, easily by body metabolism, this just requires solid support material to have biodegradable.But hyperbranched polymer gene, the pharmaceutical carrier of report mostly are nondegradable at present, not only have certain bio-toxicity, and cannot realize the abundant release to gene, medicine.In the preparation process of hyperbranched polymer, introduce functional monomer and can realize the degradability of polymer materials.Researchist's discovery, in human body cell, the concentration of reductive glutathione (GSH) is 2～10mM, much larger than the concentration (2～10 μ M) of extracellular GSH; For tumour cell, in its cell, the concentration of GSH is higher 4 times than GSH concentration in normal cell, and this makes the inside and outside reduction potential of tumour cell have larger difference.In addition, in human body, the pH of different tissues environment also there are differences, for example, the pH of human normal blood is 7.4, the extracellular environment pH of healthy tissues is 7.2～7.4, and the extracellular environment pH of tumor tissues is 6.2～6.8, tumour cell endosome and lysosomal pH value are respectively 5.5～6.5 and 4.5～5.0.Therefore, the functional monomer that can contain disulfide linkage or ketal key by introducing, make the polymkeric substance preparing there is reduction responsiveness or pH responsiveness, taking it as medicine, genophore can realize the controlled-release function to medicine, gene: in blood circulation, do not discharge medicine, gene, in the time arriving tumour acidity or reductibility environment, there is degraded and discharge fast medicine, gene, improved the result for the treatment of of medicine and the transfection efficiency of gene.
Desirable drug carrier material, except having biocompatibility, also should have initiatively targeting.Existing research has proved that a kind of membrane glycoprotein (FR) that connects glycosylation phosphatidylinositols of tumor cell surface can specific binding occur with folic acid (FA).FR all overexpressions on most of human body tumour cell are seldom expressed in healthy tissues organ.Therefore at hyperbranched polymer finishing folic acid, can give solid support material tumor-targeting, improve to a great extent the bioavailability of medicine, gene.
Summary of the invention
Goal of the invention: for solving the technical problem existing in prior art, the present invention proposes a kind of preparation method and application thereof of degradable over-branched polyamidoamine, so that a kind of polymkeric substance as pharmaceutical carrier that degradability, environment-responsive and bioavailability are high that has to be provided.
Technology contents: for realizing above-mentioned technical purpose, the present invention proposes a kind of preparation method of degradable over-branched polyamidoamine, it comprises the steps: that bifunctional monomer and 2.0～6.0mmol that 2.0～6.0mmol is contained to disulfide linkage or ketal key contain amino trifunctional monomer at methyl alcohol or N, in dinethylformamide (DMF), mix, preferably in methyl alcohol, mix, consider that methanol prices is cheap, toxicity is relatively little, environmental pollution is little, then at 40～60 DEG C, under magnetic agitation, carry out Michael addition polyreaction, after 4～8 days, again add containing of 2.0～6.0mmol amino trifunctional monomer reaction within 1～3 day, to obtain crude product, thereby two keys of polymer ends are all converted into amino, like this, on the one hand, polymer surfaces contains a large amount of amino one side and is conducive to polymer-modified, as modified the material (folic acid) with carboxyl, amino positively charged on the other hand, be conducive to combine with gene, improve the transfection efficiency of gene.Crude product is carried out to purifying, and then at room temperature vacuum-drying obtains end product degradable over-branched polyamidoamine.Purification process comprises that the existing crude product obtaining pours in a large amount of ether under vigorous stirring particularly, adopt centrifugal method to isolate throw out, and then throw out be dissolved in methyl alcohol, in the acetone soln of 5% concentrated hydrochloric acid precipitation, separate, dry.
Wherein, described bifunctional monomer is N, N '-bis-(acryloyl) cystamine, 2, any one in 2-dimethyl allene acyloxy-1-ethyl propyl ether or 2,2-DMAA base-1-ethyl propyl ether; Described trifunctional monomer is 1-(2-amine ethyl) piperazine or diethylenetriamine.
In order to increase the biocompatibility of over-branched polyamidoamine polymkeric substance, the invention allows for a kind of preparation method of over-branched polyamidoamine of degradable PEGization, comprise the steps: that bifunctional monomer and 2.0～6.0mmol that 2.0～6.0mmol is contained to disulfide linkage or ketal key contain amino trifunctional monomer at methyl alcohol or N, in dinethylformamide, mix, then at 40～60 DEG C, under magnetic agitation, carry out Michael addition polyreaction, after 4～8 days, add 2.0～6.0mmol methacrylic acid macrogol ester reaction 1～3 day, the product obtaining is carried out to purifying, then at room temperature vacuum-drying obtains the over-branched polyamidoamine of end product degradable PEGization.Wherein, above-mentioned purification process is with the preparation method in degradable over-branched polyamidoamine preparation method.
Wherein, described bifunctional monomer is N, N '-bis-(acryloyl) cystamine, 2, any one in 2-dimethyl allene acyloxy-1-ethyl propyl ether or 2,2-DMAA base-1-ethyl propyl ether; Described trifunctional monomer is 1-(2-amine ethyl) piperazine or diethylenetriamine.
The weight-average molecular weight of described methacrylic acid macrogol ester be in 350,750,1000,2000 or 5000 any one or multiple.
For the over-branched polyamidoamine that a kind of targeting is good is provided, the present invention also proposes a kind of preparation method of folic acid functionalization degradable over-branched polyamidoamine, comprises the steps:
(1) bifunctional monomer of 2.0～6.0mmol being contained to disulfide linkage or ketal key is contained amino trifunctional monomer with 2.0～6.0mmol and is mixed in organic solvent, under 40～60 DEG C, magnetic agitation, carry out Michael addition polyreaction, after 4～8 days, add 2.0～6.0mmol methacrylic acid macrogol ester reaction 1～3 day, the product obtaining is carried out to purifying, and then at room temperature vacuum-drying obtains the over-branched polyamidoamine of degradable PEGization; Wherein, above-mentioned purification process is with the preparation method in degradable over-branched polyamidoamine preparation method.
(2) 10～60 μ mol folic acid, 10～60 μ mol1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 10～60 μ mol N-maloyl imines and 10～20 μ L triethylamines are dissolved in 5～30mL DMSO, room temperature magnetic agitation is spent the night, and forms FA active ester; Then above-mentioned reaction solution is slowly added in the DMSO solution of the over-branched polyamidoamine of the degradable PEGization of preparation in 10～60 μ mol steps (1), room temperature lucifuge reaction 1～2 day, the crude product freeze-drying after purifying of dialysing in distilled water obtains end product folic acid functionalization degradable over-branched polyamidoamine.
Wherein, described bifunctional monomer is N, N '-bis-(acryloyl) cystamine, 2, any one in 2-dimethyl allene acyloxy-1-ethyl propyl ether or 2,2-DMAA base-1-ethyl propyl ether; Described trifunctional monomer is 1-(2-amine ethyl) piperazine or diethylenetriamine; The weight-average molecular weight of described methacrylic acid macrogol ester be in 350,750,1000,2000 or 5000 any one or multiple.
The present invention has further proposed over-branched polyamidoamine and the application of folic acid functionalization degradable over-branched polyamidoamine on the carrier discharging as medicine control of above-mentioned degradable over-branched polyamidoamine, degradable PEGization
Beneficial effect: the present invention is by introducing functional monomer, adopting one kettle way Michael addition polyreaction to prepare degradable environment-responsive over-branched polyamidoamine, and preparation method is simple, and purifying is easy.Polymerization process, taking methyl alcohol as solvent, adopts one kettle way Michael addition polyreaction, prepares simply, pollutes little.On this basis, modify PEG and FA and obtain the degradable environment-responsive over-branched polyamidoamine of functionalization by terminal amino group.The polymer materials preparing not only has environment-responsive and biological degradability, also has good stability and biocompatibility.Environment-responsive and the degradability of polymer carrier materials not only given in the introducing that contains disulfide linkage or ketal key function monomer, can in cell reductibility environment and sour environment, degrade, the control that can realize again medicine discharges, and has improved the utilization ratio of medicine.Use polyoxyethylene glycol (PEG) to carry out structural modification to its functional end-group, can improve the water-soluble and stability of medicine-carried system, reduce the interaction of itself and plasma proteins and non-targeted cell; Utilize the folic acid part of tumor cell surface special target to carry out targeting modification to it, thereby give the initiatively ability of target tumor cell of carrier, to improving the result for the treatment of of medicine.Taking this material as pharmaceutical carrier, in blood circulation, can keep stable, in the time arriving tumour cell environment, can discharge medicine fast, fully owing to there is degraded, the timing, the fixed point that realize medicine discharge.The product that the inventive method obtains has great application prospect in medicine control release field.
Brief description of the drawings
Fig. 1 is degradability over-branched polyamidoamine synthetic line figure;
Fig. 2 is the Raman spectrum of degradability over-branched polyamidoamine;
Fig. 3 is the potential value of degradable over-branched polyamidoamine under condition of different pH;
Fig. 4 for solid support material and DNA different mass than under carrier be combined the situation of DNA, wherein, 1 is DNA plasmid; In 2～5, the mass ratio of solid support material and DNA is respectively 10: 1,15: 1,20: 1 and 25: 1.
Fig. 5 is the schematic diagram that the degradability over-branched polyamidoamine of preparation can occur correspondingly to rupture in reductibility or sour environment.
Embodiment
Embodiment 1
Bifunctional monomer N by 3.0mmol containing disulfide linkage, N '-bis-(acryloyl) cystamine (BAC) mixes in methyl alcohol with 3.0mmol trifunctional monomer 1-(2-amine ethyl) piperazine (AEPZ), 50 DEG C, under magnetic agitation, carry out Michael addition polyreaction, after 5 days, add the AEPZ of 3mmol to react 1 day so that two keys of polymer ends are all converted into amino, the product obtaining successively adopts ether sedimentation, the methods such as acetone precipitation are carried out purifying to product, at room temperature vacuum-drying of precipitated product obtains white powder degradable over-branched polyamidoamine.The product of gained is carried out to Raman, potential test and nuclear-magnetism test, and result as shown in Figures 2 and 3.Wherein, as shown in Figure 2,507cm
-1be the absorption peak of disulfide linkage, illustrate that disulfide linkage can successfully be introduced in polymkeric substance over-branched polyamidoamine by one kettle way Michael addition polyreaction.As can be seen from Figure 3, in the scope that the degradable over-branched polyamidoamine of preparation is 3～9 at pH, electromotive force be on the occasion of, and along with acid enhancing potential value also increases, illustrate that degradable over-branched polyamidoamine surface has a large amount of amino.
The nuclear-magnetism result of the over-branched polyamidoamine of preparation is:
1H?NMR(400MHz，D
2O，δ)∶2.30-2.42(-CH
2CONH-)，2.58-2.79(>NCH
2)，3.22-3.32(-NHCH
2).
13C?NMR(400MHz，D
2O，δ)：29.50-30.08(-CH
2CONH-)，36.27-37.02(-NHCH
2CH
2SS-)，37.86-38.76(-NHCH
2)，49.06-49.81(>NCH
2).IR(KBr，cm
-1)：3,600-3，140(-NH
2，-NH)，2970-2815(CH
2，CH
3)，1,654，1,550(C＝O)。
Embodiment 2
Bifunctional monomer N by 3.0mmol containing disulfide linkage, N '-bis-(acryloyl) cystamine (BAC) mixes in methyl alcohol with 1.50mmol trifunctional monomer 1-(2-amine ethyl) piperazine (AEPZ), 50 DEG C, under magnetic agitation, carry out Michael addition polyreaction, after 5 days, add the AEPZ of 3mmol to react 2 days so that two keys of polymer ends are all converted into amino, the product obtaining successively adopts ether sedimentation, the methods such as acetone precipitation are carried out purifying to product, at room temperature vacuum-drying of precipitated product obtains the reducible degraded over-branched polyamidoamine of white powder.
Embodiment 3
Bifunctional monomer N by 2.0mmol containing disulfide linkage, N '-bis-(acryloyl) cystamine (BAC) mixes in methyl alcohol with 3.0mmol trifunctional monomer diethylenetriamine (DETA), under 50 DEG C, magnetic agitation, carry out Michael addition polyreaction, after 5 days, add the DETA of 1mmol to react 3 days so that two keys of polymer ends are all converted into amino, the product obtaining successively adopts the method such as ether sedimentation, acetone precipitation to carry out purifying to product, and at room temperature vacuum-drying of precipitated product obtains the reducible degraded over-branched polyamidoamine of white powder.
Embodiment 4
Bifunctional monomer 2 by 4.0mmol containing ketal key, 2-dimethyl allene acyloxy-1-ethyl propyl ether mixes in methyl alcohol with 4.0mmol trifunctional monomer 1-(2-amine ethyl) piperazine (AEPZ), 50 DEG C, under magnetic agitation, carry out Michael addition polyreaction, after 5 days, add the AEPZ of 3mmol to react 1 day so that two keys of polymer ends are all converted into amino, the product obtaining successively adopts ether sedimentation, the methods such as acetone precipitation are carried out purifying to product, at room temperature vacuum-drying of precipitated product obtains white powder acid-degradable over-branched polyamidoamine.
Embodiment 5
Bifunctional monomer 2 by 5.0mmol containing ketal key, 2-DMAA base-1-ethyl propyl ether mixes in methyl alcohol with 4.0mmol trifunctional monomer 1-(2-amine ethyl) piperazine (AEPZ), 50 DEG C, under magnetic agitation, carry out Michael addition polyreaction, after 5 days, add the AEPZ of 4mmol to react 1 day so that two keys of polymer ends are all converted into amino, the product obtaining successively adopts ether sedimentation, the methods such as acetone precipitation are carried out purifying to product, at room temperature vacuum-drying of precipitated product obtains white powder acid-degradable over-branched polyamidoamine.
Embodiment 6
Bifunctional monomer N by 6.0mmol containing disulfide linkage, N '-bis-(acryloyl) cystamine (BAC) mixes in methyl alcohol with 5.0mmol trifunctional monomer 1-(2-amine ethyl) piperazine (AEPZ), under 50 DEG C, magnetic agitation, carry out Michael addition polyreaction, the PEGMA reaction 2 days that adds 4mmol after 5 days is with by polymer ends grafting PEG, the product obtaining successively adopts the method such as ether sedimentation, acetone precipitation to carry out purifying to product, and at room temperature vacuum-drying of precipitated product obtains the over-branched polyamidoamine of white powder degradable PEGization.
The nuclear-magnetism result of the over-branched polyamidoamine of the degradable PEGization of preparation is as follows:
1H?NMR(400MHz，D
2O，δ)：3.58-3.72(OCh
2CH
2OOCCH(CH
3)NH-)，3.74-3.87(OCH
2CH
2OOCCH(CH
3)NH-)，3.70-3.55(-CH
2CH
2O)，3.19-3.28(-OCH
3)，3.17-3.27(-NHCH
2)，2.68-2.84(>NCH
2)，2.32-2.41(-CH
2CONH-).IR(KBr，cm
-1)：3,600-3,300(-NH
2，-NH)，2990-2800(CH
2，CH
3)，1,646，1,530(C＝O)，1，110(C-O-C)。
Embodiment 7
Bifunctional monomer N by 3.0mmol containing disulfide linkage, N '-bis-(acryloyl) cystamine (BAC) mixes in methyl alcohol with 3.0mmol trifunctional monomer 1-(2-amine ethyl) piperazine (AEPZ), under 50 DEG C, magnetic agitation, carry out Michael addition polyreaction, the PEGMA reaction 2 days that adds 1mmol after 5 days is with by polymer ends grafting PEG, the product obtaining successively adopts the method such as ether sedimentation, acetone precipitation to carry out purifying to product, and at room temperature vacuum-drying of precipitated product obtains the over-branched polyamidoamine of white powder degradable PEGization.
Embodiment 8
Bifunctional monomer N by 5.0mmol containing disulfide linkage, N '-bis-(acryloyl) cystamine (BAC) mixes in methyl alcohol with 4.0mmol trifunctional monomer 1-(2-amine ethyl) piperazine (AEPZ), under 50 DEG C, magnetic agitation, carry out Michael addition polyreaction, the PEGMA reaction 2 days that adds 2mmol after 6 days is with by polymer ends grafting PEG, the product obtaining successively adopts the method such as ether sedimentation, acetone precipitation to carry out purifying to product, and at room temperature vacuum-drying of precipitated product obtains the over-branched polyamidoamine of white powder degradable PEGization.
Embodiment 9
In DMSO, 20 μ mol folic acid (FA) and 40 μ mol1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC.HCl), 40 μ molN-maloyl imines (NHS) and 10 μ L triethylamines are dissolved in 5mL DMSO, room temperature magnetic agitation is spent the night, and forms FA active ester.Then above-mentioned reaction solution is slowly added in the over-branched polyamidoamine DMSO solution of PEGization prepared by 15 μ mol embodiment 6, room temperature lucifuge reaction 1 day, crude product is dialysed after purifying freeze-drying to form folic acid functionalization degradable over-branched polyamidoamine solid support material in distilled water.
The nuclear-magnetism result of the folic acid functionalization degradable over-branched polyamidoamine of preparation is as follows:
1h NMR (400MHz, D
2o, δ): 8.55-8.74 (=N-CH=C<), 7.62-7.73, (NH-C
6h
4-CONH-, near two amino hydrogen), 6.54-6.75 (NH-C
6h
4-CONH-, near two hydrogen of carbonyl), 4.41-4.52 (CH
2-NH-C
6h
4), 4.28-4.42 (CH
2cOOH), 3.59-3.71 (OCH
2cH
2oOCCH (CH
3) NH-), 3.75-3.85 (OCH
2cH
2oOCCH (CH
3) NH-), 3.42-3.71 (CH
2cH
2o), 3.25-3.34 (OCH
3), 3.12-3.27 (NHCH
2-), 2.68-2.94 (>NCH
2-), 2.05-2.32 (CH
2cH
2cON<), 1.93-2.08 (CH
2cH
2cON<).
Embodiment 10
In DMSO, 30 μ mol folic acid (FA) and 50 μ mol1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl), 50 μ molN-maloyl imines (NHS) and 20 μ L triethylamines are dissolved in 10mL DMSO, room temperature magnetic agitation is spent the night, and forms FA active ester.Then above-mentioned reaction solution is slowly added in the over-branched polyamidoamine DMSO solution of PEGization prepared by 10 μ mol embodiment 6, room temperature lucifuge reaction 1 day, crude product is dialysed after purifying freeze-drying to form folic acid functionalization degradable over-branched polyamidoamine solid support material in distilled water.
Embodiment 11
The over-branched polyamidoamine solid support material of the degradable PEGization of the coupling of folic acid (FA) prepared by embodiment 9 is dissolved in TE buffered soln (pH7.5), and is slowly added in the solution of isopyknic DNA according to material and the DNA mass ratio of 10: 1～25: 1.Reaction mixture mixes with the soft vortex of vortice, room temperature reaction 0.5h～2h.Then carry out cataphoretic determination, result as shown in Figure 4.In figure, be that solid support material and DNA amount ratio are the experiment of 10: 1,15: 1,20: 1 and 25: 1 from left to right, as can be seen from the figure in the time that material and DNA consumption are 10: 1, can block DNA completely and move in sepharose, illustrate that solid support material has the ability of good concentration of DNA.
Fig. 5 is the schematic diagram that the degradability over-branched polyamidoamine of preparation can occur correspondingly to rupture in reductibility or sour environment.Because functional bifunctional monomer is contained disulfide linkage or ketal key, therefore in reductibility or sour environment, can occur correspondingly to rupture.In the present invention, functional bifunctional monomer (contain disulfide linkage or contain ketal key) and contain amino trifunctional monomer 1-(2-amine ethyl) piperazine (AEPZ) or diethylenetriamine (DETA) obtains the degradable over-branched polyamidoamine that contains a large amount of amino in surface by the polymerization of one kettle way Michael addition, can obtain the degradable poly amide amine of the folate-targeted of PEGization by modifying PEG and folic acid.Because hyperbranched polymer inside has the amino that a large amount of positively chargeds are contained on a large amount of cavitys and surface, therefore can be used for encapsulated drug or gene, therefore can be used as drug carrier material.This polymer carrier materials not only good biocompatibility, there is initiatively targeting, and there is fracture and degrade in inner a large amount of disulfide linkage or ketal keys in reductibility or sour environment, therefore can effectively control the release of medicine, be a kind of desirable pharmaceutical carrier.
Claims (9)
1. the preparation method of a degradable over-branched polyamidoamine, it is characterized in that, comprise the steps: that bifunctional monomer and 2.0～6.0mmol that 2.0～6.0mmol is contained to disulfide linkage or ketal key contain amino trifunctional monomer at methyl alcohol or N, in dinethylformamide, mix, under 40～60 DEG C, magnetic agitation, carry out Michael addition polyreaction, after 4～8 days, again add the bifunctional monomer of 2.0～6.0mmol to react 1～3 day, the product obtaining is carried out to purifying, and at room temperature vacuum-drying obtains end product degradable over-branched polyamidoamine.
2. the preparation method of degradable over-branched polyamidoamine according to claim 1, it is characterized in that, described bifunctional monomer is N, N '-bis-(acryloyl) cystamine, 2, any one in 2-dimethyl allene acyloxy-1-ethyl propyl ether or 2,2-DMAA base-1-ethyl propyl ether; Described trifunctional monomer is 1-(2-amine ethyl) piperazine or diethylenetriamine.
3. the preparation method of the over-branched polyamidoamine of a degradable PEGization, it is characterized in that, comprise the steps: that bifunctional monomer and 2.0～6.0mmol that 2.0～6.0mmol is contained to disulfide linkage or ketal key contain amino trifunctional monomer at methyl alcohol or N, in dinethylformamide, mix, 40～60 DEG C, under magnetic agitation, carry out Michael addition polyreaction, after 4～8 days, add 2.0～6.0mmol methacrylic acid macrogol ester reaction 1～3 day, the product obtaining is carried out to purifying, then at room temperature vacuum-drying obtains the over-branched polyamidoamine of end product degradable PEGization.
4. the preparation method of the over-branched polyamidoamine of degradable PEGization according to claim 3, it is characterized in that, described bifunctional monomer is N, N '-bis-(acryloyl) cystamine, 2, any one in 2-dimethyl allene acyloxy-1-ethyl propyl ether or 2,2-DMAA base-1-ethyl propyl ether; Described trifunctional monomer is 1-(2-amine ethyl) piperazine or diethylenetriamine.
5. the preparation method of the over-branched polyamidoamine of degradable PEGization according to claim 3, is characterized in that, the weight-average molecular weight of described methacrylic acid macrogol ester be in 350,750,1000,2000 or 5000 any one or multiple.
6. a preparation method for folic acid functionalization degradable over-branched polyamidoamine, is characterized in that, comprises the steps:
(1) 2.0～6.0mmol is contained to the bifunctional monomer of disulfide linkage or ketal key and 2.0～6.0mmol trifunctional monomer at methyl alcohol or N, in dinethylformamide, mix, under 40～60 DEG C, magnetic agitation, carry out Michael addition polyreaction, after 4～8 days, add 2.0～6.0mmol methacrylic acid macrogol ester reaction 1～3 day, the product obtaining is carried out to purifying, and then at room temperature vacuum-drying obtains the over-branched polyamidoamine of degradable PEGization;
(2) 10～60 μ mol folic acid, 10～60 μ mol1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 10～60 μ mol N-maloyl imines and 10～20 μ L triethylamines are dissolved in 5～30mL DMSO, room temperature magnetic agitation is spent the night, and forms FA active ester; Then above-mentioned reaction solution is slowly added in the DMSO solution of the over-branched polyamidoamine of the degradable PEGization of preparation in 10～60 μ mol steps (1), room temperature lucifuge reaction 1～2 day, the crude product freeze-drying after purifying of dialysing in distilled water obtains end product folic acid functionalization degradable over-branched polyamidoamine.
7. the preparation method of folic acid functionalization degradable over-branched polyamidoamine according to claim 6, it is characterized in that, described bifunctional monomer is N, N '-bis-(acryloyl) cystamine, 2, any one in 2-dimethyl allene acyloxy-1-ethyl propyl ether or 2,2-DMAA base-1-ethyl propyl ether; Described trifunctional monomer is 1-(2-amine ethyl) piperazine or diethylenetriamine.
8. the preparation method of folic acid functionalization degradable over-branched polyamidoamine according to claim 6, is characterized in that, the weight-average molecular weight of described methacrylic acid macrogol ester be in 350,750,1000,2000 or 5000 any one or multiple.
9. claim 1 or the application of 3 or 6 prepared end products on the carrier discharging as medicine control.
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