CN103550786B - Supermolecular nano-assembly for gene therapy and preparation method thereof - Google Patents
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Abstract
The invention provides a supermolecular nano-assembly for gene therapy. The supermolecular nano-assembly is characterized by being constructed through a construction unit under the effect of inclusion of a main body and a secondary body, wherein cyclodextrin-modified gold nanoparticles serve as the main body, and anthracene-modified adamantine serves as the secondary body. The preparation method comprises the following steps of: 1) preparing the gold nanoparticles; 2) preparing N-(9-methylanthracene)-N'-adamantanecarboxamide ethylethylenediamine; 3) dissolving the prepared gold nanoparticles and N-(9-methylanthracene)-N'-adamantanecarboxamide ethylethylenediamine into water, and uniformly mixing to obtain the solution type supermolecular nano-assembly. The supermolecular nano-assembly has the advantages that DNA (Deoxyribonucleic Acid) can be effectively induced to be coagulated, and the coagulation capability can be conveniently adjusted by controlling the input ratio of the main body and the secondary body; the supermolecular nano-assembly has a wide application prospect in the gene therapy field; the preparation method is simple; the components are high in bonding capability; a novel gene vector preparation method is provided for the gene therapy.
Description
Technical field
The invention belongs to Nanosized Supramolecular Materials Composed of Host technical field, particularly a kind of supermolecule nano assembly for gene therapy and preparation method thereof.
Background technology
Gene therapy (Gene Therapy) utilizes gene (DNA or RNA) as a kind of methods for the treatment of diseases of medicine.Adopting gene therapy successfully to cure ADA Adenosine deaminase (ADA) genetic flaw disease from nineteen ninety America NI H clinical center first time, gene therapy obtains and develops fast in two more than ten years, and a lot of gene therapy approach also enters clinical experimental stage.Consider that exposed gene is difficult to be engulfed by biological cell, and the nucleic acid Enzyme be easy in body degraded, therefore found the emphasis that stable, efficient and safe genophore just becomes scientist's research, see 1) Niven, R.; Pearlman, R.; Wedeking, T.; Mackeigan, J.; Noker, P.; Simpson-Herren, L.; Smith, J. G.
j. Pharm. Sci. 1998, 87,1292-9; 2) Ortiz Mellet, C.; Garc í a Fern á ndez, J. M.; Benito, J. M.
chem. Soc. Re. 2011, 40,1586-608.Up to the present, a variety of biomolecule, such as virus, liposome, dendrimers and inorganic metal nanoparticle etc., be used for gene therapy, see 1 by as genophore) Tanaka, T.; Cao, Y.; Folkman, J.; Fine, H. A.
cancer Res. 1998, 58,3362-3369; 2) Ooya, T.; Choi, H. S.; Yamashita, A.; Yui, N.; Sugaya, Y.; Kano, A.; Maruyama, A.; Akita, H.; Ito, R.; Kogure, K.; Harashima, H.
j. Am. Chem. Soc.2006,128,3852-3; 3) Haensler, J.; Szoka Jr., F. C.
bioconjugate Chem.1993,4,372-379; 4) Wang, H.; Chen, Y.; Li, X.-Y.; Liu, Y.
mol. Pharm.2007,4,189-198.Wherein, golden nanometer particle (Gold Nanoparticle) because of its high-ratio surface, stablize low toxicity, be easy to prepare and chemical physical property that higher drug delivery ability etc. is unique, be subject to paying close attention to more and more widely, see 1) Connor, E. E.; Mwamuka, J.; Gole, A.; Murphy, C. J.; Wyatt, M. D.
small (Weinheim an der Bergstrasse, Germany) 2005, 1,325-327; 2) Shenoy, D.; Little, S.; Langer, R.; Amiji, M.
mol. Pharm. 2005, 2,357-366; 3) Sahoo, S. K.; Labhasetwar, V.
mol. Pharm. 2005, 2,373-383.The people such as Rotello have been reported the ligand modified golden nanometer particle of quaternary ammonium cation and can have been interacted, see Han, G. by charge attraction and DNA skeleton; Martin, C. T.; Rotello, V. M.
chem. Bio. Drug Des. 2006, 67,78-82.Subsequently, Klibanov seminar proves, the golden nanometer particle that dendroid polymine (PEI) is modified is compared with the PEI of unmodified, and its transfection efficiency improves 12 times, see Thomas, M.; Klibanov, A. M.
proc. Natl. Acad. Sci. USA 2003, 100,9138-9143.The people such as Rotello utilize adjacent nitrobenzyl fat as linking group further, modify on golden nanometer particle by a kind of quaternary ammonium salt, obtain the DNA nano-carrier of a kind of photoinduction release, see Han, G.; You, C.-C.; Kim, B.-J.; Turingan, R. S.; Forbes, N. S.; Martin, C. T.; Rotello, V. M.
angew. Chem. Int. Ed. Engl.2006,45,3165-3169.Although golden nanometer particle is studied widely as genophore, at present mainly through the method for covalent modification, functional gene is connected on golden nanometer particle.So just there is building-up process complexity, be difficult to obtain the shortcomings such as the nano material with sophisticated functions.On the other hand, be different from traditional covalent chemical, main research molecule weak interaction is as the supramolecular chemistry method of Van der Waals force, electrostatic interaction, pi-pi accumulation and hydrophobic interaction etc., molecule can be utilized to assemble the supramolecular aggregation obtaining having many components labyrinth, realize the insoluble problem of some covalent chemical.
On the other hand, in supramolecular chemistry research, cyclodextrin (Cyclodextrin) is the very important host compound of a class.Cyclodextrin to be joined end to end the macrocyclic compound formed by Isosorbide-5-Nitrae-glycosidic bond by D-(+)-glucopyranose units.Carry out the number of glucose unit in representative ring dextrin traditionally with L.C.Greek, modal as α-, β-and gamma-cyclodextrin are respectively containing 6,7 and 8 glucose units.The cyclodextrin hydrophobic cavity degree of depth be about 7.0, α-, β-and the cavity inside diameter of gamma-cyclodextrin are respectively 4.5,7.0 and 8.5.Owing to having hydrophobic cavity and hydrophilic outer surface, and have the microenvironment of chirality, cyclodextrin optionally various organic and inorganic the and biomolecule of bonding can form host-guest inclusion complexes.Meanwhile, cyclodextrin also has good water solublity, biocompatibility and the feature such as nontoxic, makes it more and more be subject to the extensive concern of chemist and biomedical sector expert.In research comparatively early, we find, cyclodextrin modified golden nanometer particle effectively can condense DNA and is delivered in cell, see Wang, H.; Chen, Y.; Li, X.-Y.; Liu, Y.
mol. Pharm.2007,4,189-198.The super-molecule assembling body based on cyclodextrin containing aromatic group also can condense DNA, see 1 effectively) Liu, Y.; Yu, L.; Chen, Y.; Zhao, Y.-L.; Yang, H.
j. Am. Chem. Soc.2007,129,10656-10657; 2) Liu, Y.-P.; Yu, Z.-L.; Zhang, Y.-M.; Guo, D.-S.; Liu, Y.-P.
j. Am. Chem. Soc.2008,130,10431-10439; 3) Chen, Y.; Yu, L.; Feng, X.-Z.; Hou, S.; Liu, Y.
chem. Commun.2009,4106-4108.These find to impel us to design and construct based on cyclodextrin modified golden nanometer particle and the supermolecule gene delivery system containing aromatic group object.
Summary of the invention
The object of the invention is for above-mentioned technical Analysis, a kind of supermolecule nano assembly for gene therapy and preparation method thereof is provided, the adamantane guest that this supermolecule nano assembly is modified based on cyclodextrin modified golden nanometer particle and anthracene, DNA can be condensed, and its cohesion ability can regulate by regulating Subjective and Objective ratio.
Technical scheme of the present invention:
For a supermolecule nano assembly for gene therapy, its construction unit is based on cyclodextrin modified golden nanometer particle, and the diamantane (obsolete) that anthracene is modified is object, constructs super-molecule assembling body by host-guest Inclusion property.
A described preparation method for the supermolecule nano assembly of gene therapy, step is as follows:
1) under argon shield, to the dimethyl sulphoxide solution of 6-thioctamide-6 deoxidation beta-schardinger dextrin-and sodium borohydride be dissolved with and be dissolved with the dimethyl sulphoxide solution rapid mixing of gold chloride, under room temperature, lucifuge stirs 24 hours, then adding acetonitrile makes product separate out, centrifugalize solid also washs 8-10 time with the mixed solution of dimethyl sulfoxide and acetonitrile, under 0.1MPa, obtain rufous golden nanometer particle solid after vacuum drying;
2) 9-anthracene aldehyde and diethylenetriamine being added volume ratio is in the dehydrated alcohol of 5:3 and the mixed solvent of dichloromethane, stirring at room temperature is after 24 hours, add sodium borohydride, continue stirring 8 hours, removal of solvent under reduced pressure, with dichloromethane extraction after residue distilled water wash, after organic facies anhydrous sodium sulfate drying, removal of solvent under reduced pressure, under 0.1MPa, vacuum drying obtains solid, by gained solid and 1-adamantane acid acid chloride dissolves in 20 mL anhydrous methylene chlorides, then triethylamine is added, under argon shield, stirring at room temperature is after 8 hours, removal of solvent under reduced pressure, residue is using the dichloromethane of volume ratio 10:1 and methanol mixed solvent as eluent, adopt silica gel thin-layer chromatography to be separated and obtain 1.27 grams of white solid N-(9-first anthryls)-N'-diamantane (obsolete) formamido ethylethylenediamine (An-Ad) product,
3) by above-mentioned obtained rufous golden nanometer particle solid and N-(9-first anthryl)-N'-diamantane (obsolete) formamido ethylethylenediamine is dissolved in water, and can obtained solution state supermolecule nano assembly after Homogeneous phase mixing.
Described 6-thioctamide-6 deoxidation beta-schardinger dextrin-, sodium borohydride, gold chloride, dimethyl sulfoxide and acetonitrile content are than being 1mmol:5mmol:100mmol:4.5L:4.5L.
In described mixed solution, the volume ratio of dimethyl sulfoxide and acetonitrile is 1:1.
Described 9-anthracene aldehyde, diethylenetriamine, dehydrated alcohol and the mixed solvent of dichloromethane and the amount ratio of sodium borohydride are 1.1 grams: 2.7 mL:200 mL:1.9 gram; The amount ratio of 9-anthracene aldehyde, 1-adamantane acid acyl chlorides, anhydrous methylene chloride and triethylamine is 1.1 grams: 1.0 grams: 20 mL:2.1 mL.
The concentration of described golden nanometer particle in water is 0.62 g/L, N-(9-first anthryl)-the N '-concentration of diamantane (obsolete) formamido ethylethylenediamine in water is 1 × 10
-6-2 × 10
-4mol/L.
Advantage of the present invention is: this supermolecule nano assembly can condense by inducing DNA effectively, and its cohesion ability can regulate by controlling Subjective and Objective input ratio easily, has a wide range of applications in field of gene; Its preparation method is simple, has stronger binding ability, for gene therapy provides a kind of method preparing genophore newly between component.
[accompanying drawing explanation]
Fig. 1 is that the structure of subject and object and super-molecule assembling body construct schematic diagram.
Fig. 2 is beta-schardinger dextrin-and N-(9-first anthryl) the calorimetric titration curve of-N '-diamantane (obsolete) formamido ethylethylenediamine object bonding behavior.
Fig. 3 is the transmission electron microscope picture of cyclodextrin modified golden nanometer particle.
Fig. 4 is the transmission electron microscope picture of super-molecule assembling body.
Fig. 5 is that super-molecule assembling body absorbance is with calf thymus DNA concentration curve.
Fig. 6 is under fixed dna concentration conditions, and golden nanometer particle absorbance is with N-(9-first anthryl)-N '-diamantane (obsolete) formamido ethylethylenediamine object concentration curve.
Fig. 7 is plasmid DNA (pBR322) agarose gel electrophoresis figure under different Subjective and Objective concentration.
Fig. 8 is super-molecule assembling body cohesion calf thymus DNA transmission electron microscope picture.
Fig. 9 is super-molecule assembling body cohesion calf thymus DNA atomic force microscope figure.
Figure 10 is that super-molecule assembling body is to MCF-7-7(MCF-7) 3-(4 of cell, 5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt (MTT) toxicity tests.
[detailed description of the invention]
Embodiment:
For a supermolecule nano assembly for gene therapy, its construction unit is based on cyclodextrin modified golden nanometer particle, and the diamantane (obsolete) that anthracene is modified is object, constructs super-molecule assembling body by host-guest Inclusion property; Its preparation method, step is as follows:
1) 20 mL are dissolved with gold chloride (50.0 mg, 0.1 mmol) dimethyl sulphoxide solution and 20 mL be dissolved with 6-thioctamide-6 deoxidation beta-schardinger dextrin-(20.0 mg, 0.02 mmol) and sodium borohydride (75.5 mg, 2.0 mmol) dimethyl sulphoxide solution rapid mixing, and at room temperature stir 24 hours.Then in reactant mixture, add 40 mL acetonitriles, product is settled out.By precipitation and centrifugal separation, and wash 8 times with the mixed solution of the dimethyl sulfoxide/acetonitrile of 100 mL volume ratio 1:1.The product molecular cut off of collected by centrifugation be the bag filter of 3500 to redistilled water dialysis for several times, rotary evaporation is except after desolventizing, and vacuum drying 12 hours under 80 ° of C, 0.1MPa conditions, obtains ring and stick with paste the golden nanometer particle (AuNP) modified.Elementary analysis (%): C, 10.10; H, 2.73; N, 0.30.Atomic emission spectrum (ICP) measures Au content (%): 25.7.Calculating golden nanometer particle cyclodextrin content is 0.162 mmol/g.
2) be dissolved in the mixed solvent of 125 mL dehydrated alcohol and 75 mL dichloromethane by 1.1 grams of 9-anthracene aldehyde and 2.7 mL diethylenetriamines, stirring at room temperature, after 24 hours, adds 1.9 grams of sodium borohydrides, continues stirring 8 hours.Removal of solvent under reduced pressure, residue is with 50 mL distilled water washs and with 200 mL dichloromethane extractions.After organic facies anhydrous sodium sulfate drying, removal of solvent under reduced pressure, vacuum drying under 0.1MPa.By gained solid and 1.0 grams of 1-diamantane (obsolete) acyl chlorides and be dissolved in 20 mL anhydrous methylene chlorides, then add 2.1 mL triethylamines.Under argon shield, stirring at room temperature is after 8 hours; removal of solvent under reduced pressure; residue is with the methylene chloride/methanol mixed solvent of volume ratio 10:1 for eluent, and silica gel thin-layer chromatography is separated and obtains 1.27 grams of white solid N-(9-first anthryls)-N'-diamantane (obsolete) formamido ethylethylenediamine (An-Ad) product (productive rate: 55.7%).
1h NMR (D
2o, 400MHz): δ (ppm)=1.47-1.72 (m, 12H), 1.84-1.93 (s, 3H), 3.00-3.09 (t, 2H), 3.27-3.50 (m, 6H), 5.08-5.15 (s, 2H), 7.53-7.61 (t, 2H), 7.63-7.72 (t, 2H), 8.04-8.13 (d, 2H), 8.18-8.26 (d, 2H), (8.56-8.62 s, 1H).
13c NMR (D
2o, 100MHz): δ (ppm)=183.1,130.9,130.2,129.5,127.7,125.5,122.7,47.7,43.5,40.4,38.2,36.2,35.6,27.5. high resolution mass spectrum (MALDAI, m/z): theoretical value: [M+H]+456.3015, experiment value: 456.3013. elementary analysis (%): theoretical value: C
30h
37n
3o5H
2o, C 66.03, H 8.68, N 7.70; Experiment value: C 66.29, H 8.64, N 8.00.
3) by the N-(9-first anthryl of above-mentioned 6.20 obtained mg golden nanometer particle respectively with 0.05 mg, 0.46 mg, 2.3 mg, 4.6 mg and 9.2 mg)-N '-diamantane (obsolete) formamido ethylethylenediamine object to be dissolved in 1 mL water and Homogeneous phase mixing, the super-molecule assembling body of obtained different surfaces object inclusion rate.
Fig. 1 is that the structure of subject and object and super-molecule assembling body construct schematic diagram.
Fig. 2 is beta-schardinger dextrin-and N-(9-first anthryl) the calorimetric titration curve of-N '-diamantane (obsolete) formamido ethylethylenediamine object bonding behavior, show in figure: beta-schardinger dextrin-and N-(9-first anthryl) there is higher binding constants between-N '-diamantane (obsolete) formamido ethylethylenediamine, stable host-gust inclusion complexes can be formed under experimental conditions.
Fig. 3 is the transmission electron microscope picture of cyclodextrin modified golden nanometer particle, shows in figure: obtained golden nanometer particle is mean diameter 3.3 ± 0.5 nanometer spherical particle.
Fig. 4 is the transmission electron microscope picture of super-molecule assembling body, shows in figure: after forming super-molecule assembling body, and golden nanometer particle is energy stable existence, and does not observe obvious clustering phenomena.
The experiment of this super-molecule assembling body cohesion DNA:
1) in aqueous, the concentration (0.62 g/L) of fixing super-molecule assembling body, add the calf thymus DNA of variable concentrations, measure the absorbance of solution, find that surface plasma resonance (SPR) peak of the golden nanometer particle of about 520 nm increases with DNA concentration, there is Red Shift Phenomena, prove the reunion that golden nanometer particle occurs, as shown in Figure 5.
2) in aqueous, fixing calf thymus DNA (5 × 10
-5and the concentration of cyclodextrin modified golden nanometer particle (0.62 g/L) mol/L), add the object of variable concentrations, measure the absorbance of solution, find that surface plasma resonance (SPR) peak of the golden nanometer particle of about 520 nm increases with object concentration, there is Red Shift Phenomena, prove that assembly increases along with the increase of surperficial object inclusion rate the cohesion ability of DNA, as shown in Figure 6.
3) concentration of fixing plasmid DNA (pBR 322), adds the golden nanometer particle of variable concentrations, object and assembly solution, carries out agarose gel electrophoresis experiment.Result as shown in Figure 7,1 is wherein with to be independent DNA(5 μ g/L), band 2 is DNA(5 μ g/L) and cyclodextrin modified golden nanometer particle CD-AuNP([CD]=0.90 μM), band 3 is DNA(5 μ g/L) and object An-Ad(0.90 μM), band 4-8 is DNA(5 μ g/L) and assembly (concentration is respectively: [CD]=[
3]=0.05 μM, 0.10 μM, 0.30 μM, 0.50 μM, and 0.70 μM).Result surface, along with the increase of assembly concentration, DNA mobility reduces, and after assembly concentration is more than 0.30 μM, grasping holes phenomenon appears in part DNA, as shown in Figure 7.Show that assembling physical ability condenses DNA effectively.
4) characterized by transmission electron microscope, prove that assembly can make calf thymus DNA cohesion into about the aggregation of 40 ran, as shown in Figure 8.
5) characterized by atomic force microscope, prove that filling body can make calf thymus DNA cohesion into about the aggregation of 40 ran, as shown in Figure 9.
6) 3-(4 is passed through, 5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt (MTT) cytotoxicity experiments show, under experimental concentration, super-molecule assembling body is to MCF-7-7(MCF-7) cell do not demonstrate obvious toxicity, as shown in Figure 10.
Claims (1)
1. the preparation method for the supermolecule nano assembly of gene therapy, described supermolecule nano assembly construction unit is based on cyclodextrin modified golden nanometer particle, the diamantane (obsolete) that anthracene is modified is object, construct super-molecule assembling body by host-guest Inclusion property, it is characterized in that preparation process is as follows:
1) under argon shield, to the dimethyl sulphoxide solution of 6-thioctamide-6 deoxidation beta-schardinger dextrin-and sodium borohydride be dissolved with and be dissolved with the dimethyl sulphoxide solution rapid mixing of gold chloride, under room temperature, lucifuge stirs 24 hours, then adding acetonitrile makes product separate out, centrifugalize solid also washs 8-10 time with the mixed solution of dimethyl sulfoxide and acetonitrile, under 0.1MPa, obtain rufous golden nanometer particle solid after vacuum drying;
2) 9-anthracene aldehyde and diethylenetriamine being added volume ratio is in the dehydrated alcohol of 5:3 and the mixed solvent of dichloromethane, stirring at room temperature is after 24 hours, add sodium borohydride, continue stirring 8 hours, removal of solvent under reduced pressure, with dichloromethane extraction after residue distilled water wash, after organic facies anhydrous sodium sulfate drying, removal of solvent under reduced pressure, under 0.1MPa, vacuum drying obtains solid, by gained solid and 1-diamantane (obsolete) acid chloride dissolves in 20 mL anhydrous methylene chlorides, then triethylamine is added, under argon shield, stirring at room temperature is after 8 hours, removal of solvent under reduced pressure, residue is using the dichloromethane of volume ratio 10:1 and methanol mixed solvent as eluent, adopt silica gel thin-layer chromatography to be separated and obtain 1.27 grams of white solid N-(9-first anthryls)-N'-diamantane (obsolete) formamido ethylethylenediamine product,
3) by above-mentioned obtained rufous golden nanometer particle solid and N-(9-first anthryl)-N'-diamantane (obsolete) formamido ethylethylenediamine is dissolved in water, and can obtained solution state supermolecule nano assembly after Homogeneous phase mixing;
Wherein in step 1), 6-thioctamide-6 deoxidation beta-schardinger dextrin-, sodium borohydride, gold chloride, dimethyl sulfoxide and acetonitrile content are than being 1mmol:5mmol:100mmol:4.5L:4.5L, and in mixed solution, the volume ratio of dimethyl sulfoxide and acetonitrile is 1:1;
Wherein step 2) in, the mixed solvent of 9-anthracene aldehyde, diethylenetriamine, dehydrated alcohol and dichloromethane, the amount ratio of sodium borohydride are 1.1 grams: 2.7 mL:200 mL:1.9 gram; The amount ratio of 9-anthracene aldehyde, 1-diamantane (obsolete) acyl chlorides, anhydrous methylene chloride and triethylamine is 1.1 grams: 1.0 grams: 20 mL:2.1 mL;
Wherein in step 3), the concentration of golden nanometer particle in water is 0.62 g/L, N-(9-first anthryl)-the N '-concentration of diamantane (obsolete) formamido ethylethylenediamine in water is 1 × 10
-6-2 × 10
-4mol/L.
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| CN102698286A (en) * | 2012-07-02 | 2012-10-03 | 南开大学 | Supramolecule assembly of targeting-delivery anticancer adamplatin and preparation of supramolecule assembly |
| CN103263673A (en) * | 2013-06-07 | 2013-08-28 | 南开大学 | Polysaccharide-gold-nanoparticle supermolecule assembled body as well as preparation method and application thereof |
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| CN102698286A (en) * | 2012-07-02 | 2012-10-03 | 南开大学 | Supramolecule assembly of targeting-delivery anticancer adamplatin and preparation of supramolecule assembly |
| CN103263673A (en) * | 2013-06-07 | 2013-08-28 | 南开大学 | Polysaccharide-gold-nanoparticle supermolecule assembled body as well as preparation method and application thereof |
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