CN110152017A - A kind of multi-functional super-molecule assembling body and its preparation method and application based on nano-graphene - Google Patents
A kind of multi-functional super-molecule assembling body and its preparation method and application based on nano-graphene Download PDFInfo
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- 229910021389 graphene Inorganic materials 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims abstract description 58
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 30
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 26
- 229960004853 betadex Drugs 0.000 claims abstract description 26
- -1 Four amine cations Chemical class 0.000 claims abstract description 19
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 18
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 18
- 238000010276 construction Methods 0.000 claims abstract description 7
- 230000003993 interaction Effects 0.000 claims abstract description 6
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 238000003384 imaging method Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 238000005292 vacuum distillation Methods 0.000 claims description 6
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 claims description 5
- 238000012986 modification Methods 0.000 claims description 5
- 230000004048 modification Effects 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 4
- 238000012377 drug delivery Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000005119 centrifugation Methods 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000005956 quaternization reaction Methods 0.000 claims description 2
- 238000002604 ultrasonography Methods 0.000 claims description 2
- IIYWTFLFMVZQET-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3.C1C(C2)CC3CC1CC2C3 IIYWTFLFMVZQET-UHFFFAOYSA-N 0.000 claims 10
- 150000001412 amines Chemical class 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 238000005034 decoration Methods 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 229960001156 mitoxantrone Drugs 0.000 abstract description 11
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 abstract description 11
- 239000013612 plasmid Substances 0.000 abstract description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 7
- 206010028980 Neoplasm Diseases 0.000 abstract description 6
- 201000011510 cancer Diseases 0.000 abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 5
- 238000009825 accumulation Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract description 2
- 238000001727 in vivo Methods 0.000 abstract description 2
- 150000002500 ions Chemical group 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 238000012544 monitoring process Methods 0.000 abstract description 2
- 239000000523 sample Substances 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 11
- 238000000034 method Methods 0.000 description 5
- 238000003745 diagnosis Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000002073 fluorescence micrograph Methods 0.000 description 2
- 238000001502 gel electrophoresis Methods 0.000 description 2
- 239000012216 imaging agent Substances 0.000 description 2
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004169 mitoxantrone hydrochloride Drugs 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6486—Measuring fluorescence of biological material, e.g. DNA, RNA, cells
Abstract
A kind of multi-functional super-molecule assembling body and its preparation method and application based on nano-graphene.For the assembly construction unit based on beta-cyclodextrin modified nano-graphene, the double level Four amine cations of adamantane are object, construct multi-functional super-molecule assembling body by supermolecule host-guest interaction between cyclodextrin and adamantane.The present invention selects small size nano-graphene as constructing skeleton, the accumulative, distribution and release using inherent photoluminescent property as fluorescence probe come real-time monitoring drug in vivo；The bonding and release that amphoteric ion structure can be easily achieved Plasmid DNA are formed using the ester linkage hydrolyzing in the double level Four amine cations of adamantane；It is acted on by the pi-pi accumulation between graphene and the aromatic ring of drug molecule and loads to anticancer drug mitoxantrone on water-soluble super-molecule assembling body；The multi-functional Supramolecular Assembling preparation is simple, easy to implement and cost of material is low, it is made to have broad application prospects in the novel therapeutic field of cancer.
Description
Technical field
It is controllably bonded the present invention relates to cell imaging, DNA and drug delivery techniques field, especially one kind is based on nanometer
Multi-functional super-molecule assembling body of graphene and its preparation method and application.
Background technique
Construct multi-functional synergistic treatment carrier will two kinds or more kinds of diagnosis and treatment methods be combined together and have become
A kind of potential cancer treatment method, and more and more concerns were being caused in recent years.Therefore, various to be based on inorganic nano-particle
Son, carbon nanomaterial, liposome, vesica multifunctional carrier be developed, and tumour cell is shown effectively to treat
Effect.However, these multifunctional carriers constructed by covalent modification need complicated synthesis and separation step during constructing
Suddenly, time-consuming and laborious, limit its further application.Therefore, to solve the above-mentioned problems, supermolecule host-guest interaction is to pass through
Noncovalent interaction constructs complicated molecular assembly and provides an easily and efficiently method, can be by introducing variety classes
Functional group simply implement the multifunction of system.In addition, constructing while carrying more function of imaging agents and therapeutic reagent
The diagnosis and treatment that energy carrier mediates imaging are of great significance, and can be realized early diagnosis and the early treatment of cancer.
In various imaging agents, nano-graphene is due to for example superpower fluorescent emission of its own distinctive property, anti-light
Bleachability and intermolecular pi-pi accumulation effect becomes the research hotspot of biomedicine field.Therefore, supermolecule Subjective and Objective is made
It is had a good application prospect with being applied to nano-graphene in the building of multi-functional super-molecule assembling body.
Summary of the invention
Object of the present invention is to analyze in view of the above technology and there are problems, provide a kind of based on the multi-functional of nano-graphene
Super-molecule assembling body and its preparation method and application, solves existing multifunctional carrier synthesis and separating step is complicated, time-consuming and laborious
The problems such as.The super-molecule assembling body has the controllable binding ability of DNA, cell fluorescence imaging capability and drug delivery ability,
The novel diagnosis and treatment field of cancer has broad application prospects.The assembling preparation is simple, is suitable for amplification synthesis and reality is raw
Produce application.
Technical solution of the present invention:
A kind of multi-functional super-molecule assembling body based on nano-graphene, construction unit is with the nanometer of beta-cyclodextrin modified
Based on graphene, chemical formula are as follows: C192H255N9O114, using the double level Four amine cations of adamantane as object, chemical formula are as follows:
C38H60N4O8 2+, multi-functional Supramolecular Assembling made of being constructed by supermolecule host-guest interaction between cyclodextrin and adamantane
Body；Wherein the nano-graphene of beta-cyclodextrin modified modifies nano-graphene and mono- 6- deoxidation -6- nitrine-by three propargyls
Click between beta-cyclodextrin reacts to obtain, the double level Four amine cations of adamantane be adamantane di-tertiary amine and bromoacetate into
Row quaternization reaction obtains, and the structure difference of the multi-functional super-molecule assembling body construction unit is as follows:
A kind of preparation method of the multi-functional super-molecule assembling body based on nano-graphene, comprising the following steps:
1) synthesis of the nano-graphene (HBCCD) of beta-cyclodextrin modified
Three propargyls are modified into nano-graphene and mono- 6- deoxidation -6- nitrine-beta-cyclodextrin is dissolved in anhydrous N, N- dimethyl
In formamide solution, cuprous iodide is then added, under nitrogen protection, is stirred to react 70-74h under the conditions of 80 DEG C.By reaction solution
It is cooled to room temperature, filters and filtrate is removed into solvent through vacuum distillation after removing mantoquita, then inverted preparation chromatographic column obtains yellow β-
Cyclodextrin modified nano-graphene.
2) synthesis of the double level Four amine cations (ADA) of adamantane
Adamantane di-tertiary amine is dissolved in acetonitrile, bromoacetate is then added, mixed liquor stirs 22- under the conditions of 25 DEG C
26h.Reaction solution is removed into solvent through vacuum distillation, ether is then added and generates white precipitate, solid is collected by centrifugation, and use ether
It washes twice, obtains the double level Four amine cations of white adamantane.
3) preparation of the multi-functional super-molecule assembling body (HBCCD-ADA) based on nano-graphene
By above-mentioned steps 2) made from the double level Four amine cations of adamantane are soluble in water obtains solution a, by above-mentioned steps 1)
Beta-cyclodextrin modified nano-graphene obtained, which is dissolved in dimethyl sulfoxide, obtains solution b, then mixes solution a and solution b
And ultrasound 10min at room temperature, that is, multi-functional super-molecule assembling body is prepared.
Three propargyls modification nano-graphene, mono- 6- deoxidation -6- nitrine-beta-cyclodextrin and iodate are sub- in the step 1)
The molar ratio of copper is 0.145:0.58:0.58；The anhydrous N,N-dimethylformamide solution of three propargyls modification nano-graphene
Concentration be 2.42mmol/L；The concentration of the anhydrous N,N-dimethylformamide solution of mono- 6- deoxidation -6- nitrine-beta-cyclodextrin
For 9.67mmol/L.
The concentration of the acetonitrile solution of adamantane di-tertiary amine is 0.067mol/L in the step 2)；Adamantane di-tertiary amine and bromine
The molar ratio of ethyl acetate is 1:2.5.
The concentration of the double quaternary ammonium compound cationic aqueous solutions of adamantane is 0.1mmol/L in step 3) the solution a, in solution b
The concentration of the dimethyl sulphoxide solution of beta-cyclodextrin modified nano-graphene is 1.33mmol/L, the volume ratio of solution a and solution b
For 39:1.
It is controllable that multi-functional super-molecule assembling body of the present invention based on nano-graphene can be applied to cell imaging, DNA
In bonding and drug delivery.
The advantages of the present invention are:
1) due in multi-functional super-molecule assembling body photoluminescent property, we select the nano-graphene of small size as
Skeleton is constructed, the accumulative, distribution and release of real-time monitoring drug in vivo can be used to as fluorescence probe；2)
Plasmid DNA can easily be realized by forming amphoteric ion structure using the ester linkage hydrolyzing in the double level Four amine cations of adamantane
Bonding and release；3) π-π heap between graphene and the aromatic ring of anti-tumor drug molecule (such as mitoxantrone (MTX)) can be passed through
Product effect easily loads to anticancer drug on water-soluble super-molecule assembling body；4) the multi-functional super-molecule assembling body preparation
Method is simple, easy to implement and cost of material is low, it is made to have broad application prospects in the novel therapeutic field of cancer.
Detailed description of the invention
Fig. 1 prepares schematic diagram for the multi-functional super-molecule assembling body based on nano-graphene.
Fig. 2 is the transmission electron microscope figure of the multi-functional super-molecule assembling body based on nano-graphene.
Fig. 3 is the ultra-violet absorption spectrum that the multi-functional super-molecule assembling body based on nano-graphene loads mitoxantrone.
Fig. 4 is the gel electrophoresis figure that the multi-functional super-molecule assembling body based on nano-graphene is controllably bonded Plasmid DNA.
Fig. 5 is the multi-functional super-molecule assembling body cell fluorescence image based on nano-graphene.
Specific embodiment
Below by example, the present invention is described further:
Embodiment 1:
A kind of multi-functional super-molecule assembling body based on nano-graphene, construction unit is with beta-cyclodextrin modified nanometer stone
Based on black alkene, chemical formula are as follows: C192H255N9O114, using the double level Four amine cations of adamantane as object, chemical formula are as follows:
C38H60N4O8 2+, multi-functional super-molecule assembling body is constructed by supermolecule host-guest interaction between cyclodextrin and adamantane；Wherein
Beta-cyclodextrin modified nano-graphene by three propargyls modify nano-graphene and mono- 6- deoxidation -6- nitrine-beta-cyclodextrin it
Between click react to obtain, the double level Four amine cations of adamantane are adamantane di-tertiary amine and bromoacetate carry out it is quaternized anti-
It should obtain, the structure of the multi-functional super-molecule assembling body construction unit is as follows:
The preparation method of multi-functional super-molecule assembling body of the present invention based on nano-graphene, comprising the following steps:
1) synthesis of the nano-graphene (HBCCD) of beta-cyclodextrin modified
Three propargyl of 150mg (0.145mmol) is modified into nano-graphene and the mono- 6- deoxidation -6- nitrine-β-ring of 674mg
Dextrin (0.58mmol) is dissolved in the anhydrous n,N-Dimethylformamide solution of 60mL, and 110mg (0.58mmol) iodate is then added
It is cuprous, under nitrogen protection, 72h is stirred to react under the conditions of 80 DEG C.Reaction solution is cooled to room temperature, filtering will filter after removing mantoquita
Liquid removes solvent through vacuum distillation, then inverted preparation chromatographic column obtains yellow beta-cyclodextrin modified nano-graphene；
The beta-cyclodextrin modified nano-graphene nuclear-magnetism of detection display preparation is characterized as below:1HNMR(400MHz,DMSO-d6,
TMS, ppm): δ=3.37 (m, 54H), 3.66 (m, 72H), 4.13 (m, 27H), 4.51-4.84 (m, 39H), 5.50-5.78 (m,
48H),8.29(s,3H),8.74-9.01(m,12H)。
2) synthesis of the double level Four amine cations (ADA) of adamantane
526.7mg (1mmol) adamantane di-tertiary amine is dissolved in 15mL acetonitrile, 277 μ L (2.5mmol) bromine second are then added
Acetoacetic ester, mixed liquor stir for 24 hours under the conditions of 25 DEG C.Reaction solution is removed into solvent through vacuum distillation, 50mL ether is then added
Generate white precipitate, solid be collected by centrifugation, and wash twice with ether (2 × 50mL), obtain white adamantane pair quaternary ammonium compound sun from
Son；
The double quaternary ammonium compound cation nuclear-magnetisms of adamantane of detection display preparation are characterized as below:1HNMR(400MHz,D2O,TMS,
Ppm): δ=1.15-1.19 (t, 6H), 1.66-1.77 (m, 6H), 1.88 (m, 6H), 2.02 (s, 3H), 2.12 (m, 4H), 3.27
(s,12H),3.41-3.71(m,8H),4.14-4.15(m,4H),4.30(s,4H),5.19(s,2H),7.43(s,2H),7.77
(s,1H)。
3) preparation of the multi-functional super-molecule assembling body (HBCCD-ADA) based on nano-graphene
The double level Four amine cations of 1.38mg adamantane are dissolved in 15.6mL water and obtain solution a, by 2.40mg beta-cyclodextrin
Modification nano-graphene is dissolved in 400 μ L dimethyl sulfoxides and obtains solution b, then mixes solution a and solution b and at room temperature
Multi-functional super-molecule assembling body is prepared in ultrasonic 10min.
Fig. 1 prepares schematic diagram for the multi-functional super-molecule assembling body based on nano-graphene.
Fig. 2 is the transmission electron microscope figure of the multi-functional super-molecule assembling body based on nano-graphene, passes through transmission electricity
Sub- microscopic characterization is it can be concluded that the super-molecule assembling body forms the nano spherical particle that partial size is 300nm.
Embodiment 2:
The experimental verification that the multi-functional super-molecule assembling body loads anticancer drug mitoxantrone:
0.65mg mitoxantrone hydrochloride is dissolved in 0.5mL deionized water, the oversubscription of the above-mentioned preparation of 10mL is added dropwise to
Subgroup fills in liquid solution, and mixed liquor, which is protected from light, is stirred at room temperature 12h.It is then charged into the bag filter that retention range is 500 and dialyses
Acquired solution freeze-drying can be prepared by the multi-functional super-molecule assembling body of load anticarcinogen mitoxantrone by 2h.Fig. 3 is based on nanometer
The ultra-violet absorption spectrum that the multi-functional super-molecule assembling body of graphene loads mitoxantrone.As can be seen from the figure in 500-
At 700nm, there is the characteristic absorption peak of mitoxantrone.Show that anticancer drug mitoxantrone can act on very by pi-pi accumulation
It readily loads on water-soluble super-molecule assembling body.By the standard curve of mitoxantrone calculate mitoxantrone load factor
It is 4.76%.
Embodiment 3:
The experimental verification that the multi-functional super-molecule assembling body is controllably bonded Plasmid DNA:
250mg agarose is dissolved in 25mL TAE (0.04M Tris, 0.02M acetic acid, and 2.0mM
EDTA) in buffer solution, Ago-Gel is made.The dosage of fixed every hole Plasmid DNA is 75ng, N/P ratio (assembly leaded wastewater
With the ratio of Plasmid DNA P content) it is 20, assembly hydrolysis front and back is investigated to the cohesion ability of Plasmid DNA.Fig. 4 is based on nanometer
The gel electrophoresis figure that the multi-functional super-molecule assembling body of graphene is controllably bonded Plasmid DNA.It can be seen from the figure that in N/P
When than being 20, assembly can agglomerate completely Plasmid DNA, after assembly is hydrolyzed by sodium hydroxide solution, in same N/P item
Plasmid DNA is released under part.Show to can use the ester linkage hydrolyzing in the double level Four amine cations of adamantane formed both sexes from
The bonding and release of minor structure realization Plasmid DNA.
Embodiment 4: application of the multi-functional super-molecule assembling body in cell imaging
Concrete application effect of the invention is as follows:
HCT-116 cell (human colon cancer cell) is layered on to being total to for McCoy ' the s 5A culture medium containing 10% fetal calf serum
It focuses and is cultivated in capsule for 24 hours, be added after assembly continuously cultivates for 24 hours, washed three times with PBS buffer solution, then with 4% poly first
Aldehyde solution the cells are fixed 15min.Then micro- with laser co-focusing after nucleus being dyed five minutes with DAPI (1 μ g/mL)
Sem observation.Fig. 5 is the multi-functional super-molecule assembling body cell fluorescence image based on nano-graphene.It can be seen from the figure that
Assembly shows apparent green fluorescence in the cell, shows that assembly can be used in cell imaging, in terms of cancer diagnosis
With potential application prospect.
Claims (6)
1. a kind of multi-functional super-molecule assembling body based on nano-graphene, the construction unit of the assembly is with beta-cyclodextrin modified
Nano-graphene based on, chemical formula are as follows: C192H255N9O114, using the double level Four amine cations of adamantane as object, chemical formula
Are as follows: C38H60N4O8 2+, multi-functional oversubscription subgroup made of being constructed by supermolecule host-guest interaction between cyclodextrin and adamantane
Fill body；Wherein the nano-graphene of beta-cyclodextrin modified modifies nano-graphene by three propargyls and mono- 6- deoxidation -6- is folded
Click between nitrogen-beta-cyclodextrin reacts to obtain, and the double level Four amine cations of adamantane are adamantane di-tertiary amine and bromoacetate
It carries out quaternization reaction to obtain, the structure difference of the multi-functional super-molecule assembling body construction unit is as follows:
2. a kind of preparation method of the multi-functional super-molecule assembling body based on nano-graphene as described in claim 1, feature
Be the following steps are included:
1) synthesis of the nano-graphene (HBCCD) of beta-cyclodextrin modified
Three propargyls are modified into nano-graphene and mono- 6- deoxidation -6- nitrine-beta-cyclodextrin is dissolved in anhydrous N, N- dimethyl formyl
In amine aqueous solution, cuprous iodide is then added, under nitrogen protection, is stirred to react 70-74h under the conditions of 80 DEG C；Reaction solution is cooling
It to room temperature, filters and filtrate is removed into solvent through vacuum distillation after removing mantoquita, then inverted preparation chromatographic column obtains yellow β-ring paste
Nano-graphene is adornd in refine；
2) synthesis of the double level Four amine cations (ADA) of adamantane
Adamantane di-tertiary amine is dissolved in acetonitrile, bromoacetate is then added, mixed liquor stirs 22-26h under the conditions of 25 DEG C；
Reaction solution is removed into solvent through vacuum distillation, ether is then added and generates white precipitate, solid is collected by centrifugation, and washed with ether
It washs, obtains the double level Four amine cations of white adamantane；
3) preparation of the multi-functional super-molecule assembling body (HBCCD-ADA) based on nano-graphene
By above-mentioned steps 2) made from the double level Four amine cations of adamantane are soluble in water obtains solution a, by above-mentioned steps 1) be made
Beta-cyclodextrin modified nano-graphene be dissolved in dimethyl sulfoxide and obtain solution b, then by solution a and solution b mix and
Ultrasound 10min at room temperature, that is, be prepared multi-functional super-molecule assembling body.
3. the preparation method of the multi-functional super-molecule assembling body based on nano-graphene, feature exist according to claim 2
It rubs in: three propargyls described in step 1) modification nano-graphene, mono- 6- deoxidation -6- nitrine-beta-cyclodextrin, cuprous iodide
You are than being 0.145:0.58:0.58；Three propargyls modify the concentration of the anhydrous N,N-dimethylformamide solution of nano-graphene
For 2.42mmol/L；The concentration of the anhydrous N,N-dimethylformamide solution of mono- 6- deoxidation -6- nitrine-beta-cyclodextrin is
9.67mmol/L。
4. the preparation method of the multi-functional super-molecule assembling body based on nano-graphene, feature exist according to claim 2
In: the concentration of the acetonitrile solution of adamantane di-tertiary amine described in step 2) is 0.067mol/L；Adamantane di-tertiary amine and bromoacetic acid
The molar ratio of ethyl ester is 1:2.5.
5. the preparation method of the multi-functional super-molecule assembling body based on nano-graphene, feature exist according to claim 2
In: the concentration of the double quaternary ammonium compound cationic aqueous solutions of adamantane is 0.1mmol/L in step 3) the solution a, β-ring paste in solution b
The concentration of the dimethyl sulphoxide solution of refine decorations nano-graphene is that the volume ratio of 1.33mmol/L, solution a and solution b are 39:
1。
6. the application of the multi-functional super-molecule assembling body described in claim 1 based on nano-graphene, it is characterised in that the base
In nano-graphene multi-functional super-molecule assembling body can be applied to cell imaging, DNA be controllably bonded and drug delivery in.
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