CN1380132A - Liposome and inorganic material core-shell type nano composite particle and its preparation method and application - Google Patents
Liposome and inorganic material core-shell type nano composite particle and its preparation method and application Download PDFInfo
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- CN1380132A CN1380132A CN 02111132 CN02111132A CN1380132A CN 1380132 A CN1380132 A CN 1380132A CN 02111132 CN02111132 CN 02111132 CN 02111132 A CN02111132 A CN 02111132A CN 1380132 A CN1380132 A CN 1380132A
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
- B01J2/003—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic followed by coating of the granules
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Abstract
The present invention uses liposome inner water phase as nano reactor, and uses inorganic compound as raw material to synthesize inorganic nano particles and form nano composite particles with core-shell type microstructure characteristics. At the same time to lipid membrane is used as interface, and the biological active substance is embedded in the nano composite particle, and its surface can be undergone the process of functional modification. Said invention is a new scheme for simultaneously implementing synthesis of nano particle and its tissue and application, and possesses extensive application in the fields of biological medicine research, medicine transmission, disease diagnosis and therapy and biological preparation, etc.
Description
Technical field: what the present invention relates to is a kind of liposome and inorganic material compound particle and preparation method thereof, and core-shell type nano composite particle of particularly a kind of liposome and inorganic material and its production and application belongs to biomedical engineering field.
Background technology: nanometer biotechnology is the forward position and the hot issue of current international biological technical field, has a wide range of applications and clear and definite industrialization prospect at pharmaceutical sanitary field.At present, nanometer biotechnology is very positive in the research of field of medicaments in the world.And to develop the application of nanometer technology at biomedicine field, also has a vital problem, be exactly how with good characteristic and the biological activity combination of nano particle on physicochemical properties, as the transport property and the pharmaceutically active of nano particle, sensitiveness specificity of the high-specific surface area of nano particle and bio-identification or the like.Have only well to address this problem, just might in biomedical applications, give full play to the advantage of nanometer technology, make a breakthrough.But it is difficult always at present, mainly be because the huge surface of nano particle can, and the unstability that causes, make the effect of they and bioactivator lack specificity and controllability, and will the surface be modified, the reaction of each surface location is very inhomogeneous between each particle, thereby the result also disperses very much, uncontrollable, so, this is a bottleneck problem that the development biomedical applications generally faces, and key will solve the surface stability of nano particle exactly, and excellent biological compatibility and stable biologically active are provided.By literature search, do not find identical or similar bibliographical information is arranged so far as yet with the present invention.
Summary of the invention: the present invention is directed to the deficiencies in the prior art, core-shell type nano composite particle of a kind of liposome and inorganic material and its production and application is provided, the present invention can prepare the controlled and stable, monodispersed nano-complex particle of granularity of a kind of pattern, give compound particle reliable and stable biological respinse interface, accurately controllably bring into play its biologically active, thereby be implemented in many-sided application such as biomedical research, drug delivery and biological preparation.The present invention is a nano-reactor with water in the liposome, synthetic nano-complex particle with core-shell type microstructure characteristics, with amphiphilics such as lipids is that the film material is self-assembled into liposome, the interior water that forms with this liposome is a reactor, with the inorganic compound is raw material, synthesizing inorganic nano particle therein, formation is housing with the liposome, synthetic nano particle is the core-shell type compound particle of nuclear, described liposome be granularity less than 100 microns be the self-organized colloidal particle of water in comprising of isolating with the molecular film, it is represented as phospholipid liposome, described inorganic compound raw material is water-soluble, or acid, or alkali, or the solid of organic solvent, liquid or gas, described synthetic method are chemical synthesis.
Nano-complex particle is an assembling thing, its structure is: core is the nano inoganic particle that synthesizes, and housing is a liposome, can comprise interior water between nuclear-shell, but bioactivator such as embedding medicinal in the nuclear-shell, the shell modified surface have a functional molecular of particular biological characteristic; The assembling thing comprises: the inorganic particulate core is a hydroxyapatite, calcium phosphate, calcium carbonate, barium sulfate, barium titanate, barium aluminate, magnesium aluminate, calcium aluminate, strontium aluminate, silver, gold, manganese, cobalt, nickel, silicon, germanium, selenium, and semiconducting compound, comprise the III-V compound semiconductor, the II-IV compound semiconductor, the IV-VI compound semiconductor, the V-VI compound semiconductor, oxide semiconductor, sulfide semiconductor, rare earth compound semiconductor, especially tri-iron tetroxide, di-iron trioxide, iron oxide yellow, titanium dioxide, silica, alundum (Al, zinc oxide, silver oxide, cadmium sulfide, zinc sulphide, cadmium selenide, zinc selenide, indium phosphide, indium arsenide, GaAs, and any combination of above-claimed cpd.
In compound particle, can comprise one or more medicines, or diagnostic reagent or other biological active material, on lipid film, can modify one or more and have the enhancing particle stability, directed transport, control degradation and release, or the functional molecular of effect such as specific recognition, described medicine and diagnostic reagent are small-molecule drug, albumen, nucleic acid, microorganism, cell, isotope, fluorescence labeling, bioactivators such as magnetic grain, they are embedded in the inorganic particulate, aqueous phase in the liposome, perhaps lipid film is inner or surperficial, and the embedding mode is a physical bond, biological combination, perhaps chemical bond, described functional molecular is all kinds of polymer molecules, albumen, nucleic acid, little molecule ligand, and combination, the associated methods on they and compound particle surface is a physical action, biological agent, or chemical reaction.
The core-shell type nano composite particle of liposome and inorganic material, wherein: the lipid film of compound particle constitute phospholipid molecule, lysolipid molecule, glycolipid (glycolipid) molecule, sterol (sterol) molecule, cation lipid molecule, detergent (detergent) molecule and amphiphilic polymer etc., and combination arbitrarily.
The core-shell type nano composite particle of liposome and inorganic material, wherein: the inorganic material of compound particle is a hydroxyapatite, calcium phosphate, calcium carbonate, barium sulfate, barium titanate, barium aluminate, magnesium aluminate, calcium aluminate, strontium aluminate, silver, gold, manganese, cobalt, nickel, silicon, germanium, selenium, and semiconducting compound, comprise the III-V compound semiconductor, the II-IV compound semiconductor, the IV-VI compound semiconductor, the V-VI compound semiconductor, oxide semiconductor, sulfide semiconductor, rare earth compound semiconductor, especially tri-iron tetroxide, di-iron trioxide, iron oxide yellow, titanium dioxide, silica, alundum (Al, zinc oxide, silver oxide, cadmium sulfide, zinc sulphide, cadmium selenide, zinc selenide, indium phosphide, indium arsenide, GaAs, and any combination of above-claimed cpd.
The core-shell type nano composite particle of liposome and inorganic material, wherein: the functional molecular of compound particle finishing is a hydrophilic polymer, hydrophobic polymer, part, antibody, cell factor, polypeptide, nucleic acid etc., and arbitrarily combination, molecular weight be 50-50000 Dalton. they and surface molecular act as physical action, biological agent, or chemical bond-linking, the degree of modification on surface is the 0-99% mol ratio.
The preparation method of the core-shell type nano composite particle of liposome and inorganic material is: the liposome turbid liquor of one or more ions of the question response of preparation embedding earlier, it is outer not by the ion of the question response of embedding to remove liposome, the another kind or the different kinds of ions solution that add question response then, regulate temperature, reaction conditions such as pH, mix to stir, stop reaction after reaching the reaction target of expectation, wash with buffer solution, deposit for 0-4 ℃, the continuous phase of described suspension is the physiological saline or the buffer solution of deionized water or distilled water or 0.9%, described liposome is by any one conventional method preparation, and the control particle diameter is the narrow distributed area of arbitrary single dispersion between 10nm-10um, described pH response value is pH0-pH14, and described reaction temperature is 0 ℃-100 ℃.
Medicine that is comprised in the described compound particle or other biological active material add before liposome preparation or simultaneously.
Medicine that is comprised in the described compound particle or other biological active material add when inorganic particulate is synthetic.
Medicine that is comprised in the described compound particle or other biological active material add after inorganic particulate is synthetic.
The medicine or the other biological active material that are comprised in the described compound particle added before the compound particle finishing.
Medicine that is comprised in the described compound particle or other biological active material add after the compound particle finishing.
The functional molecular on described compound particle surface is meant before liposome preparation or adds simultaneously.
The functional molecular on described compound particle surface is meant and adds when inorganic particulate is synthetic.
The functional molecular on described compound particle surface is meant after inorganic particulate is synthetic adding.
The functional molecular on described compound particle surface is meant and added before the compound particle medicine loads.
The functional molecular on described compound particle surface is meant after the compound particle medicine loads adding.
The functional molecular on bioactive molecule in the described compound particle and surface comprises physical action, chemical reaction, biological agent etc. with the associated methods of compound particle.
The core-shell type nano composite particle of liposome and inorganic material, its range of application is: biomedical research, medicine are carried, biological preparation.
The present invention has substantive distinguishing features and marked improvement, and the present invention is a kind of tissue that is synthesized to nano particle and new departure that application realizes simultaneously from nano particle, has realized the application in biomedical research, medicine conveying, biological preparation.
The specific embodiment: provide specific embodiment below in conjunction with content of the present invention:
Embodiment 1: modified hydroxyapatite-liposome nano-complex particle bionical synthetic of synexin, and with the effect of cancer cell
With the soybean lecithin is the liposome membrane material, adopts film dispersion method to prepare embedding Ca
2+Liposome, high pressure breast is even, and repeatedly through the extruding of 100nm filter membrane, crosses ion exchange column and remove the free Ca of the outer water of liposome
2+In liposome turbid liquor, add (NH
4)
2HPO
4React, magnetic agitation after half an hour, promptly gets the core-shell type nano composite particle of hydroxyapatite-liposome.With the compound particle centrifugation, clean, and filtration sterilization, be resuspended among the PBS.Get the PEG2000-PE of 80% mol ratio simultaneously, 10%Rhodamine-PE mixes the micellar solution that forms with the molten memebrane protein GALA of 10%pH responsive type, with compound particle solution mixed in equal amounts, stirs 24 hours down at 4 ℃, again the centrifugation compound particle.Promptly obtain the PEG finishing, contain the fluorescent composite nanoparticle of memebrane protein GALA.This particle is added in the cell culture fluid, can observe the fluorescence compound particle, and because GALA reduction along with pH in endosome shows the membrane fusion, hydroxyapatite is released in the cytoplasm by cytophagy.
Embodiment 2: the tri-iron tetroxide of embedding anti-cancer medicine paclitaxel-liposome composite nanoparticle synthetic, and target conveying function
With the DPPC of 65% mol ratio, 30%DOPE, 5%PEG2000-PE and taxol are dissolved in the chloroform altogether, and the rotary evaporation that reduces pressure under the normal temperature is waved clean chloroform and become film, adds FeCl then
3Solution or FeCl
2Solution or FeCl
2With FeCl
3Mixed solution or FeCl
2With Fe (NO
3)
3Mixed solution, high pressure breast is even and repeatedly through the extruding of 100nm filter membrane, crosses ion exchange column and removes the Fe of not embedding
2+And Fe
3+Ion.Drip NaOH solution or NH3HO then, the room temperature lower magnetic force stirs, and promptly gets the tri-iron tetroxide-liposome core-shell type nano composite particle of the embedding taxol of the surperficial PEG of having modification.With this particle purifying, clean sterilization.In zoopery, after the intravenous injection, the PEG of this particle surface modifies can obviously prolong its circulation timei in blood, again by the effect of externally-applied magnetic field, the detected taxol drug concentration of targeting moiety is improved a lot.
Embodiment 3: the tri-iron tetroxide of binding specificity-liposome composite nanoparticle synthetic, and the application in cancer cell detects
The DPPC for preparing 70% mol ratio, the 30%DOPE liposome, and at interior aqueous phase parcel FeCl
3Solution or FeCl
2Solution or FeCl
2With FeCl
3Mixed solution or FeCl
2With Fe (NO
3)
3Mixed solution, high pressure breast is even and repeatedly through the extruding of 100nm filter membrane, crosses ion exchange column and removes the Fe of not embedding
2+And Fe
3+Ion.Drip NaOH solution or NH3HO then, the room temperature lower magnetic force stirs, and promptly obtains the core-shell type nano composite particle of tri-iron tetroxide-liposome.With this particle purifying, to clean, sterilization mixes with the solution of mPEG-DPPE with EGFR antibody-PEG-DPPE, stirs 24 hours down at 4 ℃, again the centrifugation compound particle.Promptly obtain the magnetic composite nanoparticles with EGFR binding specificity of PEG finishing.In animal experiment, the cell (multiple cancer cell) of this particle mating surface EGFR a large amount expression specifically just can detect the existence of this class cell and the position of dense part thereof by nuclear magnetic resonance imaging then.
Claims (9)
1, the core-shell type nano composite particle of a kind of liposome and inorganic material, it is characterized in that with water in the liposome be nano-reactor, synthetic nano-complex particle with core-shell type microstructure characteristics, with amphiphilics such as lipids is that the film material is self-assembled into liposome, with the inorganic compound is raw material synthesizing inorganic nano particle, described liposome be granularity less than 100 microns be the self-organized colloidal particle of water in comprising of isolating with the molecular film, it is represented as phospholipid liposome, described inorganic compound raw material is water-soluble, or acid, or alkali, or the solid of organic solvent, liquid or gas, described synthetic method are chemical synthesis.
2, the core-shell type nano composite particle of this liposome according to claim 1 and inorganic material, it is characterized in that nano-complex particle is an assembling thing, its structure is: core is the nano inoganic particle that synthesizes, housing is a liposome, can comprise interior water between nuclear-shell, but bioactivator such as embedding medicinal in the nuclear-shell, the shell modified surface have a functional molecular of particular biological characteristic; Inorganic particulate core hydroxyapatite, calcium phosphate, calcium carbonate, barium sulfate, barium titanate, barium aluminate, magnesium aluminate, calcium aluminate, strontium aluminate, silver, gold, manganese, cobalt, nickel, silicon, germanium, selenium, and semiconducting compound, comprise the III-V compound semiconductor, the II-IV compound semiconductor, the IV-VI compound semiconductor, the V-VI compound semiconductor, oxide semiconductor, sulfide semiconductor, rare earth compound semiconductor, especially tri-iron tetroxide, di-iron trioxide, iron oxide yellow, titanium dioxide, silica, alundum (Al, zinc oxide, silver oxide, cadmium sulfide, zinc sulphide, cadmium selenide, zinc selenide, indium phosphide, indium arsenide, GaAs, and any combination of above-claimed cpd.
3, the core-shell type nano composite particle of this liposome according to claim 1 and inorganic material, it is characterized in that in compound particle, can comprising one or more medicines, or diagnostic reagent or other biological active material, on lipid film, can modify one or more and have the enhancing particle stability, directed transport, control degradation and release, or the functional molecular of effect such as specific recognition, described medicine and diagnostic reagent are small-molecule drug, albumen, nucleic acid, microorganism, cell, isotope, fluorescence labeling, bioactivators such as magnetic grain, they are embedded in the inorganic particulate, aqueous phase in the liposome, perhaps lipid film is inner or surperficial, the embedding mode is a physical bond, biological combination, perhaps chemical bond, described functional molecular is all kinds of polymer molecules, polypeptide, nucleic acid, little molecule ligand, and combination, the associated methods on they and compound particle surface is a physical action, biological agent, or chemical reaction.
4, the core-shell type nano composite particle of this liposome according to claim 1 and inorganic material, the core-shell type nano composite particle that it is characterized in that liposome and inorganic material, wherein: the lipid film of compound particle constitute phospholipid molecule, lyslipid molecule, glycolipid (glycolipid) molecule, sterol (sterol) molecule, cation lipid molecule, detergent (detergent) molecule and amphiphilic polymer etc., and combination arbitrarily.
5, the core-shell type nano composite particle of this liposome according to claim 1 and inorganic material, the core-shell type nano composite particle that it is characterized in that liposome and inorganic material, wherein: the inorganic material of compound particle is a hydroxyapatite, calcium phosphate, calcium carbonate, barium sulfate, barium titanate, barium aluminate, magnesium aluminate, calcium aluminate, strontium aluminate, silver, gold, manganese, cobalt, nickel, silicon, germanium, selenium, and semiconducting compound, comprise the III-V compound semiconductor, the II-IV compound semiconductor, the IV-VI compound semiconductor, the V-VI compound semiconductor, oxide semiconductor, sulfide semiconductor, rare earth compound semiconductor, especially tri-iron tetroxide, di-iron trioxide, iron oxide yellow, titanium dioxide, silica, alundum (Al, zinc oxide, silver oxide, cadmium sulfide, zinc sulphide, cadmium selenide, zinc selenide, indium phosphide, indium arsenide, GaAs, and any combination of above-claimed cpd.
6, the core-shell type nano composite particle of this liposome according to claim 1 and inorganic material, the core-shell type nano composite particle that it is characterized in that liposome and inorganic material, wherein: the functional molecular of compound particle finishing is a hydrophilic polymer, hydrophobic polymer, part, antibody, cell factor, polypeptide, nucleic acid etc., and combination arbitrarily, molecular weight is the physical action that act as of 50-50000 Dalton. they and surface molecular, biological agent, or chemical bond-linking, the degree of modification on surface is the 0-99% mol ratio.
7, the preparation method of the core-shell type nano composite particle of a kind of liposome and inorganic material, the liposome turbid liquor that it is characterized in that one or more ions of the question response of preparation embedding earlier, it is outer not by the ion of the question response of embedding to remove liposome, the another kind or the different kinds of ions solution that add question response then, regulate temperature, reaction conditions such as pH, mix to stir, stop reaction after reaching the reaction target of expectation, wash with buffer solution, deposit for 0-4 ℃, the continuous phase of described suspension is the physiological saline or the buffer solution of deionized water or distilled water or 0.9%, described liposome is by any one conventional method preparation, and the control particle diameter is that arbitrary single between 10nm-10um disperses narrow distributed area, and described pH response value is pH0-pH14, and described reaction temperature is 0 ℃-100 ℃.
8, the preparation method of the core-shell type nano composite particle of this liposome according to claim 7 and inorganic material is characterized in that the medicine or the other biological active material that are comprised in the described compound particle add before liposome preparation or simultaneously.
Medicine that is comprised in the described compound particle or other biological active material add when inorganic particulate is synthetic.
Medicine that is comprised in the described compound particle or other biological active material add after inorganic particulate is synthetic.
The medicine or the other biological active material that are comprised in the described compound particle added before the compound particle finishing.
Medicine that is comprised in the described compound particle or other biological active material add after the compound particle finishing.
The functional molecular on described compound particle surface is meant before liposome preparation or adds simultaneously.
The functional molecular on described compound particle surface is meant and adds when inorganic particulate is synthetic.
The functional molecular on described compound particle surface is meant after inorganic particulate is synthetic adding.
The functional molecular on described compound particle surface is meant and added before the compound particle medicine loads.
The functional molecular on described compound particle surface is meant after the compound particle medicine loads adding.
The functional molecular on bioactive molecule in the described compound particle and surface and the associated methods of compound particle comprise physical action, chemical reaction, biological agent etc.
9, the application of the core-shell type nano composite particle of a kind of liposome and inorganic material is characterized in that range of application is: biomedical research, medicine are carried, biological preparation.
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| CN 02111132 CN1380132A (en) | 2002-03-22 | 2002-03-22 | Liposome and inorganic material core-shell type nano composite particle and its preparation method and application |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02111132 CN1380132A (en) | 2002-03-22 | 2002-03-22 | Liposome and inorganic material core-shell type nano composite particle and its preparation method and application |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101721749B (en) * | 2009-12-04 | 2013-01-23 | 北京化工大学 | Ferroferric oxide/calcium phosphate nuclear shell structure nano particle and preparation method thereof |
| CN104401955A (en) * | 2014-10-24 | 2015-03-11 | 西北工业大学 | Preparation method for BSA/Zn3(PO4)3 hybrid nanoflower |
| CN106862586A (en) * | 2017-01-20 | 2017-06-20 | 中国科学院高能物理研究所 | One kind is mixed59Fe nanometer gold bars and preparation method thereof |
| CN107952076A (en) * | 2017-11-07 | 2018-04-24 | 徐州医科大学 | A kind of multivesicular liposome/porous carbon nano-complex, preparation method and application |
| CN114502269A (en) * | 2019-10-04 | 2022-05-13 | 国立大学法人北海道大学 | Three-dimensional flow channel structure and method for producing nanoparticles using same |
-
2002
- 2002-03-22 CN CN 02111132 patent/CN1380132A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101721749B (en) * | 2009-12-04 | 2013-01-23 | 北京化工大学 | Ferroferric oxide/calcium phosphate nuclear shell structure nano particle and preparation method thereof |
| CN104401955A (en) * | 2014-10-24 | 2015-03-11 | 西北工业大学 | Preparation method for BSA/Zn3(PO4)3 hybrid nanoflower |
| CN104401955B (en) * | 2014-10-24 | 2016-11-30 | 西北工业大学 | A kind of BSA/Zn3(PO4)3the preparation method of hybridized nanometer flower |
| CN106862586A (en) * | 2017-01-20 | 2017-06-20 | 中国科学院高能物理研究所 | One kind is mixed59Fe nanometer gold bars and preparation method thereof |
| CN106862586B (en) * | 2017-01-20 | 2019-02-15 | 中国科学院高能物理研究所 | One kind is mixed59Fe nanometer gold bar and preparation method thereof |
| CN107952076A (en) * | 2017-11-07 | 2018-04-24 | 徐州医科大学 | A kind of multivesicular liposome/porous carbon nano-complex, preparation method and application |
| CN114502269A (en) * | 2019-10-04 | 2022-05-13 | 国立大学法人北海道大学 | Three-dimensional flow channel structure and method for producing nanoparticles using same |
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