CN108096214A - A kind of magnetotactic bacteria quantum dot microcapsules and preparation method thereof - Google Patents
A kind of magnetotactic bacteria quantum dot microcapsules and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
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- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- 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
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/501—Inorganic compounds
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
Abstract
The present invention proposes a kind of magnetotactic bacteria quantum dot microcapsules, and the kernel of the microcapsules is magnetic corpusculum, and the mixture of homogeneous, fine and close chitosan oligosaccharide/γ polyglutamic acids/carbon quantum dot is wrapped up on magnetic corpusculum surface；The magnetic corpusculum and the mass ratio of chitosan, γ polyglutamic acids, carbon quantum dot are 1:1‑3:10‑20：1.The preparation method of the magnetotactic bacteria quantum dot microcapsules of the present invention is easy to operate, and typical nucleocapsid is presented with carbon quantum dot intelligence microcapsules in obtained magnetic corpusculum, and this quantum dot microcapsules have the ability of targeting and sustained release, have very big clinical practice future.
Description
Technical field
The present invention relates to biomedicine field, more particularly to a kind of magnetotactic bacteria quantum dot microcapsules further relate to one kind and become
The preparation method of magnetic bacterium quantum dot microcapsules.
Background technology
The transfer mode of drug has vital influence for the therapeutic effect of cancer, and wherein tumor-targeting drug passes
It passs with very big challenge.As research of the nanometer technology in biomedical sector deepens continuously, magnetic Nano material is also subject to
Many concerns.Magnetotactic bacteria (Magnetotactic bacterium) is that a kind of orientation that can make under the action of external magnetic field is transported
It is dynamic and form that nano magnetic particle --- the bacterium of magnetic corpusculum (Magnetosome), in recent years, magnetotactic bacteria and magnetic are small in vivo
Body has become new living resources and has been widely studied in multiple subject necks such as materialogy, medicine, biology, physics, geology
Domain, and be applied in multiple fields such as bionics, ecology, medicine, geology, industrial treatment, sanitary inspections.Magnetic bacterial body
Interior synthesizing chain-like arrangement has the coated Fe of outer membrane3O4Or Fe3S4Magnetic-particle --- magnetic corpusculum.Magnetic corpusculum particle is single magnetic domain
Crystal, uniform in size, nanoscale (20~120nm) have larger ratio face amount, have biomembrane coating outside particle, do not generate thin
Cellular toxicity has fabulous biocompatibility, but exposed magnetic corpusculum is due to high specific surface area, easy induced particle
Between aggregation, cause grain size increase, bad stability, be unable to reach the requirement of biomedical applications.Therefore magnetism must be passed through
The surface modification of nanostructured reduces intergranular interaction, improves its water-soluble, stability and surface-functional.
Carbon is one of element that content is most abundant in nature and forms the most basic element of life entity.Carbon amounts
Son point is made of scattered near-spherical particle, and size is in below 10nm, the novel nano carbon material with photoluminescent property.With biography
System semiconductor-quantum-point is compared, and carbon quantum dot, which not only has, is similar to the luminescent properties of traditional quantum dot and nano-scale characteristic,
And with good water solubility, chemical inertness, easy functionalization, high resistance to photobleaching, hypotoxicity and good biocompatibility etc.
Characteristic, therefore obtain extensive concern in different research fields.
Chitosan oligosaccharide is the second largest renewable natural polymer for being only second to cellulose in the world, it has biology can
The many merits such as degradation, nontoxicity, bioactivity, biocompatibility and antibiotic property.Simultaneously containing hydroxyl and amino, property in molecule
Matter is more active, it can be coupled, activated and modified.Gamma-polyglutamic acid is a kind of water-soluble biodegradable
Polymer substance, has the characteristics that edible, nontoxic, cohesiveness, moisture retention, and application field covers medicine, chemical industry, food
The many aspects such as product, cosmetics and daily chemical product.Especially in field of medicaments, as drug targeting carrier, gamma-polyglutamic acid exists
It can be biodegradable into Endogenous Amino Acids in human body, have no toxic and side effect to human body.Simultaneously as it is there are more side chain carboxyl group, it can
To be used after modifying it as pharmaceutical carrier.
How a kind of transfer mode of drug is provided, is transferred for tumor-targeting drug, is current urgent problem to be solved.
The content of the invention
The present invention proposes a kind of magnetotactic bacteria quantum dot microcapsules and preparation method thereof, by magnetic corpusculum and carbon quantum dot and
Biomaterial mixing prepares slow-release microcapsule,, can also using microcapsules as sustained release oral dosage forms according to different therapeutic purposes
The slow release formulation of target drug-carrying is used to prepare, can be applied to biomedicine field, realizes magnetically fixed target slow-release administration.
The technical proposal of the invention is realized in this way：
A kind of magnetotactic bacteria quantum dot microcapsules, the kernel of the microcapsules are the single domain structures of magnetic corpusculum, the small body surface of magnetic
Bread wraps up in the mixture of chitosan oligosaccharide, gamma-polyglutamic acid and carbon quantum dot；The magnetic corpusculum and chitosan, gamma-polyglutamic acid and carbon
The mass ratio of quantum dot is：
1 parts by weight of magnetic corpusculum
Chitosan 1-3 parts by weight
Gamma-polyglutamic acid 10-20 parts by weight
1 parts by weight of carbon quantum dot.
Optionally, the granularity of the microcapsules is less than 100nm.
Optionally, the grain size of the microcapsules is 50~80nm, and polydispersity coefficient is below 0.2.
Optionally, the molecular weight of the chitosan oligosaccharide is 1KD, and the molecular weight of gamma-polyglutamic acid is 40KD, and carbon quantum dot is with day
Right graphene is prepared for raw material.
Optionally, the grain size of the microcapsules is 50~80nm, and polydispersity coefficient is below 0.2.
Optionally, the grain size of the magnetic corpusculum is 20~50nm.
Optionally, carrying medicament is adriamycin.
The invention also provides a kind of preparation method of above-mentioned magnetotactic bacteria quantum dot microcapsules, step includes：
Step (1), native graphite alkene is added in the concentrated sulfuric acid and concentrated nitric acid mixed liquor, and mixture elder generation ultrasonic disperse is equal
It is even, after be stirred at reflux at 100 DEG C；The solution for obtaining brownish black is first cooled to room temperature, and afterwards plus deionized water dilutes；Plus carbon then
It is in sour sodium and remaining sour to the pH of solution to 8；Obtained solution is concentrated by rotary evaporation, and the inorganic salts of precipitation are crossed and are filtered out
It goes, the bag filter that the filtrate cutoff of collection is 8000~14000 is dialysed, and obtains the aqueous solution of pure carbon quantum dot；It will
The aqueous solution of carbon quantum dot carries out freezing and drains to obtain carbon quantum dot solid, is scattered in again in aqueous solution；
Step (2) will add in the chitosan oligosaccharide of 1/3~2/3 amount in dispersion liquid, mixing, after 95 DEG C are reacted 1h, ultrasound centrifuges,
After bulky grain cryomilling therein processing, remaining chitosan oligosaccharide is added in, 60 DEG C are reacted 1h again, and freeze-drying is redissolved in
In water, magnetic corpusculum is added in, after stirring evenly, adds in gamma-polyglutamic acid, magnetic agitation obtains composite micro-capsule；
Step (3) washs composite micro-capsule by absolute ethyl alcohol, and magnet separation finally in 60 DEG C of vacuum dryings, obtains
Magnetotactic bacteria quantum dot microcapsules.
Optionally, carbon quantum dot concentration 0.2mg/mL in the aqueous solution.
Optionally, in step (2), by 120~150min of bulky grain liquid cryomilling therein to granularity for 50~
100nm。
The beneficial effects of the invention are as follows：
(1) chitosan oligosaccharide utilized has the characteristics that antibacterial, nontoxic, good biocompatibility；Gamma-polyglutamic acid, which has, to be protected
The features such as wet, nontoxic, good biocompatibility；Carbon quantum dot not only has the luminescent properties for being similar to traditional quantum dot with receiving
Rice dimensional characteristic, and with good water solubility, chemical inertness, easy functionalization, high resistance to photobleaching, hypotoxicity and good life
The characteristics such as object compatibility；Magnetic corpusculum particle is single magnetic domain crystal, has larger ratio face amount, has biomembrane coating outside particle, no
Cytotoxicity is generated, there is fabulous biocompatibility, the particle of below 100nm, the party are generated after four kinds of substance cross-linking reactions
Method is easy to operate；Typical nucleocapsid is presented in obtained magnetotactic bacteria quantum dot microcapsules, and kernel is single magnetic of magnetic corpusculum
Domain structure, shell are made of homogeneous, fine and close CS/ γ-PGA/ carbon quantum dots, show good dispersiveness, and with preferable
Colloidal stability；Detected again after 40 days, as a result with it is consistent before, it was demonstrated that there is good stability.
(2) single domain structure of magnetic corpusculum is highly stable at normal temperatures, and the drug release rate included is relatively low, and is handing over
Under varying magnetic field (ACMF) effect, the magnetothermal effect based on its kernel, CS/ γ-PGA membrane structures and the permeability hair of nanocrystal surface
Changing, so as to the drug controlled release for promoting it internal；By playing the high magnetic and active targeting of carrier, in body tissue
Inside fully enrichment and alternation heat production, plays heat-therapeutic action；Meanwhile heating can also promote drug release to tumor tissues inside and
The sensitization of drug molecule, so as to play Chemotherapy.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical scheme is clearly and completely described, it is clear that
Described embodiment is only part of the embodiment of the present invention, instead of all the embodiments.Based on the implementation in the present invention
Example, those of ordinary skill in the art's all other embodiments obtained without making creative work, belongs to
The scope of protection of the invention.
The present invention provides a kind of magnetotactic bacteria quantum dot microcapsules, with higher stability and with targeting,
Biomedicine field can be used for oncotherapy.Meanwhile the present invention also provides the preparations of above-mentioned magnetotactic bacteria quantum dot microcapsules
Method, chitosan oligosaccharide, gamma-polyglutamic acid and magnetic corpusculum and carbon quantum dot is compound, and method is easy to operate.
Magnetotactic bacteria quantum dot microcapsules of the present invention and preparation method thereof are illustrated separately below.
The present invention provides a kind of magnetotactic bacteria quantum dot microcapsules, the kernels of the microcapsules is magnetic corpusculum, the small body surface of magnetic
Bread wraps up in the mixture of homogeneous, fine and close chitosan oligosaccharide/gamma-polyglutamic acid/carbon quantum dot；The magnetic corpusculum and chitosan, γ-poly-
Glutamic acid, the mass ratio of carbon quantum dot are 1:1-3:10-20：1.
The granularity of magnetotactic bacteria quantum dot microcapsules provided by the invention is less than 100nm.
Further, the molecular weight of the chitosan oligosaccharide is 1KD, and the molecular weight of gamma-polyglutamic acid is 40KD, carbon quantum dot with
Native graphite alkene is prepared for raw material.
Further, the grain size of the magnetic corpusculum is 20~50nm.
Further, the grain size of the magnetotactic bacteria quantum dot microcapsules be 50~80nm, polydispersity coefficient 0.2 with
Under.
Further, carrying medicament is adriamycin.
The raw materials used in the present invention is commercially available from market, chitosan oligosaccharide molecular size range be 1KD, gamma-polyglutamic acid molecule
Amount size is 40KD.
The present invention also provides a kind of preparation methods of above-mentioned magnetotactic bacteria quantum dot microcapsules, comprise the following steps：
The native graphite alkene of 300mg is added in the concentrated sulfuric acid of 60mL and the concentrated nitric acid mixed liquor of 20mL by step (1),
Mixture first ultrasound 2h be uniformly dispersed, after be stirred at reflux for 24 hours at 100 DEG C.The solution for obtaining brownish black is first cooled to room temperature, after
Deionized water is added to be diluted to total volume about 800mL.Then it is plus in sodium carbonate and remaining sour to the pH of solution to 8 or so.It obtains
Solution concentrated by rotary evaporation, a large amount of inorganic salts of precipitation are filtered to remove, the filtrate of collection is with cutoff
8000~14000 bag filter is dialysed four days, you can obtains the aqueous solution of pure carbon quantum dot.The aqueous solution of carbon quantum dot is carried out
Freezing, which is drained, can obtain carbon quantum dot solid, be scattered in again in aqueous solution；
Step (2) will add in the chitosan oligosaccharide of 1/3~2/3 amount in aqueous solution, mixing, after 95 DEG C are reacted 1h, ultrasound centrifuges,
It after bulky grain cryomilling therein processing, adds in remaining 60 DEG C of chitosan oligosaccharide and reacts 1h again, be freeze-dried, be redissolved in water
In, magnetic corpusculum is added in, adriamycin is added in after stirring 30min, after stirring evenly, adds in gamma-polyglutamic acid, magnetic agitation 12h is obtained
To microcapsules；
Step (3) washs composite micro-capsule by absolute ethyl alcohol, and magnet separation finally in 60 DEG C of vacuum dryings, must become
Magnetic bacterium quantum dot microcapsules.
In above-mentioned steps (1)~step (3), the numerical value of used quality and volume is only schematical, this field skill
Art personnel according to the present invention can instruct, and is improved according to the proportionate relationship of quality and volume, without should be by above-mentioned steps
In limitation of the concrete numerical value as the scope of the present invention.
Further, in step (1), carbon quantum dot concentration 0.2mg/mL in the aqueous solution.
Further, in step (2), by 120~150min of the bulky grain chitosan oligosaccharide cryomilling to granularity for 50~
100nm。
Further, in step (2), the chitosan oligosaccharide concentration is 0.4mg/mL.
Further, in step (2), the gamma-polyglutamic acid concentration is 2mg/mL.
Further, in step (2), the magnetic bulk concentration is 0.2mg/mL.
Magnetic corpusculum and carbon quantum dot and biomaterial mixing are prepared slow-release microcapsule by the present invention, according to different treatment mesh
, using microcapsules as sustained release oral dosage forms, it can be used for preparing the slow release formulation of target drug-carrying, can be applied to biological doctor
Magnetically fixed target slow-release administration is realized in medicine field.
The chitosan oligosaccharide that the present invention utilizes has the characteristics that antibacterial, nontoxic, good biocompatibility；Gamma-polyglutamic acid has
There is the features such as moisturizing, nontoxic, good biocompatibility；Carbon quantum dot not only has the luminescent properties for being similar to traditional quantum dot
With nano-scale characteristic, and with good water solubility, chemical inertness, easy functionalization, high resistance to photobleaching, hypotoxicity and well
The characteristics such as biocompatibility, magnetic corpusculum particle is single magnetic domain crystal, has larger ratio face amount, has biomembrane bag outside particle
Quilt does not generate cytotoxicity, has fabulous biocompatibility, and the particle of below 100nm is generated after four kinds of substance cross-linking reactions,
This method is easy to operate.Typical nucleocapsid is presented in obtained magnetotactic bacteria quantum dot microcapsules, and kernel is magnetic corpusculum
Single domain structure, shell are made of homogeneous, fine and close CS/ γ-PGA/ carbon quantum dots, show good dispersiveness, and have
Preferable colloidal stability；Detected again after 40 days, as a result with it is consistent before, it was demonstrated that there is good stability.
The single domain structure of magnetic corpusculum of the present invention is highly stable at normal temperatures, and the drug release rate included is relatively low, and
Under alternating magnetic field (ACMF) effect, the magnetothermal effect based on its kernel, the CS/ γ-PGA membrane structures of nanocrystal surface and infiltration
Property change, so as to the drug controlled release for promoting it internal.By playing the high magnetic and active targeting of carrier, in body
Fully enrichment and alternation heat production, plays heat-therapeutic action in tissue.Meanwhile heating can also promote drug release in tumor tissues
Portion and the sensitization of drug molecule, so as to play Chemotherapy.The effect of complex carrier combination magnetic thermotherapy and chemotherapy of the present invention
Mode, institute's carrying medicament can realize the growth for effectively inhibiting tumour whithin a period of time, be had more than single thermotherapy or chemotherapy
The future of clinical practice application.
The preparation method of the magnetotactic bacteria quantum dot microcapsules of the present invention is carried out specifically with reference to specific embodiment
It is bright.
Embodiment 1
A kind of preparation method of magnetotactic bacteria quantum dot microcapsules, step include：
The native graphite alkene of 300mg is added in the concentrated sulfuric acid of 60mL and the concentrated nitric acid mixed liquor of 20mL by step (1), is mixed
Close object first ultrasound 2h be uniformly dispersed, after be stirred at reflux for 24 hours at 100 DEG C.The solution for obtaining brownish black is first cooled to room temperature, rear to add
Deionized water is diluted to total volume about 800mL.Then it is plus in sodium carbonate and remaining sour to the pH of solution to 8 or so.It obtains
Solution is concentrated by rotary evaporation, and a large amount of inorganic salts of precipitation are filtered to remove, and the filtrate cutoff of collection is 8000
~14000 bag filter is dialysed four days, you can obtains the aqueous solution of pure carbon quantum dot.
In above-mentioned steps (1), the aqueous solution of carbon quantum dot is carried out freezing to drain to can obtain carbon quantum dot solid, again
It is dissolved in 10mL water, concentration 0.2mg/mL；
Step (2) adds in 1.5mg chitosan oligosaccharides into step (1) reaction system, mixing, after 95 DEG C of reaction 1h, ultrasound
Bulky grain cryomilling 120min therein to granularity is 50nm, 60 DEG C of 2.5mg chitosan oligosaccharides is added to react again by 10min, centrifugation
1h, freeze-dried 12h are redissolved in 10mL water, and 30min is stirred after adding in 2mg magnetic corpusculums, add in 1mL 5mg/mL Ah
Mycin methanol solution, is stirring evenly and then adding into the gamma-polyglutamic acid of 20mg, and magnetic agitation 12h obtains microcapsules；
Step (3) washs composite micro-capsule by absolute ethyl alcohol, and magnet separation finally in 60 DEG C of vacuum dryings, obtains iridium
Nana intelligent combination drug.
Grain size is 50-80nm to iridium nana intelligent combination drug made from the present embodiment 1 after testing, and typical nucleocapsid knot is presented
Structure, kernel are the single domain structures of magnetic corpusculum, and homogeneous, fine and close chitosan oligosaccharide, gamma-polyglutamic acid and carbon amounts are wrapped up in magnetic corpusculum surface
The mixture (CS/ γ-PGA/ carbon quantum dots) of son point；The matter of the magnetic corpusculum and chitosan, gamma-polyglutamic acid and carbon quantum dot
Amount is than being 1:2:10:1, and favorable dispersibility, polydispersity coefficient have preferable colloidal stability below 0.2；
Magnetotactic bacteria quantum dot microcapsules drug load factor is 7.89%, and medicine encapsulation ratio 92.17%, drug concentration reaches
The sustainable release 72h of effective concentration, there is good sustained release performance.It is detected after 40 days, it is as a result consistent with its, it was demonstrated that have good
Stability.
Embodiment 2：
A kind of preparation method of magnetotactic bacteria quantum dot microcapsules, step include：
The native graphite alkene of 300mg is added in the concentrated sulfuric acid of 60mL and the concentrated nitric acid mixed liquor of 20mL by step (1), is mixed
Close object first ultrasound 2h be uniformly dispersed, after be stirred at reflux for 24 hours at 100 DEG C.The solution for obtaining brownish black is first cooled to room temperature, rear to add
Deionized water is diluted to total volume about 800mL.Then it is plus in sodium carbonate and remaining sour to the pH of solution to 8 or so.It obtains
Solution is concentrated by rotary evaporation, and a large amount of inorganic salts of precipitation are filtered to remove, and the filtrate cutoff of collection is 8000
~14000 bag filter is dialysed four days, you can obtains the aqueous solution of pure carbon quantum dot.The aqueous solution of carbon quantum dot is freezed
It drains and can obtain carbon quantum dot solid, be redissolved in 10mL water, concentration 0.2mg/mL；
Step (2) adds in 1mg chitosan oligosaccharides into step (1) reaction system, mixing, after 95 DEG C of reaction 1h, ultrasonic 10min,
Bulky grain cryomilling 120min therein to granularity is 50nm, 60 DEG C of 2mg chitosan oligosaccharides is added to react 1h again by centrifugation, chilled
Dry 12h, is redissolved in 10mL water, stirs 30min after adding in 2mg magnetic corpusculums, the 5mg/mL adriamycin methanol for adding in 1mL is molten
Liquid, is stirring evenly and then adding into the gamma-polyglutamic acid of 25mg, and magnetic agitation 12h obtains microcapsules；
Step (3) washs composite micro-capsule by absolute ethyl alcohol, and magnet separation finally in 60 DEG C of vacuum dryings, obtains iridium
Nana intelligent combination drug.
Grain size is 50-80nm to iridium nana intelligent combination drug made from the present embodiment 2 after testing, and typical nucleocapsid knot is presented
Structure, kernel are the single domain structures of magnetic corpusculum, and homogeneous, fine and close chitosan oligosaccharide, gamma-polyglutamic acid and carbon amounts are wrapped up in magnetic corpusculum surface
The mixture (CS/ γ-PGA/ carbon quantum dots) of son point；The matter of the magnetic corpusculum and chitosan, gamma-polyglutamic acid and carbon quantum dot
Amount is than being 2:3:25:2, and favorable dispersibility, polydispersity coefficient have preferable colloidal stability below 0.2；
Magnetotactic bacteria quantum dot microcapsules drug load factor is 5.43%, and medicine encapsulation ratio 87.96%, drug concentration reaches
The sustainable release 72h of effective concentration, there is good sustained release performance.It is detected after 40 days, it is as a result consistent with its, it was demonstrated that have good
Stability.
Embodiment 3：
A kind of preparation method of magnetotactic bacteria quantum dot microcapsules, step include：
The native graphite alkene of 300mg is added in the concentrated sulfuric acid of 60mL and the concentrated nitric acid mixed liquor of 20mL by step (1), is mixed
Close object first ultrasound 2h be uniformly dispersed, after be stirred at reflux for 24 hours at 100 DEG C.The solution for obtaining brownish black is first cooled to room temperature, rear to add
Deionized water is diluted to total volume about 800mL.Then it is plus in sodium carbonate and remaining sour to the pH of solution to 8 or so.It obtains
Solution is concentrated by rotary evaporation, and a large amount of inorganic salts of precipitation are filtered to remove, and the filtrate cutoff of collection is 8000
~14000 bag filter is dialysed four days, you can obtains the aqueous solution of pure carbon quantum dot.The aqueous solution of carbon quantum dot is freezed
It drains and can obtain carbon quantum dot solid, be redissolved in 10mL water, concentration 0.2mg/mL；
Step (2) adds in 2mg chitosan oligosaccharides into step (1) reaction system, mixing, after 95 DEG C of reaction 1h, ultrasonic 10min,
Bulky grain cryomilling 120min therein to granularity is 50nm, 60 DEG C of 4mg chitosan oligosaccharides is added to react 1h again by centrifugation, chilled
Dry 12h, is redissolved in 10mL water, stirs 30min after adding in 2mg magnetic corpusculums, the 5mg/mL adriamycin methanol for adding in 1mL is molten
Liquid, is stirring evenly and then adding into the gamma-polyglutamic acid of 30mg, and magnetic agitation 12h obtains microcapsules；
Step (3) washs composite micro-capsule by absolute ethyl alcohol, and magnet separation finally in 60 DEG C of vacuum dryings, obtains iridium
Nana intelligent combination drug.
Grain size is 80-130nm to iridium nana intelligent combination drug made from the present embodiment 3 after testing, and typical nucleocapsid is presented
Structure, kernel are the single domain structures of magnetic corpusculum, and homogeneous, fine and close chitosan oligosaccharide, gamma-polyglutamic acid and carbon are wrapped up in magnetic corpusculum surface
The mixture (CS/ γ-PGA/ carbon quantum dots) of quantum dot；The magnetic corpusculum and chitosan, gamma-polyglutamic acid and carbon quantum dot
Mass ratio is 1:3:15:1, and favorable dispersibility, polydispersity coefficient have preferable colloidal stability below 0.2；
Magnetotactic bacteria quantum dot microcapsules drug load factor is 4.32%, and medicine encapsulation ratio 89.56%, drug concentration reaches
The sustainable release 72h of effective concentration, there is good sustained release performance.It is detected after 40 days, it is as a result consistent with its, it was demonstrated that have good
Stability.
Comparative example 1
Difference from Example 1 is：Step (2) adds in 4mg chitosan oligosaccharides and 20mg into step (1) reaction system
Gamma-polyglutamic acid, 95 DEG C reaction 2h, then ultrasound, be centrifuged off bulky grain after, obtain magnetotactic bacteria quantum dot microcapsules.
Grain size is 90nm to the magnetotactic bacteria quantum dot microcapsules of 1 gained of comparative example after testing, and polydispersity coefficient is left 0.3
The right side, compared to complex carrier, colloidal stability is poor；Drug concentration reaches the sustainable release 60h of effective concentration.It is examined after 40 days
It surveys, occurs significantly building up phenomenon, it is poor compared with the magnetotactic bacteria quantum dot microcapsule stability in embodiment 1.
Comparative example 2
Difference from Example 1 is：Step (2) adds in 4mg chitosan oligosaccharides and 20mg into step (1) reaction system
Gamma-polyglutamic acid, 60 DEG C reaction 2h, then ultrasound, be centrifuged off bulky grain after, obtain magnetotactic bacteria quantum dot microcapsules.
The magnetotactic bacteria quantum dot microcapsules of 2 gained of comparative example, grain size is 120nm after testing, and polydispersity coefficient is left 0.3
The right side, compared to complex carrier, colloidal stability is poor；Drug concentration reaches the sustainable release 60h of effective concentration.It is examined after 40 days
It surveys, occurs significantly building up phenomenon, it is poor compared with the magnetotactic bacteria quantum dot microcapsule stability in embodiment 1.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
With within principle, any modifications, equivalent replacements and improvements are made should all be included in the protection scope of the present invention god.
Claims (10)
1. a kind of magnetotactic bacteria quantum dot microcapsules, it is characterised in that：The kernel of the microcapsules is the single domain structure of magnetic corpusculum,
The mixture of magnetic corpusculum surface package chitosan oligosaccharide, gamma-polyglutamic acid and carbon quantum dot；The magnetic corpusculum and chitosan, γ-poly- paddy
Propylhomoserin and the mass ratio of carbon quantum dot are：
1 parts by weight of magnetic corpusculum
Chitosan 1-3 parts by weight
Gamma-polyglutamic acid 10-20 parts by weight
1 parts by weight of carbon quantum dot.
2. magnetotactic bacteria quantum dot microcapsules according to claim 1, it is characterised in that：The granularity of the microcapsules is less than
100nm。
3. magnetotactic bacteria quantum dot microcapsules according to claim 2, it is characterised in that：The grain size of the microcapsules for 50~
80nm, polydispersity coefficient is below 0.2.
4. magnetotactic bacteria quantum dot microcapsules according to claim 1, it is characterised in that：The molecular weight of the chitosan oligosaccharide is
1KD, the molecular weight of gamma-polyglutamic acid is 40KD, and carbon quantum dot is prepared by raw material of native graphite alkene.
5. magnetotactic bacteria quantum dot microcapsules according to claim 1, it is characterised in that：The magnetotactic bacteria quantum dot is micro-
The grain size of capsule is 50~80nm, and polydispersity coefficient is below 0.2.
6. magnetotactic bacteria quantum dot microcapsules according to claim 1, it is characterised in that：The grain size of the magnetic corpusculum is 20
~50nm.
7. magnetotactic bacteria quantum dot microcapsules according to claim 1, it is characterised in that：Carrying medicament is adriamycin.
8. a kind of preparation method of the magnetotactic bacteria quantum dot microcapsules as described in any one of claim 1~7, which is characterized in that
Step includes：
Step (1), native graphite alkene is added in the concentrated sulfuric acid and concentrated nitric acid mixed liquor, and mixture elder generation ultrasonic disperse is uniform, after
It is stirred at reflux at 100 DEG C；The solution for obtaining brownish black is first cooled to room temperature, and afterwards plus deionized water dilutes；Plus sodium carbonate then
Remaining acid is neutralized to the pH of solution to 8；Obtained solution is concentrated by rotary evaporation, and the inorganic salts of precipitation are filtered to remove,
The bag filter that the filtrate cutoff of collection is 8000~14000 is dialysed, and obtains the aqueous solution of pure carbon quantum dot；By carbon amounts
The aqueous solution of son point carries out freezing and drains to obtain carbon quantum dot solid, is scattered in again in aqueous solution；
Step (2) will add in the chitosan oligosaccharide of 1/3~2/3 amount in dispersion liquid, mixing, after 95 DEG C are reacted 1h, ultrasound centrifuges, by it
In bulky grain cryomilling processing after, add in remaining chitosan oligosaccharide, 60 DEG C are reacted 1h again, freeze-drying, be redissolved in water,
Magnetic corpusculum is added in, after stirring evenly, adds in gamma-polyglutamic acid, magnetic agitation obtains composite micro-capsule；
Step (3) washs composite micro-capsule by absolute ethyl alcohol, and magnet separation finally in 60 DEG C of vacuum dryings, obtains magnetotactic
Bacterium quantum dot microcapsules.
9. preparation method according to claim 8, which is characterized in that carbon quantum dot concentration 0.2mg/ in the aqueous solution
mL。
10. preparation method according to claim 8, it is characterised in that：In step (2), by bulky grain liquid liquid nitrogen therein
120~150min of ball milling to granularity be 50~100nm.
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| CN109395086A (en) * | 2018-11-29 | 2019-03-01 | 曲阜师范大学 | A kind of graphene oxide base composite nano pharmaceutical carrier and preparation method thereof |
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