CN108653741A - A kind of natural sericin microballoon and its preparation method and application of metal organic coordination polymer package - Google Patents
A kind of natural sericin microballoon and its preparation method and application of metal organic coordination polymer package Download PDFInfo
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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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
- A61K9/5021—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)
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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
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/14—Polymerisation; cross-linking
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
- A61L2300/406—Antibiotics
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/43—Hormones, e.g. dexamethasone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
Abstract
The present invention relates to a kind of sericin microballoons and the preparation method and application thereof, including：（1）High temperature alkaline extraction extracts the sericin in silk cocoon, is configured to pure silk glue protein solution；（2）Sericin solution is added in corn oil, is dispersed with stirring, crosslinking agent is added dropwise, obtains sericin microballoon；（3）Acetone is added in mixed emulsion, sericin microballoon is cured；（4）Washing, it is dry, obtain sericin microsphere solid；（5）Sericin microballoon is incubated altogether with drug, obtains carrying medicine sericin microballoon；（6）Aldehydes matter and metal ion are added under neutral or weak basic condition, obtains the load medicine sericin microballoon of metal organic coordination polymer package.It is sericin micro-sphere structure stabilization prepared by the present invention, uniform particle diameter, well dispersed in water, remain the fluorescent characteristic of sericin itself.The load medicine sericin microballoon wrapped up by metal organic coordination polymer has both the features such as carrying drug ratio is high, pH is sensitive.
Description
Technical field
The present invention relates to bio-medical composition field, a kind of natural sericin microballoon and organic by metal is referred specifically to
The load medicine sericin microballoon and its preparation method and application of coordination polymer package.
Background technology
Sericin（Silk Sericin）It is a kind of natural polymer stickiness that fibroin albumen surface is wrapped in silk cocoon
Albumen accounts for about the 20-30% of entire silk cocoon content, is mainly made of the polypeptide that molecular weight is 24-400 kDa, including serine,
18 kinds of amino acid such as aspartic acid, glycine.For a long time since the deficiency that people recognize sericin causes it in silk weaving
It is treated as offal treatment in industry, wastes the resource of a large amount of preciousnesses, and causes environmental pollution.In recent years it is found that silk gum
Albumen is in moisturizing, antibacterial, anti-oxidant, anticoagulation and promotees cell Proliferation and stick etc. have outstanding behaviours, while its is good
Good hydrophily, biodegradability and biocompatibility makes it obtain extensive concern in biomedical materials field.Mesh
Sericin and the doping of other high molecular materials are prepared into composite hydrogel holder or composite membrane by preceding existing researcher, are applied to
Organizational project reparation and drug delivery system.In addition, researcher obtains undegradable sericin using lithium bromide extracting method,
The silk gum hydrogel of a variety of injectables is prepared for using simple chemical crosslinking, these hydrogels have good biocompatibility
And degradability, can sertoli cell adherency and proliferation, and a variety of soft tissues can be promoted to damage as tissue engineering bracket material
Wound is repaired.Sericin has good gelation, biofacies as a kind of sustainable, natural macromolecular material for easily obtaining
Capacitive, biodegradability and n cell adhesion property are concerned in organizational project reparation and the research of pharmaceutical carrier,
With prodigious development prospect.
Microballoon（microsphere）It is to utilize the grain size of natural or synthetic high molecular material preparation between 1-100 μm
Spheric granules.Since many drugs can not be used directly, or the effect directly used is undesirable, and people utilize high molecular material packet
It buries drug and drug bearing microsphere is made, to achieve the effect that control administration.Polymer microsphere not only has immobilization carrier distinctive
The advantages that being easily isolated and extracting also has cheap, large specific surface area, favorable dispersibility, is easy to functionalization and biology
The advantages such as compatibility is adjustable.With the intensification that people recognize sericin, concern and exploration of the researchers to silk gum microballoon
Also more and more.The method for preparing silk gum microballoon at present includes mainly that the solidification precipitation method, spray drying process and spray chilling are dry
Dry cross-linking method, however these methods have the following disadvantages：1）Preparation process is complicated, is not easy to implement, as atomizing freeze drying method needs
Silk gum mixed solution is sprayed and is condensed and is collected into -80 DEG C of spaces, just can get silk gum microballoon after freeze-dried；2）It is obtained
Microspherulite diameter size is difficult to accurately control, and the silk gum microballoon such as prepared using the solidification precipitation method, pattern is difficult to control with size；
3）The rate of release for carrying drug is not easy to control, and the load medicine silk gum such as prepared using the solidification precipitation method or atomizing freeze drying method is micro-
Ball drug releasing rate is too fast.
Based on the above, we for the first time using water-in-oil emulsification method combination chemical crosslink technique successfully prepared regular appearance,
The sericin microballoon of uniform particle diameter, favorable dispersibility.This method is simple and practicable, yield is high, non-toxic by-products, preparation process without
Poison is harmless；Silk gum microsphere features smooth surface, the size of acquisition are controllable（5-100 μm）, have both fluorescent characteristic；The microballoon is based on silk
The good biocompatibility of glue protein itself and cell adhesion can effectively carry out the carrying of drug and cell.Further, it utilizes
The method of LBL self-assembly superscribes multiple layer metal organic coordination polymer on the drug bearing microsphere surface, can be wrapped up by changing
The rate of release of drug is controlled in the number of plies of the polymer of microsphere surface, and response intelligence can be carried out according to the pH value of environment
Drug can be discharged.The silk gum microballoon of natural sericin microballoon and metal organic coordination polymer package prepared by emulsion process is in medicine
The research fields such as object carrier, cell carrier, tumour diagnosis and treatment, fluorescent tracing and organizational project are with a wide range of applications.
Invention content
It is an object of the invention to overcome the shortcomings of previous method for preparing microsphere, provide it is a kind of it is simple for process, yield is high, raw
The preparation side of the load medicine sericin microballoon of the good sericin microballoon of object compatibility and metal organic coordination polymer package
Method and purposes.
In order to achieve the above objectives, the load medicine of sericin microballoon provided by the invention, metal organic coordination polymer package
Sericin microballoon and preparation method thereof, the preparation method comprises the following steps：
(1) a certain amount of silk cocoon is weighed, sericin is extracted with high temperature alkaline extraction, can be obtained natural silk through centrifugation, dialysis, freeze-drying
Glue protein solid；
(2) gained sericin solid in step (1) is dissolved in the sericin solution that water is configured to 10 wt% concentration；
(3) gained sericin solution in step (2) is added dropwise in corn oil and (contains a certain amount of emulsifier tween -20), stirred
Mixing keeps its fully emulsified；
(4) crosslinking agent is added dropwise in gained lotion into step (3), stirring keeps its full cross-linked；
(5) acetone is added dropwise in gained lotion into step (4), stirring makes it fully cure；
(6) mixed liquor obtained by step (5) is centrifuged into obtain cured sericin microballoon, acetone washs three times, and vacuum, which is drained, to be obtained
Pure natural sericin microsphere solid.
(7) by natural sericin microballoon obtained by step (6) and drug hybrid reaction, the sericin of carrying medicament is obtained
Microballoon.
(8) will carry obtained by step (7) medicine silk gum microballoon in buffer solution with aldehydes matter such as tannic acid and metal ion such as
It is reacted in ferric ion solutions, obtains the load medicine silk gum microballoon wrapped up by metal organic coordination polymer；Or using obtained by step (6)
Reacted with aldehydes matter such as tannic acid and metal ion such as ferric ion solutions in natural sericin microballoon buffer solution, obtain by
The natural silk gum microballoon of metal organic coordination polymer package.
Further, the silk cocoon selected in the step (1) is normal silkworm silk cocoon kind（White jade, bright moon etc.）, silkworm
Fibroin deletion form mutating variety（185Nd-s, 140Nd-sDeng）It is purchased from Inst. of Silkworm, Chinese Academy of Agricultural Sciences.
Further, the detailed process for extracting sericin includes the following steps：
1) a certain amount of silk cocoon is weighed, is shredded, is washed with water, moisture removal is removed in extruding；
2) silk cocoon fragment obtained by step 1) is soaked in the Na of a concentration of 0.01-0.20 mol/L2CO3In aqueous solution, 80-100
DEG C, 600 rpm heating stirrings are reacted 0.5-1 hours, wherein 20-30 mL Na are added in every gram of silk cocoon2CO3Aqueous solution；
3) solution in step 2) is centrifuged into 5-10 min with 3500 rpm, removes infusible precipitate, obtains clear solution；
4) by acquired solution in step 3) with MW:The bag filter of 3500 Da was dialysed 2-3 days in deionized water, every 6 hours
It is primary to change water；
5) acquired solution in step 4) is centrifuged into 10-15 min with 8000 rpm, removes infusible precipitate, obtains clear solution；
6) acquired solution in step 5) is quick-frozen in liquid nitrogen, it is placed in 2-3 days in vacuum freeze drier and is lyophilized up to complete,
Pure sericin solid is obtained, -20 DEG C of refrigerators is placed in and is sealed.
Further, the dosage of sericin solution and corn oil is 1 in the step (3):5-20, i.e. 1 mL: 5-20
mL；- 20 dosage of emulsifier tween is 1-10% in corn oil, i.e. contains Tween-20 100-1000 μ L in 10 mL corn oils, stir
It is 800 rpm to mix speed, and emulsification times are 10-30 min.
Further, crosslinking agent glutaraldehyde concentration is 25% in the step (4), and addition is the 5-20% of reaction system,
That is 25% glutaraldehyde 0.5-2.0 mL are added in 10 mL reaction systems；Mixing speed is 800 rpm, and crosslinking time is 1-4 hours.
Further, the amount that acetone is added in the step (5) is 5-10 times of reaction system, i.e. 10 mL reaction systems
Middle addition acetone 50-100 mL；Mixing speed is 800 rpm, and hardening time is 20-60 minutes.
Further, drug is antitumor drug, hormone or antibiotic in the step (7).
Further, the Tris buffer concentrations of pH 7.0-9.0 are 10-20 mM, the tannin of addition in the step (8)
Acid solution and ferric chloride hexahydrate solution concentration are respectively 20-40 mg/mL and 10-20 mg/mL, and addition is 0.5-
1.0%, i.e. tannic acid and each 5-10 μ L of ferric chloride hexahydrate solution are added in 1 mL systems.
Further, the tannic acid used in the step (8) could alternatively be as anthocyanidin, catechin, gallic acid,
Other common natural polyphenol substances such as ursin and the polymer of catechol modification.
Further, the ferric ion solutions used in the step (8) could alternatively be aluminium ion, copper ion, magnesium ion
Deng other metal ion solutions.
The present invention provides a kind of microsphere supported preparation sides of the natural sericin of metal organic coordination polymer package
Method.
The present invention can by adjust sericin concentration, emulsifier concentration and water-oil factor etc. control microballoon size and
Form, while the rate of release of drug can be controlled by changing the number of plies for the metal organic coordination polymer that surface is wrapped up,
It can be used for different biomedical uses.
The solution of the present invention has the following advantages：
（1）This method is easy to operate, cost is relatively low, yield is high, is generally applicable in, does not need Special complex instrument etc.；（2）It is manufactured
Sericin microballoon is with good stability, biocompatibility and bioactivity, and appearance is regular, size is controllable, grain size is equal
One, favorable dispersibility；（3）Drug can be controlled by increasing or decreasing the number of plies of microsphere surface metal organic coordination polymer
Rate of release.There is wide application in fields such as organizational project, tumour diagnosis and treatment, fluorescent tracing, pharmaceutical carrier and cell carriers
Foreground.
Description of the drawings
It with sericin solution concentration is 10 wt%, emulsifier concentration 2%, water-oil factor 1 that Fig. 1, which is in the embodiment of the present invention,:
10,15 min of emulsification times, sericin microballoon obtained is dispersed in water the shape appearance figure under simple microscope.
It with sericin solution concentration is 10 wt%, emulsifier concentration 2%, water-oil factor 1 that Fig. 2, which is in the embodiment of the present invention,:
10,15 min of emulsification times, sericin microballoon obtained is dispersed in water the shape appearance figure under fluorescence microscope.
It with sericin solution concentration is 10 wt%, emulsifier concentration 2%, water-oil factor 1 that Fig. 3, which is in the embodiment of the present invention,:
10,15 min of emulsification times, the shape appearance figure under sericin microballoon drying regime obtained under simple microscope.
It with sericin solution concentration is 10 wt%, emulsifier concentration 2%, water-oil factor 1 that Fig. 4, which is in the embodiment of the present invention,:
10,15 min of emulsification times, the shape appearance figure under sericin microballoon drying regime obtained under fluorescence microscope.
It with sericin solution concentration is 10 wt%, emulsifier concentration 2%, water-oil factor 1 that Fig. 5, which is in the embodiment of the present invention,:
10,15 min of emulsification times, the scanning electron microscope shape appearance figure of sericin microballoon obtained.
It with sericin solution concentration is 15 wt%, emulsifier concentration 2%, water-oil factor 1 that Fig. 6, which is in the embodiment of the present invention,:
10,15 min of emulsification times, sericin microballoon obtained is dispersed in water the shape appearance figure under simple microscope.
It with sericin solution concentration is 15 wt%, emulsifier concentration 2%, water-oil factor 1 that Fig. 7, which is in the embodiment of the present invention,:
10,15 min of emulsification times, sericin microballoon obtained is dispersed in water the shape appearance figure under fluorescence microscope.
It with sericin solution concentration is 10 wt%, emulsifier concentration 6%, water-oil factor 1 that Fig. 8, which is in the embodiment of the present invention,:
10,15 min of emulsification times, sericin microballoon obtained is dispersed in water the shape appearance figure under simple microscope.
It with sericin solution concentration is 10 wt%, emulsifier concentration 6%, water-oil factor 1 that Fig. 9, which is in the embodiment of the present invention,:
10,15 min of emulsification times, sericin microballoon obtained is dispersed in water the shape appearance figure under fluorescence microscope.
It with sericin solution concentration is 10 wt%, emulsifier concentration 2%, water-oil factor 1 that Figure 10, which is in the embodiment of the present invention,:
20,15 min of emulsification times, sericin microballoon obtained is dispersed in water the shape appearance figure under simple microscope.
It with sericin solution concentration is 10 wt%, emulsifier concentration 2%, water-oil factor 1 that Figure 11, which is in the embodiment of the present invention,:
20,15 min of emulsification times, sericin microballoon obtained is dispersed in water the shape appearance figure under fluorescence microscope.
Figure 12 be wrap up different number of plies tannic acid-iron ion coordination polymers natural sericin microballoon it is substantially apparent
Figure.
Figure 13 is the substantially apparent of the load medicine sericin microballoon of the different number of plies tannic acid-iron ion coordination polymers of package
Figure.
Figure 14 is to wrap up the load medicine sericin microballoon of different number of plies tannic acid-iron ion coordination polymers in different pH
Under the conditions of drug release patterns figure.
Figure 15 is shadow of the sericin microballoon to red blood cell in blood for wrapping up 2 layers of tannic acid-iron ion coordination polymer
It rings.
Figure 16 is to wrap up the sericin microballoon of 2 layers of tannic acid-iron ion coordination polymer to tumor cell activity
It influences.
Figure 17 is the load medicine sericin microballoon and free drug pair for wrapping up 2 layers of tannic acid-iron ion coordination polymer
The influence of tumor cell activity.
Specific implementation mode
In order to keep technical scheme of the present invention and advantage clearer, with reference to the accompanying drawings and embodiments, to the present invention into
Row is further to be described in detail.Described herein specific examples are only used to explain the present invention, is not intended to limit the present invention.
In order to make the public have a better understanding the present invention, some are described to detailed in the datail description of the present invention specifically below
Detail section.
With reference to embodiment, the present invention is described further：
Silk cocoon used in the present invention is silkworm silk cocoon（White jade, bright moon etc.）Or fibroin deletion form silk cocoon（185Nd-s, 140Nd- sDeng）；Corn oil used is food grade non-trans genie corn germ bud oil；Remaining agents useful for same is that analysis is pure.
Embodiment 1：The synthesis of natural sericin microballoon
（1）20 g silk cocoons are cleaned and are drained, 400 mL, 0.02 mol/L Na are soaked in2CO3In solution, at 100 DEG C, 600
Agitating and heating is reacted 1 hour under the conditions of rpm, and 3500 rpm centrifuge 5 minutes removal infusible precipitates after cooling, and upper layer is taken to clarify
Solution is dialysed 2-3 days in deionized water with 3500 Da bag filters, and solution is centrifuged with 8000 rpm and removes within 10 minutes insoluble sink
It forms sediment, takes clear solution quick-frozen vacuum freeze drier that is placed in liquid nitrogen in upper layer to be lyophilized completely, obtain pure sericin
Solid；
（2）1 mL of sericin solution for configuring 10 wt%, that is, take 100 mg sericins to be dissolved in 1 mL deionized waters, will
It is added on dropwise in the corn oil containing 2% emulsifier tween -20, water-oil factor 1:10, i.e. 10 mL of corn oil used（Containing emulsification
200 μ L of agent Tween-20）, emulsified 15 minutes of 800 rpm room temperature conditions；
（3）The addition crosslinking agent glutaraldehyde into mixed emulsion, a concentration of 25%, addition is the 10% of reaction system, that is, is added 25%
Glutaraldehyde 1 mL, 800 rpm are crosslinked 2 hours under room temperature；
（4）Acetone is added into mixed emulsion, addition is 4-5 times of reaction system, that is, 50 mL of acetone, 800 rooms rpm are added
Cure 40 minutes under the conditions of temperature；
（5）Mixed emulsion is centrifuged 8 minutes with 3500 rpm, abandons supernatant, you can obtains sericin microsphere particle；
（6）Silk gum microballoon is washed with acetone three times, and 3500 rpm are centrifuged 8 minutes every time, and final sediment vacuum is drained
Obtain sericin microballoon.
As a result as shown in Figs. 1-5, using sericin microballoon prepared by the emulsion process, grain size is equal for the sphere of regular appearance
One, favorable dispersibility, is provided simultaneously with natural fluorescent characteristic in water, and the microballoon after drying still can keep its regular morphology simultaneously
It can be seen that apparent fluorescence.
Embodiment 2：The influence that various concentration sericin synthesizes sericin microballoon
（1）20 g silk cocoons are cleaned and are drained, 400 mL, 0.02 mol/L Na are soaked in2CO3In solution, at 100 DEG C, 600
Agitating and heating is reacted 1 hour under the conditions of rpm, and 3500 rpm centrifuge 5 minutes removal infusible precipitates after cooling, and upper layer is taken to clarify
Solution is dialysed 2-3 days in deionized water with 3500 Da bag filters, and solution is centrifuged with 8000 rpm and removes within 10 minutes insoluble sink
It forms sediment, takes clear solution quick-frozen vacuum freeze drier that is placed in liquid nitrogen in upper layer to be lyophilized completely, obtain pure sericin
Solid；
（2）The 100 μ L of sericin solution for configuring 15 wt%, that is, take 15 mg sericins to be dissolved in 100 μ L deionized waters,
It is added on dropwise in the corn oil containing 2% emulsifier tween -20, water-oil factor 1:10, i.e. 1 mL of corn oil used（Containing emulsification
20 μ L of agent Tween-20）, emulsified 15 minutes of 800 rpm room temperature conditions；
（3）The addition crosslinking agent glutaraldehyde into mixed emulsion, a concentration of 25%, addition is the 10% of reaction system, that is, is added 25%
Glutaraldehyde 100 μ L, 800 rpm are crosslinked 2 hours under room temperature；
（4）Acetone is added into mixed emulsion, addition is 4-5 times of reaction system, that is, 5 mL of acetone, 800 rooms rpm are added
Cure 40 minutes under the conditions of temperature；
（5）Mixed emulsion is centrifuged 8 minutes with 3500 rpm, abandons supernatant, you can obtains sericin microsphere particle；
（6）Silk gum microballoon is washed with acetone three times, and 3500 rpm are centrifuged 8 minutes every time, and final sediment vacuum is drained
Obtain sericin microballoon.
As a result as shown in fig. 6-7, with the increase of sericin solution concentration, the grain size of microballoon gradually increases, and fluorescence is special
Property does not change.
Embodiment 3：The influence that various dose emulsifier synthesizes sericin microballoon
（1）20 g silk cocoons are cleaned and are drained, 400 mL, 0.02 mol/L Na are soaked in2CO3In solution, at 100 DEG C, 600
Agitating and heating is reacted 1 hour under the conditions of rpm, and 3500 rpm centrifuge 5 minutes removal infusible precipitates after cooling, and upper layer is taken to clarify
Solution is dialysed 2-3 days in deionized water with 3500 Da bag filters, and solution is centrifuged with 8000 rpm and removes within 10 minutes insoluble sink
It forms sediment, takes clear solution quick-frozen vacuum freeze drier that is placed in liquid nitrogen in upper layer to be lyophilized completely, obtain pure sericin
Solid；
（2）The 100 μ L of sericin solution for configuring 10 wt%, that is, take 10 mg sericins to be dissolved in 100 μ L deionized waters,
It is added on dropwise in the corn oil containing 6% emulsifier tween -20, water-oil factor 1:10, i.e. 1 mL of corn oil used（Containing emulsification
60 μ L of agent Tween-20）, emulsified 15 minutes of 800 rpm room temperature conditions；
（3）The addition crosslinking agent glutaraldehyde into mixed emulsion, a concentration of 25%, addition is the 10% of reaction system, that is, is added 25%
Glutaraldehyde 100 μ L, 800 rpm are crosslinked 2 hours under room temperature；
（4）Acetone is added into mixed emulsion, addition is 4-5 times of reaction system, that is, 5 mL of acetone, 800 rooms rpm are added
Cure 40 minutes under the conditions of temperature；
（5）Mixed emulsion is centrifuged 8 minutes with 3500 rpm, abandons supernatant, you can obtains sericin microsphere particle；
（6）Silk gum microballoon is washed with acetone three times, and 3500 rpm are centrifuged 8 minutes every time, and final sediment vacuum is drained
Obtain sericin microballoon.
As a result as Figure 8-9, as the increase of emulsification agent dose, the grain size of microballoon significantly increase, fluorescent characteristic does not change
Become, but pattern tends to be irregular, therefore selects 2% emulsifier for dose,optimum.
Embodiment 4：The influence that different water-oil factors synthesize sericin microballoon
（1）20 g silk cocoons are cleaned and are drained, 400 mL, 0.02 mol/L Na are soaked in2CO3In solution, at 100 DEG C, 600
Agitating and heating is reacted 1 hour under the conditions of rpm, and 3500 rpm centrifuge 5 minutes removal infusible precipitates after cooling, and upper layer is taken to clarify
Solution is dialysed 2-3 days in deionized water with 3500 Da bag filters, and solution is centrifuged with 8000 rpm and removes within 10 minutes insoluble sink
It forms sediment, takes clear solution quick-frozen vacuum freeze drier that is placed in liquid nitrogen in upper layer to be lyophilized completely, obtain pure sericin
Solid；
（2）The 100 μ L of sericin solution for configuring 10 wt%, that is, take 10 mg sericins to be dissolved in 100 μ L deionized waters,
It is added on dropwise in the corn oil containing 2% emulsifier tween -20, water-oil factor 1:20, i.e. 2 mL of corn oil used（Containing emulsification
40 μ L of agent Tween-20）, emulsified 15 minutes of 800 rpm room temperature conditions；
（3）The addition crosslinking agent glutaraldehyde into mixed emulsion, a concentration of 25%, addition is the 10% of reaction system, that is, is added 25%
Glutaraldehyde 100 μ L, 800 rpm are crosslinked 2 hours under room temperature；
（4）Acetone is added into mixed emulsion, addition is 4-5 times of reaction system, that is, 10 mL of acetone, 800 rooms rpm are added
Cure 40 minutes under the conditions of temperature；
（5）Mixed emulsion is centrifuged 8 minutes with 3500 rpm, abandons supernatant, you can obtains sericin microsphere particle；
（6）Silk gum microballoon is washed with acetone three times, and 3500 rpm are centrifuged 8 minutes every time, and final sediment vacuum is drained
Obtain sericin microballoon.
As a result as shown in figs. 10-11, as the increase of water-oil factor, the grain size of microballoon gradually increase, fluorescent characteristic does not change.
In conjunction with above example and diagram, it can be seen that by controlling and changing sericin solution concentration, emulsifier content
And the sericin microballoon of different-grain diameter and pattern can be made in water-oil factor, make it have and be more widely applied.
Embodiment 5：The synthesis of the sericin microballoon of different number of plies metal organic coordination polymer packages
（1）The aldehydes matter that this research uses is tannic acid, and metal ion is iron ion.0.80 g tannic acid solids are dissolved in 20
ML deionized waters are made into the tannic acid solution of 40 mg/mL.0.20 g Iron(III) chloride hexahydrate solids are dissolved in 20 mL deionizations
Water is made into the ferric ion solutions of 10 mg/mL.
（2）5 mg sericin microballoons are scattered in 0.5 mL deionized waters, and 5 μ L ferric ion solutions are added after ultrasonic disperse,
5 μ L tannic acid solutions are added after being vortexed 1 minute, 20 mM pH, 8.0 Tris buffer solutions, 0.5 mL is added after being vortexed 1 minute,
6000 rpm centrifuge the sericin microballoon for obtaining the encapsulating of ferric tannate ionic conductance polymerization object for 4 minutes, deionized water washing 3
Time.
（3）It repeats（2）Middle step obtains the sericin microballoon of different number of plies metal organic coordination polymer packages.
As a result as shown in figure 12, it is followed successively by does not wrap up and wrap up 1,2,3,5 layer of tannic acid-iron ion polycomplexation from left to right
Close the sericin microballoon of object, it is seen that sericin microballoon, which is dispersed in water, to be creamy white, through metal organic coordination polymer packet
The silk gum microballoon wrapped up in is in then grey black, and as the color that increases of the package number of plies is deepened.
Embodiment 6：The synthesis of the load medicine sericin microballoon of different number of plies metal organic coordination polymer packages
（1）The aldehydes matter that this research uses is tannic acid, and metal ion is iron ion.The drug bearing microsphere that this research uses is to take
Carry the sericin microballoon of adriamycin.0.80 g tannic acid solids are dissolved in the tannin that 20 mL deionized waters are made into 40 mg/mL
Acid solution.0.20 g Iron(III) chloride hexahydrate solids are dissolved in the ferric ion solutions that 20 mL deionized waters are made into 10 mg/mL.
（2）5 mg carry medicine sericin microballoon and are scattered in 0.5 mL deionized waters, and it is molten that 5 μ L iron ions are added after ultrasonic disperse
5 μ L tannic acid solutions are added in liquid after being vortexed 1 minute, 20 mM pH, 8.0 Tris buffer solutions, 0.5 mL is added after being vortexed 1 minute,
6000 rpm centrifuge the load medicine sericin microballoon for obtaining the encapsulating of ferric tannate ionic conductance polymerization object for 4 minutes, deionization washing
It washs 3 times.
（3）It repeats（2）Middle step obtains the load medicine sericin microballoon of different number of plies metal organic coordination polymer packages.
As a result as shown in figure 13, it is followed successively by does not wrap up and wrap up 1,2,3,5 layer of tannic acid-iron ion polycomplexation from left to right
Close the load medicine sericin microballoon of object, it is seen that the sericin microballoon of adriamycin, which is dispersed in water, again takes on a red color, organic through metal
The load medicine silk gum microballoon of coordination polymer package is in then peony, and as the color that increases of the package number of plies is deepened.
Embodiment 7：Drug release of the load medicine sericin microballoon of metal organic coordination polymer encapsulating under condition of different pH
（1）This research uses broad-spectrum anti-cancer drug doxorubicin hydrochloride.100 mg doxorubicin hydrochlorides are dissolved in 200 mL PBS
In (pH 8.5), 500 mg sericin microballoons are added, room temperature is protected from light stirring 24 hours, is washed with deionized water 3 times, freezes completely
It is dry to obtain carrying medicine sericin microballoon；
（2）It takes 5 mg to carry medicine sericin microballoon to be scattered in 0.5 mL deionized waters, 5 μ L chlorinations is added after ultrasonic disperse
Ferrous solution（10 mg/mL）, 5 μ L tannic acid solutions are added after being vortexed 1 minute（40 mg/mL）, 20 mM are added after being vortexed 1 minute
8.0 Tris buffer solutions of pH, 0.5 mL, 6000 rpm, which are centrifuged, obtains the load medicine sericin microballoon that tannic acid is encapsulated for 4 minutes, goes
The 3 times repetition encapsulatings of ion water washing obtain the load medicine sericin microballoon of different number of plies tannic acid encapsulatings；
（3）The load medicine sericin microballoon that 3 mg difference number of plies tannic acid are encapsulated is divided in 42 mL EP pipes（1mg is every
Pipe）, it is separately added into the buffer solution of 1 mL pH 5.0,6.5 and 7.4, in 37oSlowly vibrating incubation is protected from light in C incubators, not
Same time point takes the absorbance at 494 nm of supernatant UV spectrophotometer measuring, is calculated not according to adriamycin standard curve
With the amount for the adriamycin that time point releases, while replacing different buffer solutions and continuing to be incubated.
As a result as shown in figure 14, illustrate the drug releasing rate of the load medicine sericin microballoon as tannic acid encapsulates the number of plies
Increase and gradually slow down, while there is the load medicine sericin microballoon pH sensitivity characteristics, i.e. acid condition drug to be promoted to release
It puts, is consequently adapted to drug release in cellular inclusion.
Embodiment 8：The blood compatibility of natural sericin microballoon and the sericin microballoon of metal organic coordination polymer encapsulating
Property
（1）Natural sericin microsphere surface is encapsulated into two layers of tannic acid-iron ion coordination polymer, and will encapsulate and do not encapsulate
Sericin microballoon the solution of various concentration gradient is made into after alcohol disinfecting, in addition using PBS buffer solution as negative control,
0.2% Triton X, 100 solution is as positive control.
（2）The normal anti-freezing blood specimen of blood routine is chosen, 800 rpm are centrifuged 5 minutes, abandoned supernatant, washed with PBS buffer solution
Red blood cell 2-3 times collects lower layer's red blood cell, is made into 2% red cell suspension.
（3）The microsphere suspensions of 100 μ L various concentrations and 900 μ L red cell suspensions are mixed, it is small to be incubated 4 in 37 DEG C of shaking tables
When, 8000 rpm are centrifuged 10 minutes, collect supernatant.
（4）The supernatant of collection is detected with microplate reader to the absorbance at its 545 nm.
As a result as shown in figure 15, it is seen that the sericin microballoon of sericin microballoon or metal organic coordination polymer package
Addition the rupture of red blood cell, i.e. its blood compatibility can't be caused good.
Embodiment 9：The cytocompatibility of natural sericin microballoon and the sericin microballoon of metal organic coordination polymer encapsulating
Property
（1）Natural sericin microsphere surface is encapsulated into two layers of tannic acid-iron ion coordination polymer, and will encapsulate and do not encapsulate
Sericin microballoon the solution of various concentration gradient is made into after alcohol disinfecting；
（2）By natural sericin microballoon and the sericin microballoon and 4T1 of encapsulating two layers of tannic acid-iron ion coordination polymer
Cell uses mtt assay to detect 4T1 cell viabilities after being incubated altogether 24 hours and 48 hours.
As a result as shown in figure 16, respectively cell and microballoon be incubated altogether 24,48 hours after as a result, showing natural silk gum egg
The vigor of 4T1 cells is all had no significant effect whether no matter Bai Weiqiu is using tannic acid-iron ion coordination polymer encapsulating, explanation
The biocompatibility of the sericin microballoon is good.
Embodiment 10：The load medicine sericin microballoon for encapsulating two layers of tannic acid-iron ion coordination polymer kills tumour cell
Wound acts on
（1）The sericin microsphere surface for being loaded with adriamycin is encapsulated into two layers of tannic acid-iron ion coordination polymer, and will encapsulating
With the solution for being made into various concentration gradient after non-encapsulated load medicine albumen silk gum microballoon alcohol disinfecting；
（2）By free adriamycin, load medicine sericin microballoon and the load medicine silk for encapsulating two layers of tannic acid-iron ion coordination polymer
Glue protein microballoon uses mtt assay to detect 4T1 cell viabilities after being incubated altogether 24 hours and 48 hours with 4T1 cells.
As a result as shown in figure 17, respectively cell and drug bearing microsphere be incubated altogether 24,48 hours after as a result, showing encapsulating two
The load medicine sericin microballoon of layer tannic acid-iron ion coordination polymer has 4T1 cells certain lethal effect, can effectively send out
Wave its antitumor action.
Statement is finally needed, the above list is only specific embodiments of the present invention, and the present invention is not limited to above
Embodiment, can also there are many deformations, therefore directly or all deformations for associating by content disclosed in this invention, be considered as
It is protection scope of the present invention.
Claims (9)
1. the preparation method of natural sericin microballoon, the natural sericin microballoon is porous made of natural sericin
Microballoon, preparation method includes the following steps：
(1) silk cocoon is weighed, sericin is extracted with high temperature alkaline extraction, can be obtained pure natural silk gum egg through centrifugation, dialysis, freeze-drying
White solid；
(2) gained sericin solid in step (1) is dissolved in the sericin solution that water is configured to 10 wt% concentration；
(3) gained sericin solution in step (2) is added dropwise in the corn oil containing emulsifier tween -20, stirring makes it
It is fully emulsified to obtain lotion；
(4) be added dropwise chemical cross-linking agent into lotion obtained by step (3), stirring keep its full cross-linked crosslinked emulsions；
(5) acetone is added dropwise into crosslinked emulsions obtained by step (4), stirring makes it fully cure；
(6) mixed liquor obtained by step (5) is centrifuged into obtain cured sericin microballoon, acetone washs three times, and being drained through vacuum can
Obtain pure natural sericin microballoon.
2. preparation method according to claim 1, it is characterised in that：The extraction of sericin solid in the step (1)
Method includes the following steps：
1) common silkworm silk cocoon or fibroin deletion form mutation silk cocoon are weighed, is shredded, is cleaned with deionized water, it is more to squeeze removal
Remaining moisture obtains silk cocoon fragment；
2) silk cocoon fragment obtained by step 1) is soaked in the Na of a concentration of 0.01-0.2 mol/L2CO3In solution, in 80-100
DEG C, heating stirring is reacted 0.5-1 hours under the conditions of 600 rpm, wherein every gram of silk cocoon is scattered in 10-50 mL Na2CO3Solution；
3) solution obtained in step 2) is centrifuged into 5 min with 3500 rpm, removes infusible precipitate, obtains clear solution I；
4) gained clear solution I in step 3) is dialysed 2-3 days in deionized water, it is primary to change water every 6 hours；It obtains
Analyse solution；
5) gained dialysis solution in step 4) is centrifuged into 10 min with 8000 rpm, removes infusible precipitate, obtains clarifying molten
Liquid II；
6) gained clear solution II in step 5) is quick-frozen in liquid nitrogen, 2-3 days are placed in vacuum freeze drier until complete
Freeze-drying, obtains pure sericin solid, is placed in -20 DEG C of refrigerators and is sealed.
3. preparation method according to claim 1, it is characterised in that：In the step (3) sericin solution with containing breast
The dosage volume ratio of the corn oil of agent Tween-20 is 1:5-100；Emulsifier tween-in corn oil containing emulsifier tween -20
20 with the dosage volume ratio of corn oil be 0.1-10：100, mixing speed is 800 rpm, and emulsification times are 5-30 minutes；
Chemical cross-linking agent is glutaraldehyde or Geniposide in the step (4), and addition is the 5-50% of lotion volume；Mixing speed
For 800 rpm, crosslinking time is 1-3 hours；
The amount that acetone is added in the step (5) is 5-20 times of crosslinked emulsions volume；Mixing speed is 800 rpm, when solidification
Between be 40 minutes.
4. natural sericin microballoon made from the either method described in claim 1-3.
5. carrying medicine silk gum microballoon, the natural sericin microballoon described in claim 4 and drug physical mixed obtain carrying medicament
Load medicine silk gum microballoon.
6. load medicine silk gum microballoon according to claim 5, it is characterised in that：The drug be antitumor drug, hormone or
Antibiotic.
7. the load medicine silk gum microballoon of metal organic coordination polymer package carries medicine silk gum microballoon in neutrality described in claim 5
Or reacted with aldehydes matter and metal ion solution under weak basic condition, obtain the load medicine wrapped up by metal organic coordination polymer
Silk gum microballoon；The aldehydes matter includes tannic acid, anthocyanidin, catechin, gallic acid, ursin or catechol group
The polymer of modification；The metal ion includes one or more of iron ion, aluminium ion, copper ion, magnesium ion.
8. the natural silk gum microballoon of metal organic coordination polymer package, the natural sericin microballoon described in claim 4 exist
It is reacted with aldehydes matter and metal ion solution under neutral or weak basic condition, obtains being wrapped up by metal organic coordination polymer
Carry medicine silk gum microballoon.
9. the load medicine that metal organic coordination polymer described in natural sericin microballoon, claim 7 described in claim 4 wraps up
The natural sericin microballoon that metal organic coordination polymer described in sericin microballoon or claim 8 wraps up is swollen in preparation
Application in tumor diagnosis and treatment material, drug delivery materials, cell carrier material, fluorescent tracing material, tissue engineering material.
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