CN110496228A - The perfluocarbon oxygen carrying microballoon and its preparation method and application for magnetic thermotherapy with targeting - Google Patents
The perfluocarbon oxygen carrying microballoon and its preparation method and application for magnetic thermotherapy with targeting Download PDFInfo
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Abstract
The present invention provides a kind of perfluocarbon oxygen carrying microballoon and its preparation method and application for magnetic thermotherapy with targeting, preparation method is that perfluocarbon is emulsified into lotion, the water-soluble perfluorocarbon emulsion for carrying oxygen is oxygenated and is disinfected, the lotion and magnetic nano-particle, which are wrapped in chitosan, forms microballoon, connects polyethylene glycol and folic acid in microsphere surface to improve the water solubility of microballoon and realize target function；The present invention is using perfluocarbon as oxygen carrying material, it is wrapped in chitosan together with magnetic nano-particle, surface is modified to improve its water solubility with peg molecule, it is grafted folate molecule simultaneously, the microballoon of core-shell structure is formed, which may be implemented the slow release effect of oxygen, and Shell Materials have good biocompatibility and targeting, magnetic particle can play magnetic heat-therapeutic action in magnetic field, to improve the ability of killing tumour；The complex microsphere can alleviate the anaerobic condition of tumor locus, and improve the effect of extraneous adjuvant treatment.
Description
Technical field
The invention belongs to nano materials and biomedical material technology, and in particular to a kind of to be used for targeting
Perfluocarbon oxygen carrying microballoon of magnetic thermotherapy and its preparation method and application.
Background technique
Oxygen deficit problem caused by tumor vessel exception, cell hyperproliferation etc. is almost common in all solid tumors shows
As some researches show that anoxic is the one of the major reasons of oncotherapy failure.Especially for radiotherapy, oxygen is to generate to kill
The essential elements of dead tumor promotion oxygen.Therefore, an important factor for hypoxic tumor microenvironment is usually radiotherapeutic-resistant.Many objects
Matter, such as hemoglobin, manganese dioxide etc. have been used to alleviate the micro-environmental hypoxia of tumour, but they have certain limit
System.Such as hemoglobin can cause acute nephrotoxicity and acute hypertension, constitute a serious threat to the life of patient, and titanium dioxide
Tumour H of the oxygenation level by tumor environment again that manganese is realized2O2The limitation of amount, and Mn2+Itself has certain toxicity.
Summary of the invention
Aiming at the shortcomings in the prior art, primary and foremost purpose of the invention be to provide it is a kind of with targeting for magnetic thermotherapy
The preparation method of perfluocarbon oxygen carrying microballoon magnetic nano-particle and oxygen carrying microballoon are combined, made during the preparation process
While microballoon target tumor, in conjunction with external magnetic heat effect, the purpose for discharging oxygen in tumor locus, killing tumour is realized.
A second object of the present invention is to provide the above-mentioned perfluocarbon oxygen carrying microballoons for magnetic thermotherapy with targeting.
Third object of the present invention is to provide the above-mentioned perfluocarbon oxygen carrying microballoons for magnetic thermotherapy with targeting
Application.
In order to achieve the above objectives, solution of the invention is:
For the present invention using PFCs as oxygen carrying lotion, magnetic nano-particle acts on magnetic thermotherapy carrier, and poly ethyldiol modified shell is poly-
Sugar, folic acid are Shell Materials, and the oxygen carrying microballoon that can be used for magnetic thermotherapy with targeting is obtained using chemical graft process.It is this micro-
Ball can solve the storage problem of perfluocarbon very well, alleviate the anaerobic environment of tumor locus, and can greatly improve killing tumour
Effect.
A kind of preparation method of the perfluocarbon oxygen carrying microballoon for magnetic thermotherapy with targeting comprising following step
It is rapid:
(1), egg yolk lecithin is added in tyrode's solution, 4-6 times emulsified at 25-30 DEG C, each duration is
5-10s is spaced 30-60s, obtains basic emulsion；
(2), the perfluocarbon stoste of volume fraction >=97% is added in basic emulsion, emulsifies 4-7 times, emulsifies every time
Time is 5-10s, and every minor tick 30-60s obtains perfluocarbon original lotion；
(3), by perfluocarbon original absorbing emulsions oxygen, perfluorocarbon emulsion is obtained；
(4), by perfluorocarbon emulsion filtration sterilization, the sterile lotion of perfluocarbon is obtained；
(5), polyethylene glycol-carboxylic acid is soluble in water, obtain the first solution；Folic acid is dissolved in dimethyl sulfoxide, obtains
Two solution；Chitosan is dissolved in the glacial acetic acid solution that mass fraction is 1-3%, obtains third solution；
(6), the first solution and the second solution are mixed, and 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide is added
The solution of hydrochloride and N- hydroxysuccinimide stirs to get the first mixed liquor；
(7), third solution is added in the first mixed liquor, is protected from light to obtain the second mixed liquor at 20-25 DEG C；
(8), the second mixed liquor is dialysed 2-3 days with phosphate buffered saline solution and distilled water, obtains polyethylene glycol and folic acid
The chitosan solution of grafting；
(9), the chitosan for polyethylene glycol and folic acid grafting being added in the sterile lotion of perfluocarbon and magnetic nano-particle is molten
In liquid, third mixed liquor is obtained；Saxol and surfactant are mixed, the 4th mixed liquor is obtained；By third mixed liquor
It is added in the 4th mixed liquor, stirs to get the 5th mixed liquor；
(10), sodium tripolyphosphate is soluble in water, sodium tripolyphosphate solution is obtained, by sodium tripolyphosphate solution under ice bath
It is added in the 5th mixed liquor, stirs to get the 6th mixed liquor；
(11), the 6th mixed liquor is successively washed with petroleum ether and isopropanol, obtain having targeting for magnetic thermotherapy
Perfluocarbon oxygen carrying microballoon.
Further, in step (1), mass percent of the egg yolk lecithin in tyrode's solution is 17-20%；When emulsification,
The power of the ultrasonic emulsifier used is 350-450W.
Further, in step (2), the volume ratio of basic emulsion and perfluocarbon stoste is 1:1-1.4:1；When emulsification,
The power of the ultrasonic emulsifier used is 350-450W.
Further, in step (2), perfluocarbon in perfluocarbon stoste be selected from perfluorotributylamine, perfluor cyclopropylamine,
One or more of perfluorooctyl bromide, phenyl-hexafluoride and FtBu.
Further, in step (3), the time of perfluocarbon original absorbing emulsions oxygen is 15-20min.
Further, in step (4), when filtration sterilization, the diameter of the sterile filters used is 0.65-0.8 μm.
Further, in step (5), the mass ratio of polyethylene glycol-carboxylic acid and chitosan is 1:4-1:6, and folic acid and shell are poly-
The mass ratio of sugar is 1:20-1:25.
Further, in step (6), the molar ratio of chitosan and N- hydroxysuccinimide is 1:3-1:5, N- hydroxyl fourth
The molar ratio of imidodicarbonic diamide and 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride is 1:1.5-1:5.
Further, in step (6), the time of stirring is 20-40min.
Further, in step (7), the time being protected from light is 18-26h.
Further, in step (8), the pH value of phosphate buffered saline solution is 7.4.
Further, in step (9), magnetic nano-particle be selected from one of ferroso-ferric oxide and manganese-zinc ferrite with
On.
Further, in step (9), the mass ratio of saxol and surfactant is 15:1-25:1.
Further, in step (9), the time of stirring is 2-4h, and the temperature of stirring is 40-60 DEG C.
Further, in step (9), surfactant is selected from one or more of sorbester p17 or Tween 80.
Further, in step (10), the time of stirring is 2-4h.
Further, the mass ratio of added chitosan is 1:12-1:8 in sodium tripolyphosphate and step (5) in step (10).
A kind of perfluocarbon oxygen carrying microballoon for magnetic thermotherapy with targeting, is obtained by above-mentioned preparation method.
A kind of above-mentioned perfluocarbon oxygen carrying microballoon for magnetic thermotherapy with targeting is swollen in treatment tumour and alleviation
Application in tumor anaerobic environment.
By adopting the above scheme, the beneficial effects of the present invention are:
The first, perfluocarbon (PFCs) of the invention is a kind of chemicals with good biocompatibility, biologically inert
Matter, and as its unique chemical structure (hydrogen atom on molecule is all replaced fluorine atom), make PFCs also while having
There are high hydrophobicity and hypoergia, this makes it have the ability of dissolution bulk gas.Also, PFCs lotion can be prepared into nanometer
Grade, this small size allow them to be transported to oxygen in the smallest capillary, and oxygen can be effectively discharged in anaerobic environment
Gas, to there is very extensive application in field of tissue engineering technology.
The second, the perfluocarbon oxygen carrying microballoon Shell Materials that can be used for magnetic thermotherapy with targeting of the invention are poly- for shell
Sugar, polyethylene glycol and folic acid, chitosan has good biocompatibility and biological degradability, but it is not water-soluble high, because
This needs to be modified with polyethylene glycol, improves its dissolubility in water.Folic acid can over-express in tumour cell, and
It is limited expression, the function that this feature can be positioned with active targeting in normal tissue or organ.And magnetic Nano
Introducing for particle can combine extraneous adjuvant treatment with the effect of microballoon oxygen carrying itself, can effectively improve killing tumour
Effect.
Third, preparation method of the invention are simple, and raw material sources are extensive, easy to operate, and the microballoon prepared works well.
In short, perfluocarbon (PFCs) is a kind of inert chemi-cal substance with good biocompatibility, have hyperoxia molten
The advantages that Xie Du, low surface tension, hydrophobic lipophobic, inertia and safety and biocompatibility, has been used to medically various
Treatment.Since the water solubility of liquid PFCs is bad, it is made into lotion generally to improve its hydrophily.Micro-sphere structure packet
Covering oxygen carrying lotion may be implemented the effect of slow release in vivo, while folic acid is added to realize its targeting.And it is magnetic
The introducing of nanoparticle can combine magnetic heat cure with oxygen release treatment, to greatly improve the effect of killing tumour.
Specific embodiment
The present invention provides a kind of perfluocarbon oxygen carrying microballoon and preparation method thereof for magnetic thermotherapy with targeting
And application.
The present invention for oxygen carrying material, is wrapped in chitosan, table with perfluocarbon (PFCs) together with magnetic nano-particle
Face is modified to improve its water solubility with PEG molecule, while being grafted folate molecule, forms the microballoon of core-shell structure, the microballoon
The slow release effect of oxygen may be implemented, Shell Materials have good biocompatibility and targeting, and magnetic particle can be in magnetic
Magnetic heat-therapeutic action is played in, improves the ability of killing tumour.The complex microsphere can alleviate the anaerobic condition of tumor locus, and
Greatly improve the effect of extraneous adjuvant treatment.
<preparation method of the perfluocarbon oxygen carrying microballoon for magnetic thermotherapy with targeting>
The preparation method of the perfluocarbon oxygen carrying microballoon for magnetic thermotherapy with targeting of the invention includes following step
It is rapid:
(1), the preparation of the sterile lotion of PFCs: egg yolk lecithin is added in tyrode's solution (Tyrode solution), in 25-30
It is emulsified 4-6 times at DEG C using ultrasonic emulsifier, each duration is 5-10s, is spaced 30-60s, obtains basic emulsion；In
The perfluocarbon stoste of volume fraction >=97% is added in basic emulsion, is emulsified 4-7 times using ultrasonic emulsifier, is emulsified every time
Time is 5-10s, every minor tick 30-60s, obtains perfluocarbon original lotion, spare；Perfluocarbon original lotion is put into hyperbaric oxygen
In cabin, oxygen is fully absorbed, obtains perfluorocarbon emulsion；The perfluorocarbon emulsion that oxygenation finishes is crossed using sterile filters and is filtered out
Bacterium obtains the sterile lotion of perfluocarbon, spare；
(2), the preparation of Shell Materials: polyethylene glycol-carboxylic acid (PEG-COOH) is soluble in water, obtain the first solution；Leaf
Sour (FA) is dissolved in dimethyl sulfoxide (DMSO), obtains the second solution；Chitosan (CS) is dissolved in the ice second that mass fraction is 1-3%
In acid solution, third solution is obtained；First solution and the second solution are mixed, and 1- (3- dimethylamino-propyl) -3- second is added
The solution of base carbodiimide hydrochloride (EDC) and N- hydroxysuccinimide (NHS), stirs to get the first mixed liquor；By third
Solution is added dropwise in the first mixed liquor, is protected from light to obtain the second mixed liquor at 20-25 DEG C；After reaction, it uses respectively
Phosphate-buffered salt (PBS) solution and distilled water dialyse the second mixed liquor 2-3 days, obtain polyethylene glycol (PEG) and folic acid (FA)
Chitosan (CS) solution of grafting；
(3), the preparation of the perfluocarbon oxygen carrying microballoon for magnetic thermotherapy with targeting: by the sterile lotion of perfluocarbon
It is added in polyethylene glycol and the chitosan solution of folic acid grafting with magnetic nano-particle, obtains third mixed liquor (as water phase)；
Saxol and surfactant are mixed, the 4th mixed liquor is obtained (as oily phase)；Water phase is slowly dropped in oily phase,
2-4h is stirred at 40-60 DEG C obtains the 5th mixed liquor；Sodium tripolyphosphate is soluble in water, obtain sodium tripolyphosphate solution, In
Sodium tripolyphosphate solution is added in the 5th mixed liquor under ice bath, stirring 2-4h obtains the 6th mixed liquor；By the 6th mixed liquor according to
It is secondary to be washed 2-3 times with petroleum ether and isopropanol, obtain the perfluocarbon oxygen carrying microballoon for magnetic thermotherapy with targeting.
Wherein, in step (1), mass percent of the egg yolk lecithin in tyrode's solution can be 17-20%, preferably
17%；When emulsification, the power of the ultrasonic emulsifier used can be 350-450W, preferably 450W.
In step (1), the volume ratio of basic emulsion and perfluocarbon stoste can be 1:1-1.4:1, preferably 1:1；
When emulsification, the power of the ultrasonic emulsifier used can be 350-450W, preferably 450W.
In step (1), it is pungent that the perfluocarbon in perfluocarbon stoste is selected from perfluorotributylamine, perfluor cyclopropylamine, perfluor
One or more of bromide, phenyl-hexafluoride and FtBu.
In step (1), the time that perfluocarbon original lotion is placed in hyperbaric oxygen chamber can be 15-20min, preferably
20min。
In step (1), the diameter of sterile filters can be 0.65-0.8 μm, preferably 0.8 μm.
In step (2), the mass ratio of polyethylene glycol-carboxylic acid and chitosan is 1:4-1:6, the quality of folic acid and chitosan
Than for 1:20-1:25.
In step (2), the molar ratio of chitosan and N- hydroxysuccinimide is 1:3-1:5, and N- maloyl is sub-
The molar ratio of amine and 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride is 1:1.5-1:5.
In step (2), the time of stirring can be 20-40min, preferably 20min.
In step (2), the time being protected from light can be 18-26h, preferably 18h.
In step (2), the pH value of phosphate buffered saline solution is 7.4.
In step (3), magnetic nano-particle is selected from ferroso-ferric oxide (Fe3O4One or more of) and manganese-zinc ferrite.
In step (3), the mass ratio of saxol and surfactant is 15:1-25:1.
In step (3), surfactant is selected from one or more of sorbester p17 (Span 80) or Tween 80.
The mass ratio of added chitosan is 1:12-1:8 in sodium tripolyphosphate and step (2) in step (3).
<the perfluocarbon oxygen carrying microballoon for magnetic thermotherapy with targeting>
The perfluocarbon oxygen carrying microballoon for magnetic thermotherapy of targeting of the invention is obtained by above-mentioned preparation method.
<application of the perfluocarbon oxygen carrying microballoon for magnetic thermotherapy with targeting>
The perfluocarbon oxygen carrying microballoon for magnetic thermotherapy with targeting of the invention can be in treatment tumour and alleviation
It is applied in tumor hypoxia environment.
The present invention is further illustrated with reference to embodiments.
Embodiment 1:
The preparation method of the perfluorotributylamine oxygen carrying microballoon for magnetic thermotherapy with targeting of the present embodiment includes such as
Lower step:
(1), egg yolk lecithin is added in Tyrode solution, mass percent shared by egg yolk lecithin is 17%, In
It is emulsified 6 times, power 450W at 25 DEG C using ultrasonic emulsifier, each duration is 10s, is spaced 30s, obtains basic cream
Liquid；
(2), the perfluorotributylamine stoste that volume fraction is 97%, three fourth of basic emulsion and perfluor are added in basic emulsion
The volume ratio of amine stoste is 1:1, is emulsified 7 times, power 450W using ultrasonic emulsifier by above-mentioned steps, the time emulsified every time
For 10s, every minor tick 60s, perfluorotributylamine original lotion is obtained, it is spare；
(3), perfluorotributylamine original lotion is put into 20min in hyperbaric oxygen chamber, fully absorbs oxygen, obtains perfluorotributylamine
Lotion；
(4), the perfluorotributylamine lotion filtration sterilization that the sterile filters for the use of diameter being 0.8 μm finish oxygenation, obtains
The sterile lotion of perfluorotributylamine, it is spare；
(5), 0.05g polyethylene glycol-carboxylic acid (PEG-COOH) is soluble in water, obtain the first solution；0.01g folic acid (FA)
It is dissolved in dimethyl sulfoxide (DMSO), obtains the second solution；It is molten that 0.2g chitosan (CS) is dissolved in the glacial acetic acid that mass fraction is 1%
In liquid, third solution is obtained；
(6), the first solution and the second solution are mixed, and 1.018g 1- (3- dimethylamino-propyl) -3- ethyl carbon is added
The solution of diimmonium salt hydrochlorate (EDC) and 0.4074g N- hydroxysuccinimide (NHS), stirring 20min obtain the first mixing
Liquid；
(7), third solution is added dropwise in the first mixed liquor, 18h is protected from light at 20 DEG C and obtains the second mixed liquor；
(8), after reaction, respectively with pH phosphate-buffered salt (PBS) solution for being 7.4 and distilled water by the second mixed liquor
Dialysis 2 days obtains chitosan (CS) solution of polyethylene glycol (PEG) and folic acid (FA) grafting；
(9), by the sterile lotion of perfluorotributylamine and 0.02g Fe3O4What nanoparticle addition polyethylene glycol and folic acid were grafted
In chitosan solution, obtain third mixed liquor (as water phase)；60mL saxol and 4mLSpan 80 is (living as surface
Property agent) mixing, obtain the 4th mixed liquor (as oily phase)；Water phase is slowly dropped in oily phase, 2h is stirred at 60 DEG C and is obtained
5th mixed liquor；
(10), 0.017g sodium tripolyphosphate (STPP) is soluble in water, sodium tripolyphosphate solution is obtained, by three under ice bath
Polyphosphate sodium solution is added dropwise in the 5th mixed liquor, and stirring 2h obtains the 6th mixed liquor；
(11), the 6th mixed liquor (i.e. completely reacted lotion) is successively washed 2 times with petroleum ether and isopropanol, is had
The perfluorotributylamine oxygen carrying microballoon for magnetic thermotherapy of targeting.
Embodiment 2:
The present embodiment with targeting for the perfluor cyclopropylamine of magnetic thermotherapy and the system of perfluorooctyl bromide oxygen carrying microballoon
Preparation Method includes the following steps:
(1), egg yolk lecithin is added in Tyrode solution, mass percent shared by egg yolk lecithin is 20%, In
It is emulsified 4 times, power 350W at 25 DEG C using ultrasonic emulsifier, each duration is 5s, is spaced 30s, obtains basic cream
Liquid；
(2), perfluor cyclopropylamine and the perfluorooctyl bromide stoste that volume fraction is 97%, basis cream are added in basic emulsion
The volume ratio of liquid and perfluor cyclopropylamine and perfluorooctyl bromide stoste is 1.4:1, using ultrasonic emulsifier by above-mentioned steps emulsification 4
Secondary, power 350W, the time emulsified every time is 5s, every minor tick 30s, obtains perfluor cyclopropylamine and the former cream of perfluorooctyl bromide
Liquid, it is spare；
(3), perfluor cyclopropylamine and perfluorooctyl bromide original lotion are put into 15min in hyperbaric oxygen chamber, fully absorb oxygen, obtains
To perfluor cyclopropylamine and perfluoro capryl bromoiodide emulsion；
(4), perfluor cyclopropylamine and perfluoro capryl bromoiodide emulsion that the sterile filters for the use of diameter being 0.65 μm finish oxygenation
Filtration sterilization obtains perfluor cyclopropylamine and the sterile lotion of perfluorooctyl bromide, spare；
(5), 0.03g polyethylene glycol-carboxylic acid (PEG-COOH) is soluble in water, obtain the first solution；0.0072g folic acid
(FA) it is dissolved in dimethyl sulfoxide (DMSO), obtains the second solution；0.18g chitosan (CS) is dissolved in the ice that mass fraction is 3%
In acetic acid solution, third solution is obtained；
(6), the first solution and the second solution are mixed, and 5.6072g 1- (3- dimethylamino-propyl) -3- ethyl is added
The solution of carbodiimide hydrochloride (EDC) and 0.6733g N- hydroxysuccinimide (NHS), it is mixed that stirring 40min obtains first
Close liquid；
(7), third solution is added dropwise in the first mixed liquor, 26h is protected from light at 20 DEG C and obtains the second mixed liquor；
(8), after reaction, respectively with pH phosphate-buffered salt (PBS) solution for being 7.4 and distilled water by the second mixed liquor
Dialysis 2 days obtains chitosan (CS) solution of polyethylene glycol (PEG) and folic acid (FA) grafting；
(9), perfluor cyclopropylamine and the sterile lotion of perfluorooctyl bromide and 0.02g manganese-zinc ferrite nanoparticle are added poly-
In ethylene glycol and the chitosan solution of folic acid grafting, obtain third mixed liquor (as water phase)；By 64mL saxol and
2.56mL Tween 80 (as surfactant) mixing, obtains the 4th mixed liquor (as oily phase)；Water phase is slowly dropped to oil
Xiang Zhong stirs 4h at 40 DEG C and obtains the 5th mixed liquor；
(10), 0.0225g sodium tripolyphosphate (STPP) is soluble in water, sodium tripolyphosphate solution is obtained, it will under ice bath
Sodium tripolyphosphate solution is added dropwise in the 5th mixed liquor, and stirring 4h obtains the 6th mixed liquor；
(11), the 6th mixed liquor (i.e. completely reacted lotion) is successively washed 2 times with petroleum ether and isopropanol, is had
The perfluor cyclopropylamine and perfluorooctyl bromide oxygen carrying microballoon for magnetic thermotherapy of targeting.
Wherein, perfluor cyclopropylamine and the mass ratio of perfluorooctyl bromide are 1:1.
Embodiment 3:
The preparation method of the phenyl-hexafluoride oxygen carrying microballoon for magnetic thermotherapy with targeting of the present embodiment includes following step
It is rapid:
(1), egg yolk lecithin is added in Tyrode solution, mass percent shared by egg yolk lecithin is 18%, In
It is emulsified 6 times, power 400W at 25 DEG C using ultrasonic emulsifier, each duration is 8s, is spaced 40s, obtains basic cream
Liquid；
(2), the phenyl-hexafluoride stoste that addition volume fraction is 97% in basic emulsion, basic emulsion and phenyl-hexafluoride stoste
Volume ratio is 1.2:1, is emulsified 6 times, power 400W using ultrasonic emulsifier by above-mentioned steps, and the time emulsified every time is 10s,
Every minor tick 40s obtains phenyl-hexafluoride original lotion, spare；
(3), phenyl-hexafluoride original lotion is put into 18min in hyperbaric oxygen chamber, fully absorbs oxygen, obtain phenyl-hexafluoride lotion；
(4), the phenyl-hexafluoride lotion filtration sterilization that the sterile filters for the use of diameter being 0.7 μm finish oxygenation, obtains hexafluoro
The sterile lotion of benzene, it is spare；
(5), 0.04g polyethylene glycol-carboxylic acid (PEG-COOH) is soluble in water, obtain the first solution；0.008g folic acid
(FA) it is dissolved in dimethyl sulfoxide (DMSO), obtains the second solution；0.2g chitosan (CS) is dissolved in the ice second that mass fraction is 2%
In acid solution, third solution is obtained；
(6), the first solution and the second solution are mixed, and it is sub- that 2g 1- (3- dimethylamino-propyl) -3- ethyl carbon two is added
The solution of amine hydrochlorate (EDC) and 0.5g N- hydroxysuccinimide (NHS), stirring 40min obtain the first mixed liquor；
(7), third solution is added dropwise in the first mixed liquor, 18h is protected from light at 25 DEG C and obtains the second mixed liquor；
(8), after reaction, respectively with pH phosphate-buffered salt (PBS) solution for being 7.4 and distilled water by the second mixed liquor
Dialysis 2 days obtains chitosan (CS) solution of polyethylene glycol (PEG) and folic acid (FA) grafting；
(9), by the sterile lotion of phenyl-hexafluoride, 0.01g Fe3O4Nanoparticle and 0.1g manganese-zinc ferrite nanoparticle are added poly-
In ethylene glycol and the chitosan solution of folic acid grafting, obtain third mixed liquor (as water phase)；By 56mL saxol and 4mL
Span 80 (as surfactant) mixing, obtains the 4th mixed liquor (as oily phase)；Water phase is slowly dropped in oily phase,
2h is stirred at 60 DEG C obtains the 5th mixed liquor；
(10), 0.02g sodium tripolyphosphate (STPP) is soluble in water, sodium tripolyphosphate solution is obtained, by three under ice bath
Polyphosphate sodium solution is added dropwise in the 5th mixed liquor, and stirring 2h obtains the 6th mixed liquor；
(11), the 6th mixed liquor (i.e. completely reacted lotion) is successively washed 2 times with petroleum ether and isopropanol, is had
The phenyl-hexafluoride oxygen carrying microballoon for magnetic thermotherapy of targeting.
Embodiment 4:
The preparation side of the FtBu oxygen carrying microballoon for magnetic thermotherapy with targeting of the present embodiment
Method includes the following steps:
(1), egg yolk lecithin is added in Tyrode solution, mass percent shared by egg yolk lecithin is 20%, In
It is emulsified 6 times, power 400W at 25 DEG C using ultrasonic emulsifier, each duration is 10s, is spaced 40s, obtains basic cream
Liquid；
(2), in basic emulsion be added volume fraction be 97% FtBu stoste, basic emulsion and
The volume ratio of FtBu stoste is 1.4:1, is emulsified 6 times using ultrasonic emulsifier by above-mentioned steps, power is
400W, the time emulsified every time are 10s, every minor tick 30s, obtain FtBu original lotion, spare；
(3), FtBu original lotion is put into 18min in hyperbaric oxygen chamber, fully absorbs oxygen, obtained complete
Fluorine (t-butylcyclohexane) lotion；
(4), the FtBu lotion that oxygenation finishes is crossed and is filtered out by the sterile filters for the use of diameter being 0.8 μm
Bacterium obtains the sterile lotion of FtBu, spare；
(5), 0.045g polyethylene glycol-carboxylic acid (PEG-COOH) is soluble in water, obtain the first solution；0.088g folic acid
(FA) it is dissolved in dimethyl sulfoxide (DMSO), obtains the second solution；0.2g chitosan (CS) is dissolved in the ice second that mass fraction is 3%
In acid solution, third solution is obtained；
(6), the first solution and the second solution are mixed, and it is sub- that 3g 1- (3- dimethylamino-propyl) -3- ethyl carbon two is added
The solution of amine hydrochlorate (EDC) and 0.55g N- hydroxysuccinimide (NHS), stirring 20min obtain the first mixed liquor；
(7), third solution is added dropwise in the first mixed liquor, 20h is protected from light at 20 DEG C and obtains the second mixed liquor；
(8), after reaction, respectively with pH phosphate-buffered salt (PBS) solution for being 7.4 and distilled water by the second mixed liquor
Dialysis 3 days obtains chitosan (CS) solution of polyethylene glycol (PEG) and folic acid (FA) grafting；
(9), polyethylene glycol is added in the sterile lotion of FtBu and 0.02g manganese-zinc ferrite nanoparticle
In the chitosan solution of folic acid grafting, obtain third mixed liquor (as water phase)；By 56mL saxol and 4mL Span
80 (as surfactant) mixing, obtain the 4th mixed liquor (as oily phase)；Water phase is slowly dropped in oily phase, in 50 DEG C
Lower stirring 2h obtains the 5th mixed liquor；
(10), 0.017g sodium tripolyphosphate (STPP) is soluble in water, sodium tripolyphosphate solution is obtained, by three under ice bath
Polyphosphate sodium solution is added dropwise in the 5th mixed liquor, and stirring 2h obtains the 6th mixed liquor；
(11), the 6th mixed liquor (i.e. completely reacted lotion) is successively washed 2 times with petroleum ether and isopropanol, is had
The FtBu oxygen carrying microballoon for magnetic thermotherapy of targeting.
The above-mentioned description to embodiment is that this hair can be understood and used for the ease of those skilled in the art
It is bright.Those skilled in the art obviously readily can make various modifications to these embodiments, and described herein one
As principle be applied in other embodiments, without having to go through creative labor.Therefore, the present invention is not limited to the above embodiments.
Those skilled in the art's principle according to the present invention, not departing from improvement that scope of the invention is made and modification all should be at this
Within the protection scope of invention.
Claims (10)
1. a kind of preparation method of the perfluocarbon oxygen carrying microballoon for magnetic thermotherapy with targeting, it is characterised in that: it is wrapped
Include following steps:
(1), egg yolk lecithin is added in tyrode's solution, 4-6 times emulsified at 25-30 DEG C, each duration is 5-
10s is spaced 30-60s, obtains basic emulsion；
(2), the perfluocarbon stoste of volume fraction >=97% is added in the basic emulsion, emulsifies 4-7 times, emulsifies every time
Time is 5-10s, and every minor tick 30-60s obtains perfluocarbon original lotion；
(3), by the perfluocarbon original absorbing emulsions oxygen, perfluorocarbon emulsion is obtained；
(4), by the perfluorocarbon emulsion filtration sterilization, the sterile lotion of perfluocarbon is obtained；
(5), polyethylene glycol-carboxylic acid is soluble in water, obtain the first solution；Folic acid is dissolved in dimethyl sulfoxide, and it is molten to obtain second
Liquid；Chitosan is dissolved in the glacial acetic acid solution that mass fraction is 1-3%, obtains third solution；
(6), first solution and the second solution are mixed, and 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide is added
The solution of hydrochloride and N- hydroxysuccinimide stirs to get the first mixed liquor；
(7), the third solution is added in first mixed liquor, is protected from light to obtain the second mixed liquor at 20-25 DEG C；
(8), second mixed liquor is dialysed 2-3 days with phosphate buffered saline solution and distilled water, obtains polyethylene glycol and folic acid
The chitosan solution of grafting；
(9), the shell that the polyethylene glycol and folic acid grafting is added in the sterile lotion of the perfluocarbon and magnetic nano-particle is gathered
In sugar juice, third mixed liquor is obtained；Saxol and surfactant are mixed, the 4th mixed liquor is obtained；By described
Three mixed liquors are added in the 4th mixed liquor, stir to get the 5th mixed liquor；
(10), sodium tripolyphosphate is soluble in water, sodium tripolyphosphate solution is obtained, by the sodium tripolyphosphate solution under ice bath
It is added in the 5th mixed liquor, stirs to get the 6th mixed liquor；
(11), the 6th mixed liquor is successively washed with petroleum ether and isopropanol, obtain it is described with targeting for magnetic
The perfluocarbon oxygen carrying microballoon of thermotherapy.
2. preparation method according to claim 1, it is characterised in that: in step (1), the egg yolk lecithin is in tyrode's solution
In mass percent be 17-20%；When the emulsification, the power of the ultrasonic emulsifier used is 350-450W.
3. preparation method according to claim 1, it is characterised in that: in step (2), the basic emulsion and perfluocarbon
The volume ratio of stoste is 1:1-1.4:1；When the emulsification, the power of the ultrasonic emulsifier used is 350-450W.
4. preparation method according to claim 1, it is characterised in that: complete in the perfluocarbon stoste in step (2)
Fluorocarbons is selected from one of perfluorotributylamine, perfluor cyclopropylamine, perfluorooctyl bromide, phenyl-hexafluoride and FtBu
More than.
5. preparation method according to claim 1, it is characterised in that: in step (3), the perfluocarbon original absorbing emulsions
The time of oxygen is 15-20min；And/or
In step (4), when the filtration sterilization, the diameter of the sterile filters used is 0.65-0.8 μm.
6. preparation method according to claim 1, it is characterised in that: in step (5), the polyethylene glycol-carboxylic acid and shell
The mass ratio of glycan is 1:4-1:6, and the mass ratio of the folic acid and chitosan is 1:20-1:25.
7. preparation method according to claim 1, it is characterised in that: in step (6), the chitosan and N- hydroxyl fourth two
Imido molar ratio is 1:3-1:5, N- hydroxysuccinimide and 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide salt
The molar ratio of hydrochlorate is 1:1.5-1:5；And/or
In step (6), the time of the stirring is 20-40min；And/or
In step (7), the time being protected from light is 18-26h；And/or
In step (8), the pH value of the phosphate buffered saline solution is 7.4.
8. preparation method according to claim 1, it is characterised in that: in step (9), the magnetic nano-particle is selected from four
One or more of Fe 3 O and manganese-zinc ferrite；And/or
In step (9), the mass ratio of the saxol and surfactant is 15:1-25:1；And/or
In step (9), the time of the stirring is 2-4h, and the temperature of the stirring is 40-60 DEG C；And/or
In step (9), the surfactant is selected from one or more of sorbester p17 or Tween 80；And/or
In step (10), the time of the stirring is 2-4h；And/or
The mass ratio of added chitosan is 1:12-1:8 in sodium tripolyphosphate and step (5) in step (10).
9. a kind of perfluocarbon oxygen carrying microballoon for magnetic thermotherapy with targeting, it is characterised in that: it is by claim 1-8
Described in any item preparation methods obtain.
10. a kind of swollen in treatment by the perfluocarbon oxygen carrying microballoon for magnetic thermotherapy as claimed in claim 9 with targeting
Application in tumor and alleviation tumor hypoxia environment.
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