CN109529033A - A kind of stable oxygen carrier microvesicle and its preparation method and application - Google Patents
A kind of stable oxygen carrier microvesicle and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of simple and easy, efficient oxygen carrier, stability is good and the oxygen carrier microvesicle and preparation method thereof of uniform particle sizes, and the application of its interior irradiation and external exposure sensitizer in radiotherapy, the oxygen carrier microvesicle includes shell and filling gas, shell includes phosphatide and stabilizer, and filling gas includes oxygen and fluoro-gas.
Description
Technical field
The present invention relates to medicine technical fields, and in particular to a kind of stable oxygen carrier microvesicle and preparation method thereof and answers
With.
Background technique
In recent years, the cancer illness rate and mortality in China are rising year by year, and seriously threaten people's health.
Conventional tumor therapeuticing method is to perform the operation, based on radiation and chemotherapy.Wherein radiotherapy (radiotherapy, radiotherapy) is to utilize to put
A kind of local therapeutic approaches of beta ray therapy tumour.About nearly 70% malignant tumor patient needs to be controlled with radiation over the course for the treatment of
It treats, 40% malignant tumour can be eradicated with radiotherapy.The basic principle of radiotherapy is α, β, the γ generated using radioactive isotope
X-ray, electric wire, proton beam and other particles beams that ray and all kinds of roentgenotherapia machines or accelerator generate etc. are to hydrone
Ionization, generate free radicals.Free radical interacts with large biological molecule (RH) again, acts on DNA chain and causes DNA
Chain fracture.This process need to depend on the presence of oxygen.But weary oxygen (alternatively referred to as anoxic) situation inside solid tumor makes to swell
Oncocyte is also easy to produce radioactivity resistance, increases the risk of recurrence and transfer.Large dosage of radioactive ray also can be to tumour Peripheral blood for just
Normal tissue causes very macrolesion, causes the abnormal even failure of related organ function, seriously reduces patients ' life quality, reduce life
Deposit the phase.So attempting to introduce radiosensitizer in clinical practice.Generally with some high electrophilic reagent (such as Xiao Ji imidazoles or nitre
Base benzene derivative) it is used as sensitizer, tumour cell is improved to the sensibility of ray.But these chemical sensitizers while indifference
The killing for increasing normal cell and its be not easy to measure in the concentration of tumour cell, and toxic side effect is big.Both domestic and external
The oxygen concentration that person attempts directly to improve tumor section makes to suffer to improve tumour to the sensibility of radiation, such as in radiotherapy
Person inhales pure oxygen or carries out radiotherapy in Hyperbaric oxygen chamber.Since there has been no finely grind for the damage problem of high concentration oxygen normal tissue
Study carefully, these methods are not yet promoted.Other scholars are using the fluorocarbon emulsion (FC) that can carry a large amount of oxygen come to the weary of tumor tissues
Oxygen area conveys oxygen.But fluorocarbon emulsion do not pass through due to safety problem and other side effects before clinical test.In order to
It solves the above problems, the present invention is tumour to the area Fa Yang of tumor tissues conveying oxygen in conjunction with ultrasound control using oxygen carrier microvesicle
Radio therapy sensitization improves a safely and effectively scheme.
Microvesicle has clinically been widely applied as acoustic contrast agent, and the trade name for ratifying listing includes SonoVue,
Optison and Definity.There is the patent for the microvesicle preparation for being largely used to acoustic contrast agent in the country at present.Such as
It is main component as multiple that CN200810217176, which discloses one kind by synthetic phospholipid, its poly- diethyl 01 derivatives and glycolipid ingredient,
Adipose membrane is closed, the microvesicle of filling perfluorocarbon gas in film.CN200310122421.2 disclose another with phospholipid composition be at
The microvesicle that may be used as acoustic contrast agent of membrane material, the microvesicle by phospholipid composition (1%-10%), foaming agent (5%-15%),
Polymer (70-90%), stabilizer (0.5%-10%) and fluorocarbon gas composition.In addition, CN200480002975.2 is disclosed
The lipid microbubble contrast agent of lyophilized matrix a kind of, microvesicle is rebuild by lyophilized matrix before the injection.In addition, microvesicle is certain
Cavitation effect is generated under the ultrasonic excitation of energy to rupture.In conjunction with this phenomenon, microvesicle be largely used as carrier come into
The internal transport of row drug, gene, antibody etc. pinpoints release.
Oxygen is transmitted using oxygen carrier microvesicle to be still in infancy to human body anoxia tissue, usually utilizes oxygen carrier microvesicle
In anoxic caused by injured because of respiratory tract blocking or lung and hypoxemia to supplying oxygen in blood.Such as
CN103212094A discloses a kind of fluorine oxygen microvesicle and is used to oxygen release in hypoxic brain tissue, with realize directly, fixed point and high
Effect oxygen supply, the aerobic requirement for meeting nerve cell.And the oxygen carrier microvesicle for being used for radio therapy sensitization is faced with new need in application scenarios
It asks.First, the filling gas of oxygen carrier microvesicle is oxygen, and the filling gas (SF of the microvesicle for acoustic contrast agent6Or C3F8) phase
Than the higher stability for causing oxygen carrier microvesicle of diffusion coefficient is poor in water, it is difficult to store, so can be realized before preferably injecting
Easily it is prepared in situ.Secondly, ultrasonic microbubble etc. belongs to blood pool contrast medium contrast agent, be distributed always in the blood vessels, diameter compared with
Greatly, generally at 1-8 μm.Oxygen carrier microvesicle partial size for blood oxygen is similar.But it is needed for the oxygen carrier microvesicle of radio therapy sensitization
Inside tumor is reached across vascular wall, it requires that partial size is smaller, diameter generally will be at 1 μm or less.At present there is no meet with
The oxygen carrier microvesicle that can be used for radio therapy sensitization that upper two o'clock requires.
The research of oxygen carrier microvesicle disclosed by the invention for radio therapy sensitization there is no relevant report both at home and abroad, and this combination is super
The technology of acoustic control and microvesicle oxygen has good application and development prospect, safe and reliable and efficient clinically to provide one
Radiosensitization sense scheme.
Summary of the invention
The object of the present invention is to provide a kind of simple and easy, efficient oxygen carrier, stability is good and the oxygen carrier microvesicle of uniform particle sizes
And preparation method thereof, the interior irradiation and external exposure sensitizer being particularly suitable for application in radiotherapy overcome existing sensitizer such as
Xiao Ji imidazoles bring serious side effects.
The purpose of the invention is achieved by the following technical solution:
A kind of stable oxygen carrier microvesicle, including shell and filling gas, the shell include phosphatide and following stabilizer
One of or it is a variety of: dimyristoyl phosphatidyl choline (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearyl phosphorus
Phosphatidylcholine (DSPC), dilauroyl lecithin (DLPC), 1,2- dioleyl phosphatidyl choline (DOPC), 1- palmityl
Base -2- oleoyl lecithin (POPC), two peanut phosphatidyl cholines (DAPC), distearoylphosphatidylethanolamine
(DSPE), dipalmitoylphosphatidylethanolamine (DPPE), two myristoyl phosphatidyl-ethanolamines (DMPE), dilauroyl
Phosphatidyl-ethanolamine (DLPE), dioleoylphosphatidylethanolamine (DOPE), distearoylphosphatidylglycerol (DSPG), two palm fibres
Palmitic acid acyl phosphatidyl glycerol (DPPG), GLYCEROL,DIMYRISTOYL PHOSPHATIDYL (DMPG), dilauroylphosphatidylglycerol (DLPG), two is hard
Fatty acyl group phosphatidic acid (DSPA), dipalmitoylphosphatidic acid (DPPA), Dimyristoyl phosphatidic acid (DMPA), two lauroyl
Base phosphatidic acid (DLPA), bis- palmityl-SN- glycerol-3-phosphate sodium salt (DOPA) of 1,2-, dipalmitoylphosphatidylserine
(DPPS), distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-mPEG2000), distearoylphosphatidylethanolamine-
Polyethylene glycol (DSPE-mPEG5000), the poly- two-folic acid of second (DSPE-PEG-FA) of distearoylphosphatidylethanolamine-, two is hard
Fatty acyl group phosphatidyl-ethanolamine-polyethylene glycol-cyclic peptide (DSPE-PEG-cRGD), polyoxyethylene poly-oxygen propylene aether block copolymerization
Object；The filling gas includes one of oxygen and following fluoro-gas or a variety of: sulfur hexafluoride, perfluoropropane, perfluor
Butane, perflenapent steam, perflexane steam.
Further, the oxygen carrier microvesicle, further includes cryoprotector.
Preferably, the cryoprotector includes one of following carbohydrate or a variety of: glucose, galactolipin,
Fructose, sucrose, trehalose, dextran, soluble starch, polyethylene glycol, mannitol.
Preferably, the phosphatide is Distearoyl Phosphatidylcholine (DSPC).
Preferably, the filling gas is the mixed gas of oxygen and sulfur hexafluoride, and oxygen and sulfur hexafluoride ratio are 4:1
To 8:1.Alternatively, the filling gas is the mixed gas of oxygen and perflenapent steam, oxygen and perflenapent steam rates
For 4:1 to 8:1.Or the filling gas is the mixed gas of oxygen and perflexane steam, oxygen and perflexane steam
Vapour ratio is 4:1 to 8:1.
Preferably, the oxygen carrier microvesicle is micron order microvesicle, and average grain diameter is 1.0 μm -4.0 μm.
Alternatively, the oxygen carrier microvesicle is nanoscale microvesicle, average grain diameter is 0.2 μm -0.8 μm.
A kind of preparation method of the oxygen carrier microvesicle is provided simultaneously, comprising the following steps:
A. by phosphatide and stabilizer, heating water bath dissolves in glycerol and aqueous solution of propylene glycol, obtains phospholipid solution；Its
In, the stabilizer includes dimyristoyl phosphatidyl choline (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearyl
Phosphatidyl choline (DSPC), dilauroyl lecithin (DLPC), 1,2- dioleyl phosphatidyl choline (DOPC), 1- palm
Acyl group -2- oleoyl lecithin (POPC), two peanut phosphatidyl cholines (DAPC), distearoylphosphatidylethanolamine
(DSPE), dipalmitoylphosphatidylethanolamine (DPPE), two myristoyl phosphatidyl-ethanolamines (DMPE), two lauroyl
Base phosphatidyl-ethanolamine (DLPE), dioleoylphosphatidylethanolamine (DOPE), distearoylphosphatidylglycerol (DSPG), two palm fibres
Palmitic acid acyl phosphatidyl glycerol (DPPG), GLYCEROL,DIMYRISTOYL PHOSPHATIDYL (DMPG), dilauroylphosphatidylglycerol (DLPG), two
Stearyl phosphatidic acid (DSPA), dipalmitoylphosphatidic acid (DPPA), Dimyristoyl phosphatidic acid (DMPA), two laurels
Acyl phospholipids acid (DLPA), bis- palmityl-SN- glycerol-3-phosphate sodium salt (DOPA) of 1,2-, dipalmitoylphosphatidylserine
(DPPS), distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-mPEG2000), distearoylphosphatidylethanolamine-
Polyethylene glycol (DSPE-mPEG5000), the poly- two-folic acid of second (DSPE-PEG-FA) of distearoylphosphatidylethanolamine-, two is hard
Fatty acyl group phosphatidyl-ethanolamine-polyethylene glycol-cyclic peptide (DSPE-PEG-cRGD), polyoxyethylene poly-oxygen propylene aether block copolymer
One of or it is a variety of；
B. the step a phospholipid solution prepared is sealed in container, fills the gaseous mixture of oxygen and fluoro-gas；Wherein,
The fluoro-gas includes pentane, hexane, heptane, octane, nonane, decane, cyclooctane, cyclononane, cyclodecane, perflenapent,
Perflexane, PF 5070, perfluorooctane, Perfluorononane, perfluorooctane, perfluoro bromide octane, one in perfluor -15- crown- 5- ether
Kind is a variety of；
C. before use, obtaining the stabilization oxygen carrier microvesicle for being used for radio therapy sensitization by mechanical oscillation.
Another preparation method of the oxygen carrier microvesicle is provided again, comprising the following steps:
A. by phosphatide and stabilizer, heating water bath dissolves in glycerol and aqueous solution of propylene glycol, obtains phospholipid solution；Its
In, the stabilizer includes dimyristoyl phosphatidyl choline (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearyl
Phosphatidyl choline (DSPC), dilauroyl lecithin (DLPC), 1,2- dioleyl phosphatidyl choline (DOPC), 1- palm
Acyl group -2- oleoyl lecithin (POPC), two peanut phosphatidyl cholines (DAPC), distearoylphosphatidylethanolamine
(DSPE), dipalmitoylphosphatidylethanolamine (DPPE), two myristoyl phosphatidyl-ethanolamines (DMPE), dilauroyl
Phosphatidyl-ethanolamine (DLPE), dioleoylphosphatidylethanolamine (DOPE), distearoylphosphatidylglycerol (DSPG), two palm fibres
Palmitic acid acyl phosphatidyl glycerol (DPPG), GLYCEROL,DIMYRISTOYL PHOSPHATIDYL (DMPG), dilauroylphosphatidylglycerol (DLPG), two is hard
Fatty acyl group phosphatidic acid (DSPA), dipalmitoylphosphatidic acid (DPPA), Dimyristoyl phosphatidic acid (DMPA), dilauroyl
Phosphatidic acid (DLPA), bis- palmityl-SN- glycerol-3-phosphate sodium salt (DOPA) of 1,2-, dipalmitoylphosphatidylserine
(DPPS), distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-mPEG2000), distearoylphosphatidylethanolamine-
Polyethylene glycol (DSPE-mPEG5000), the poly- two-folic acid of second (DSPE-PEG-FA) of distearoylphosphatidylethanolamine-, two is hard
Fatty acyl group phosphatidyl-ethanolamine-polyethylene glycol-cyclic peptide (DSPE-PEG-cRGD), polyoxyethylene poly-oxygen propylene aether block copolymer
One of or it is a variety of；
B. the organic solvent not soluble in water that boiling point is 60-160 DEG C is added in the phospholipid solution prepared by step a, passes through
Ultrasound or Mechanical Crushing obtain nanometer or micron-sized lotion；
C. cryoprotector is added in the lotion prepared by step b, obtains lyophilized matrix by freeze-drying, is sealed in container,
The gaseous mixture of oxygen and fluoro-gas is filled, the stabilization oxygen carrier microvesicle for being used for radio therapy sensitization is obtained；Wherein, the fluoro-gas packet
Include pentane, hexane, heptane, octane, nonane, decane, cyclooctane, cyclononane, cyclodecane, perflenapent, perflexane, perfluor heptan
One of alkane, perfluorooctane, Perfluorononane, perfluorooctane, perfluoro bromide octane, perfluor -15- crown- 5- ether are a variety of.
Preferably, the organic solvent in the b step includes one of following solvent or a variety of: pentane, hexane, heptan
Alkane, octane, nonane, decane, cyclooctane, cyclononane, cyclodecane, perflenapent are perflexane, PF 5070, perfluorooctane, complete
Fluorine nonane, perfluorooctane, perfluoro bromide octane, perfluor -15- crown- 5- ether.
Two kinds of microvesicle preparation methods are optionally applied to different scenes.First, it can be weighed using desivac preparation lyophilized matrix
The oxygen carrying microvesicle built.For example, with synthetic phospholipid and its polyethyleneglycol derivative such as Distearoyl Phosphatidylcholine (DSPC), two palm fibres
Palmitic acid acyl phosphatidyl glycerol (DPPG) etc. configures phospholipid solution, and the organic solvent that PF 5070 etc. is not soluted in water is added and does oily phase.So
Emulsion is dispersed by mechanical stirring or ultrasonication afterwards.The partial size of oil droplet is the same as the parameter for adjusting mechanical stirring or ultrasonication
To control at 0.3-4.0 μm.Emulsion freezes after being distributed to the protective agent such as polyethylene glycol that freeze-drying in vial and is added
Moisture therein and oily phase are done, then the gaseous mixture of oxygen and oxygen and other gases is added in sealing.Microvesicle is using preceding addition
Physiological saline, gently being vibrated with water can obtain.This microvesicle is dried powder, and convenient storage is easy to transport, clinical use side
Just, but microbubble concentration is lower.The microvesicle can be used for interior irradiation radiotherapy, and a small amount of multiple injection oxygen carrying microvesicle is needed to carry out radiotherapy increasing
It is quick.Second, oxygen carrier microvesicle is prepared in situ by phospholipid solution and mechnical oscillator.For example, with synthetic phospholipid and its polyethylene glycol
Derivative such as dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-
The configuration phospholipid solution such as mPEG5000), is then dispensed in vial and seals with rubber stopper, then set the air in bottle
It changes oxygen or oxygen into and extracts the gaseous mixture of fluoro-gas.Glass bottle containing phospholipid solution is stored in 4 DEG C of refrigerators to protect
It deposits.It can be obtained milky microvesicle suspension before use, reconciling device mechanical oscillation 60 seconds (4000rpm) using silver mercury capsule.
This kind of microvesicle is to be prepared in situ, and microbubble concentration is high, which is used for external exposure radiotherapy, can largely inject oxygen carrying microvesicle and carry out radiotherapy
Enhanced sensitivity.
A kind of application of the oxygen carrier microvesicle is provided again, is used as external exposure sensitizer in radiotherapy.
Another application of the oxygen carrier microvesicle is provided again, is used as in radiotherapy in I125 radioactive particle
Irradiate sensitizer.
Detailed description of the invention
Fig. 1 oxygen carrier microvesicle (example 5) is crushed after high-energy ultrasonic effect in the intracorporal ultrasonic signal of tumor-bearing mice and microvesicle
Discharge oxygen.(a) ultrasound image at microvesicle injection pre-neoplastic position；(b) the ultrasound figure of tumor locus after microvesicle is injected about 2 seconds
Picture, ultrasonic signal start to occur in tumor locus；(c) ultrasound image of tumor locus after microvesicle is injected about 15 seconds, ultrasound letter
Number reach most strong；(d) it is acted on two minutes for breaking up microvesicle high-energy ultrasonic (MI=1.2), the ultrasound image of tumor locus.
Fig. 2 ultrasonic in combination microvesicle acts on the Oxygen saturation variation of lower tumor locus.Oxygen saturation refers to oxygenated blood red eggs
The ratio of the sum of white light acoustic signal intensity and oxygen-containing/not oxygen-containing hemoglobin photoacoustce signal intensity.
Effect of enhanced sensitivity is irradiated in Fig. 3 oxygen carrier microvesicle.Four groups of mouse point: group 1:PBS control；Group 2: microvesicle；Group 3: particle and
Group 4: particle+microvesicle.(a) under different condition each group tumor growth curve, P value: P < 0.01 * *, (every group of n=5).(b) ten two
The average tumor size of each group, P value: P < 0.01 * *, (every group of n=5) after its treatment.(c) bush of each group after treating for 12 days
The MIcrosope image of the tumor tissue section of essence-eosin stains (H&E) and keratin (CK) dyeing.
Specific embodiment
Detailed description in next step made to the present invention below with reference to embodiment, but to be not limited to this several for embodiments of the present invention
Kind.
Embodiment 1: the desivac preparation of micron order phosphatide oxygen carrier microvesicle
The Distearoyl Phosphatidylcholine (DSPC) of 20mg, the dipalmitoylphosphatidylglycerol of 20mg are measured with assay balance
(DPPG), the Macrogol 4000 (PEG4000) of the palmitinic acid of 2mg and 100mg are put into flask, are added 5mL's into flask
Then the 10wt% glycerine water solution of 35ml is added, under the conditions of 65 DEG C in propylene glycol, heating water bath 20min under the conditions of 55 DEG C
Heating water bath 20min.Stop heating, above-mentioned phospholipid solution is cooled to room temperature.Then phospholipid solution is placed in ice-water bath, be added
3.2ml PF 5070, using high-speed homogenization machine at the emulsified above-mentioned mixed liquor of 13,000-17,000rpm condition one minute.Institute
The average grain diameter of the PF 5070 lotion obtained is between 1.0 μm -4 μm.Pass through after PF 5070 lotion is stood room temperature to be restored
Centrifugation is resuspended and washes away excessive phosphatide and other small molecules.It is finally distributed to the 10wt% Macrogol 4000 aqueous solution of 40ml,
(every bottle of 1ml) is encapsulated into vial.Vial is placed in liquid nitrogen and is cooled down rapidly, is then frozen by freeze dryer
It is dry.Bottle containing freeze-dried powder is sealed with rubber stopper, then the air in bottle is extracted out, refills oxygen or configured
Gaseous mixture.It needs to place gas in angel bottle before use to stablize.In use, only needing to inject by syringe into bottle
4ml physiological saline, and gently vibrated with hand.
Embodiment 2: nanoscale phosphatide oxygen carrier microvesicle desivac preparation
Phospholipid solution preparation method is with case study on implementation 1, thin using ultrasound after 3.2ml PF 5070 is added to phospholipid solution
Born of the same parents are crushed the emulsified above-mentioned mixed liquor of instrument one minute, and the average grain diameter of resulting PF 5070 lotion is between 0.2 μm -0.8 μm.
Subsequent PF 5070 lotion purification and freeze-drying and microvesicle preparation method are the same as case study on implementation 1.
Embodiment 3: the targeting phosphatide oxygen carrier microvesicle preparation that freeze-drying saves for a long time
The Distearoyl Phosphatidylcholine (DSPC) of 16mg, the dipalmitoylphosphatidylglycerol of 16mg are measured with assay balance
(DPPG), the palmitinic acid of 2mg, the distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-mPEG2000) of 4mg, 4mg's
Distearoylphosphatidylethanolamine-polyethylene glycol-folic acid (DSPE-PEG-FA) or distearoylphosphatidylethanolamine-
The Macrogol 4000 (PEG4000) of polyethylene glycol-cyclic peptide (DSPE-PEG-cRGD) and 100mg are put into flask, into flask
The propylene glycol of 5mL is added, then the 10wt% glycerine water solution of 35ml is added in heating water bath 20min under the conditions of 55 DEG C,
Heating water bath 20min under the conditions of 65 DEG C.Subsequent PF 5070 emulsification, the purification of gained lotion and freeze-drying and microvesicle preparation method
With case study on implementation 1.
Embodiment 4: the preparation of phosphatide oxygen carrier microvesicle is largely prepared
The dipalmitoylphosphatidic acid (DPPA) of 3mg, the dipalmitoylphosphatidylcholine of 24mg are measured with assay balance
(DPPC), the dipalmitoylphosphatidylethanolamine (DPPE) of 3mg, the poly- second two of the distearoylphosphatidylethanolamine-of 10mg
Alcohol (DSPE-mPEG5000) is put into flask, the propylene glycol of 5ml and the distilled water of 30ml is added into flask, in 55 DEG C of conditions
Then lower heating water bath 20min is added the solution of the sodium chloride configuration of the glycerol and 0.45g of 5ml, is warming up to 70 DEG C of heating
20min.Phospholipid solution is cooled to room temperature, and the pH to 6.5 of solution is adjusted with 1M HCl and 1M NaOH.Phospholipid solution is dispensed into
Vial (every bottle of 1.6ml), then seals with rubber stopper, and then extracts the air in bottle out, refills oxygen or configuration
Good gaseous mixture.4 DEG C of refrigerators are placed into save.Before use, reconciling device mechanical oscillation 60 seconds (4000rpm) i.e. using silver mercury capsule
It can get milky microvesicle suspension.
Embodiment 5: the oxygen carrier microvesicle preparation of oxygen filling
Preparation method will be equipped with the sealed glass jars of freeze-dried powder, refill oxygen with case study on implementation 1.Before use
It needs to place gas in angel bottle to stablize.In use, only needing to inject 4ml physiological saline into bottle by syringe, it is used in combination
Hand gently vibrates.
Embodiment 6:SF6Microvesicle preparation
Preparation method will be equipped with the sealed glass jars of freeze-dried powder, refill SF6 with case study on implementation 1.It is needed before use
Gas in angel bottle is placed to stablize.In use, only needing to inject 4ml physiological saline into bottle by syringe, and use hand
Gently vibrate.
Embodiment 7:O2/SF6The oxygen carrier microvesicle preparation of gaseous mixture filling
Preparation method will be equipped with the sealed glass jars of freeze-dried powder, refill oxygen and SF with case study on implementation 16Mixing
Gas (volume ratio 5/1).It needs to place gas in angel bottle before use to stablize.In use, only needing through syringe to bottle
Middle injection 4ml physiological saline, and gently vibrated with hand.
Embodiment 8:O2The oxygen carrier microvesicle preparation of/perflenapent mixture of steam filling
Preparation method will be equipped with the sealed glass jars of freeze-dried powder, refill oxygen and perflenapent with case study on implementation 1
Mixture of steam (volume ratio 5/1).It needs to place gas in angel bottle before use to stablize.In use, only needing to pass through note
Emitter injects 4ml physiological saline into bottle, and is gently vibrated with hand.
Embodiment 9:O2The oxygen carrier microvesicle preparation of/perflexane mixture of steam filling
Preparation method will be equipped with the sealed glass jars of freeze-dried powder, refill oxygen and perflexane with case study on implementation 1
Mixture of steam (volume ratio 5/1).It needs to place gas in angel bottle before use to stablize.In use, only needing to pass through note
Emitter injects 4ml physiological saline into bottle, and is gently vibrated with hand.
Embodiment 10: the measurement of oxygen carrier microvesicle partial size and particle diameter distribution
The case study on implementation 5-8 microvesicle of situ configuration takes 100ul to be added in 2ml PBS solution, passes through instrument Zetaplus
(Brookhaven, UK) measures the partial size of microvesicle using direct light scattering method.The concentration of microvesicle by hemocytometer (Neubauer,
Spain it) measures.The results are shown in Table 1.By table 1, the result shows that, oxygen, which is mixed into certain fluoro-gas, can make the microvesicle grain of recombination
Diameter is smaller, and concentration is higher.The solubility in water of fluoro-gas is lower, more stable in microvesicle reconstruction process.Instead, pure oxygen is made
To fill gas, microvesicle is easy that microvesicle fusion occurs in reconstruction process, and ablation, so concentration is lower, average grain diameter is larger.
The physical parameter of the microvesicle of the different filling gas of table 1..
Embodiment 11: ultrasonic cavitation of the phosphatide oxygen carrier microvesicle in nude mouse tumor model
It is injected intraperitoneally using 10% chloraldurate, oxygen carrier microvesicle prepared by the case study on implementation 6 of 100 μ l passes through caudal vein
Injection kind has in the nude mouse of nasopharyngeal carcinoma (nasopharyngeal carcinoma, NPC) tumour.It is persistently seen by ultrasonic image
It examines, as a result as shown in Figure 1.After injecting 2s, ultrasonic signal starts to occur in tumor locus.After general 15s, tumor locus ultrasound letter
When number reaching most strong, ultrasound intensity is improved to MI=1.2, makes within prolonged exposure microvesicle about 2 minutes its rupture, discharges oxygen, is swollen
Tumor position ultrasonic signal disappears, and shows that microvesicle is broken up completely.The oxygen content of tumor section passes through 128 photoacoustic imager of Nexus
(Endra, US) measures oxygen-containing hemoglobin signal and not oxygen-containing hemoglobin signal strength to determine, as a result as shown in Fig. 2, surpassing
Sound joint oxygen carrier microvesicle effect can make the Oxygen saturation of tumor locus increase by 3 times or so.
Embodiment 12: phosphatide oxygen carrier microvesicle internally irradiates the effect of enhanced sensitivity analysis of radiotherapy
It is subcutaneous that Human NPC (nasopharyngeal carcinoma, NPC) cell CEN2 is planted in mouse, is formed swollen
Tumor model, to tumour growth to volume 160mm3.Mouse is randomly divided into four groups, every group six.It is respectively labeled as group 1:PBS pairs
According to group, this group of mouse only injects 100 μ l PBS solution daily, does not do other processing；Group 2: microvesicle, this group of mouse are injected daily
100 μ l case study on implementation, 5 oxygen carrier microvesicle and then ultrasonic excitation, do not do other processing；Group 3: particle, this group of mouse tumor position are planted
Enter 125I particle, does not do other processing；Group 4: particle+microvesicle, this group of mouse tumor position are implanted into 125I particle, this group of mouse
Injection 100 μ l case study on implementation, 5 oxygen carrier microvesicle and then ultrasonic excitation daily.Measurement each group mouse tumor size daily, each group mouse
It treats 12 days.Tumor growth curve and treatment 12 days after mouse gross tumor volume it is as shown in Figure 3.Fig. 3 .a and Fig. 3 .b are shown
Compared with organizing 2 (microvesicles) of 1 (PBS control group) and group, organizes 3 (particles) and 4 (particles+microvesicle) of group show significant tumour growth
Inhibitory effect.It is compared with 3 applications radiotherapies of group, group 4 dense makes to control by the oxygen of ultrasonic in combination microvesicle increase tumor locus
Therapeutic effect increases~105%.The pathological analysis of each group tumor biopsy shown in Fig. 3 .c is shown to be compared with other groups, group 4 (microvesicle+
Particle) maximum killing is caused to tumour cell.It is micro- in oxygen carrier that the raising of 4 significant therapeutic effects of group is attributed to ultrasonication
Bubble is that the oxygen content of tumor region significantly improves, and increases tumor hypoxia area cell to the radiosensitivity of ray.
In conclusion the present invention is made actual sample and test is used for multiple times such as specification and diagramatic content, from making
It is seen with the effect of test, the provable present invention can reach its desired purpose, and practical value is unquestionable.It is provided above
Embodiment is only used to conveniently illustrate the present invention, and is not intended to limit the present invention in any form, any affiliated technology neck
Has usually intellectual in domain, if without departing from the scope of the technical features of the present invention, utilizing disclosed technology
The equivalent embodiment for locally changing or modifying made by content, and without departing from technical feature content of the invention, still fall within
In the range of the technology of the present invention feature.
Claims (14)
1. a kind of stable oxygen carrier microvesicle, including shell and filling gas, it is characterised in that:
The shell includes one of phosphatide and following stabilizer or a variety of: dimyristoyl phosphatidyl choline (DMPC),
Dipalmitoylphosphatidylcholine (DPPC), Distearoyl Phosphatidylcholine (DSPC), dilauroyl lecithin (DLPC), 1,2-
Dioleyl phosphatidyl choline (DOPC), 1- palmityl -2- oleoyl lecithin (POPC), two peanut phosphatidyl cholines
(DAPC), distearoylphosphatidylethanolamine (DSPE), dipalmitoylphosphatidylethanolamine (DPPE), two myristoyls
Phosphatidyl-ethanolamine (DMPE), dilauroyl phosphatidyl-ethanolamine (DLPE), dioleoylphosphatidylethanolamine (DOPE), two
Stearyl phosphatidyl glycerol (DSPG), dipalmitoylphosphatidylglycerol (DPPG), GLYCEROL,DIMYRISTOYL PHOSPHATIDYL (DMPG), two
Lauroyl phosphatidyl glycerol (DLPG), distearoylphosphatidic acid (DSPA), dipalmitoylphosphatidic acid (DPPA), two nutmegs
Acyl phospholipids acid (DMPA), dilauroyl phosphatidic acid (DLPA), bis- palmityl-SN- glycerol-3-phosphate sodium salt of 1,2-
(DOPA), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-
), mPEG2000 distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-mPEG5000), distearyl acyl group phosphatidyl ethanol
Poly- two-the folic acid of second (DSPE-PEG-FA) of amine-, distearoylphosphatidylethanolamine-polyethylene glycol-cyclic peptide (DSPE-PEG-
CRGD), polyoxyethylene poly-oxygen propylene aether block copolymer；
The filling gas include one of oxygen and following fluoro-gas or a variety of: sulfur hexafluoride, perfluoropropane, entirely
Fluorine butane, perflenapent steam, perflexane steam.
2. oxygen carrier microvesicle as described in claim 1, which is characterized in that further include cryoprotector.
3. oxygen carrier microvesicle as claimed in claim 2, which is characterized in that the cryoprotector includes in following carbohydrate
It is one or more: glucose, galactolipin, fructose, sucrose, trehalose, dextran, soluble starch, polyethylene glycol, sweet dew
Alcohol.
4. oxygen carrier microvesicle as described in claim 1, which is characterized in that the phosphatide is Distearoyl Phosphatidylcholine
(DSPC)。
5. oxygen carrier microvesicle as described in claim 1, which is characterized in that the filling gas is the mixing of oxygen and sulfur hexafluoride
Gas, oxygen and sulfur hexafluoride ratio are 4:1 to 8:1.
6. oxygen carrier microvesicle as described in claim 1, which is characterized in that the filling gas is oxygen and perflenapent steam
Mixed gas, oxygen and perflenapent steam rates are 4:1 to 8:1.
7. oxygen carrier microvesicle as described in claim 1, which is characterized in that the filling gas is oxygen and perflexane steam
Mixed gas, oxygen and perflexane steam rates are 4:1 to 8:1.
8. oxygen carrier microvesicle as claimed in claim 1 or 2, which is characterized in that the oxygen carrier microvesicle is micron order microvesicle, average grain
Diameter is 1.0 μm -4.0 μm.
9. oxygen carrier microvesicle as claimed in claim 1 or 2, which is characterized in that the oxygen carrier microvesicle is nanoscale microvesicle, average grain
Diameter is 0.2 μm -0.8 μm.
10. the preparation method of oxygen carrier microvesicle as described in claim 1, which comprises the following steps:
A. by phosphatide and stabilizer, heating water bath dissolves in glycerol and aqueous solution of propylene glycol, obtains phospholipid solution；Wherein, institute
Stating stabilizer includes dimyristoyl phosphatidyl choline (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearyl phosphatide
Phatidylcholine (DSPC), dilauroyl lecithin (DLPC), 1,2- dioleyl phosphatidyl choline (DOPC), 1- palmityl-
2- oleoyl lecithin (POPC), two peanut phosphatidyl cholines (DAPC), distearoylphosphatidylethanolamine (DSPE),
Dipalmitoylphosphatidylethanolamine (DPPE), two myristoyl phosphatidyl-ethanolamines (DMPE), dilauroyl phosphatidyl
Ethanol amine (DLPE), dioleoylphosphatidylethanolamine (DOPE), distearoylphosphatidylglycerol (DSPG), two palmityl phosphatide
Acyl glycerol (DPPG), GLYCEROL,DIMYRISTOYL PHOSPHATIDYL (DMPG), dilauroylphosphatidylglycerol (DLPG), distearyl acyl group phosphorus
Resin acid (DSPA), dipalmitoylphosphatidic acid (DPPA), Dimyristoyl phosphatidic acid (DMPA), dilauroyl phosphatidic acid
(DLPA), bis- palmityl-SN- glycerol-3-phosphate sodium salt (DOPA) of 1,2-, dipalmitoylphosphatidylserine (DPPS), two
Stearoyl phosphatidyl ethanol amine-polyethylene glycol (DSPE-mPEG2000), distearoylphosphatidylethanolamine-polyethylene glycol
(DSPE-mPEG5000), the poly- two-folic acid of second (DSPE-PEG-FA) of distearoylphosphatidylethanolamine-, distearyl acyl group phosphorus
Acyl ethanol amine-polyethylene glycol-cyclic peptide (DSPE-PEG-cRGD), one of polyoxyethylene poly-oxygen propylene aether block copolymer
Or it is a variety of；
B. the step a phospholipid solution prepared is sealed in container, fills the gaseous mixture of oxygen and fluoro-gas；Wherein, described
Fluoro-gas includes pentane, hexane, heptane, octane, nonane, decane, cyclooctane, cyclononane, cyclodecane, perflenapent, perfluor
One of hexane, PF 5070, perfluorooctane, Perfluorononane, perfluorooctane, perfluoro bromide octane, perfluor -15- crown- 5- ether or
It is a variety of；
C. before use, obtaining the stabilization oxygen carrier microvesicle for being used for radio therapy sensitization by mechanical oscillation.
11. the preparation method of oxygen carrier microvesicle as claimed in claim 2, which comprises the following steps:
A. by phosphatide and stabilizer, heating water bath dissolves in glycerol and aqueous solution of propylene glycol, obtains phospholipid solution；Wherein, institute
Stating stabilizer includes dimyristoyl phosphatidyl choline (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearyl phosphatide
Phatidylcholine (DSPC), dilauroyl lecithin (DLPC), 1,2- dioleyl phosphatidyl choline (DOPC), 1- palmityl-
2- oleoyl lecithin (POPC), two peanut phosphatidyl cholines (DAPC), distearoylphosphatidylethanolamine (DSPE),
Dipalmitoylphosphatidylethanolamine (DPPE), two myristoyl phosphatidyl-ethanolamines (DMPE), dilauroyl phosphatidyl
Ethanol amine (DLPE), dioleoylphosphatidylethanolamine (DOPE), distearoylphosphatidylglycerol (DSPG), two palmityl phosphatide
Acyl glycerol (DPPG), GLYCEROL,DIMYRISTOYL PHOSPHATIDYL (DMPG), dilauroylphosphatidylglycerol (DLPG), distearyl acyl group phosphorus
Resin acid (DSPA), dipalmitoylphosphatidic acid (DPPA), Dimyristoyl phosphatidic acid (DMPA), dilauroyl phosphatidic acid
(DLPA), bis- palmityl-SN- glycerol-3-phosphate sodium salt (DOPA) of 1,2-, dipalmitoylphosphatidylserine (DPPS), two
Stearoyl phosphatidyl ethanol amine-polyethylene glycol (DSPE-mPEG2000), distearoylphosphatidylethanolamine-polyethylene glycol
(DSPE-mPEG5000), the poly- two-folic acid of second (DSPE-PEG-FA) of distearoylphosphatidylethanolamine-, distearyl acyl group phosphorus
Acyl ethanol amine-polyethylene glycol-cyclic peptide (DSPE-PEG-cRGD), one of polyoxyethylene poly-oxygen propylene aether block copolymer
Or it is a variety of；
B. the organic solvent not soluble in water that boiling point is 60-160 DEG C is added in the phospholipid solution prepared by step a, passes through ultrasound
Or Mechanical Crushing obtains nanometer or micron-sized lotion；
C. cryoprotector is added in the lotion prepared by step b, obtains lyophilized matrix by freeze-drying, is sealed in container, fills
The gaseous mixture of oxygen and fluoro-gas obtains the stabilization oxygen carrier microvesicle for being used for radio therapy sensitization；Wherein, the fluoro-gas includes penta
Alkane, hexane, heptane, octane, nonane, decane, cyclooctane, cyclononane, cyclodecane, perflenapent, perflexane, PF 5070,
One of perfluorooctane, Perfluorononane, perfluorooctane, perfluoro bromide octane, perfluor -15- crown- 5- ether are a variety of.
12. the preparation method of oxygen carrier microvesicle as claimed in claim 11, which is characterized in that the organic solvent in the b step
Including one of following solvent or a variety of: pentane, hexane, heptane, octane, nonane, decane, cyclooctane, cyclononane, the ring last of the ten Heavenly stems
Alkane, perflenapent, perflexane, PF 5070, perfluorooctane, Perfluorononane, perfluorooctane, perfluoro bromide octane, perfluor -15-
Crown- 5- ether.
13. oxygen carrier microvesicle as claimed in claim 1 or 2 is used as external exposure sensitizer in radiotherapy.
14. oxygen carrier microvesicle as claimed in claim 1 or 2 is used as in radiotherapy and irradiates enhanced sensitivity in I125 radioactive particle
Agent.
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