CN101773676B - Liquid fluorocarbon supported polymer nanometer ultrasonic imaging micelle and preparation method thereof - Google Patents
Liquid fluorocarbon supported polymer nanometer ultrasonic imaging micelle and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a liquid fluorocarbon supported polymer nanometer ultrasonic imaging micelle and a preparation method thereof. The liquid fluorocarbon supported polymer nanometer ultrasonic imaging micelle comprises the following components in parts by weight: 1 part of amphiphilic copolymer of polyethylene glycol and poly lactide or polycaprolactone and 1-20 parts of liquid fluorocarbon ultrasonic imaging reagent. The liquid fluorocarbon supported by the polymer nanometer ultrasonic imaging micelle is perfluorooctyl bromide, and the obtained micelle is of monometer grade, has narrow particle size distribution, stable performance in water, obvious ultrasonic imaging effect in vitro and obvious imaging under animal skin, is expected to be further applied in vivo and to other tissues and organs and has great application prospect in the filed of disease diagnosis.
Description
Technical field
The present invention relates to polymer chemistry and biomedical engineering field, but be specifically related to liquid fluorocarbon supported polymer nano ultrasonic imaging micelle of a kind of targetingization and preparation method thereof.
Background technology
Ultrasonic is one of the most frequently used, most important iconography means, with other image means relatively, have economy, easy, radiationless, advantage such as can repeat repeatedly to check, clinical practice is extensive, popularizes easily.
It is at present commonly used that acoustic contrast agent---microvesicle belongs to the blood pool imaging agent; Its diameter and erythrocyte are close, have reached several microns, in body is gone in intravenous injection after; Can arrive the microcirculation of body tissue's internal organs through pulmonary circulation; Through changing the acoustic impedance difference of scanning object interface, produce tangible radiography imaging results, improved the ultrasonic ability that detects and Differential Diagnosis ability to focus.But it is, still not enough to the diagnosis capability of specific focus because common contrast agent belongs to the specific general contrast agent of inorganization.
In order better to realize the imaging of focus specificity; Be necessary the acoustic contrast agent that adopts granule littler; The nanoscale acoustic contrast agent is optimal selection: 1) particle diameter reaches nanoscale and helps reducing that RE is removed, reticuloendothelial system absorbs and cytophagous identification, thereby prolongs its circulation time in vivo; 2) can organize the target area through the arrival of capillary endothelial cell gap smoothly, and can pass through the high retention effect of high penetration (enhanced permeability and retention effect, EPR effect) and in lesion tissue, realize the passive target enrichment.For tumor tissues, because that endothelial cells in tumor neogenetic blood vessels connects is loose, and lacks lymphatic return, so nanoparticle more easily from the blood vessel entering, but is difficult to return in the blood vessel through lymphatic return; 3) link with ligands specific easily, selectivity combines with the focus specific molecular, realizes initiatively targeted imaging.
The nanoscale acoustic contrast agent of existing research both at home and abroad mainly be divided into three types of nanometer grade liposome contrast agent, nanoscale microbubble contrast agent and nanoscale liquid fluorocarbon Emulsions; But exist processing technology immature at present; Granule is bigger than normal, is prone to be eliminated, and the body-internal-circulation time is shorter; Be difficult for carrying out finishing, the limited deficiency that waits of echo reinforced effects.Preceding two types of contrast agent are owing to receive the defective of sheathing material and method for preparing itself; All exist in various degree particle size distribution range more extensively, in vivo short, Attenuated posterior e-cho of persistent period obviously, shortcomings such as effect instability, the gasgraphy agent is more owing to introduce gas and possibly have a negative impact at organization internal.Though then one type of contrast agent imaging results is better, the activation of surfactant is very unstable, and high dilution and temperature condition with higher are easy to take place contrast agent inactivation and sedimentary phenomenon in vivo.
Than other nanoparticles, polymer nano micelle has following advantage: 1) preparation process is simple, utilizes amphipathic nature polyalcohol self assembly in aqueous solution to form the nanoparticle of the relative homogeneous of particle diameter, and can wrap a year hydrophobic content; 2) particle diameter is little and controlled, to the hundreds of nanometer, has stronger tissue permeability from tens nanometers, is difficult for being eliminated; 3) critical micelle concentration of nano-micelle is extremely low, in water, has good stability, in blood circulation, has the long half-life; 4) carry out chemical modification or introducing targeting group easily, realize initiatively targeted imaging and treatment.
The then stable performance of liquid fluorocarbon class contrast agent, the ultrasonic echo effect is remarkable, and its most outstanding advantage is that it can be used as a kind of potential multi-functional contrast agent, promptly not only can be used as acoustic contrast agent, can also be as CT, MRI and radionuclide imaging contrast agent.The hot bromine of perfluor for example, its boiling point has reached 144 ℃, and chemical property is stable, wrap to be expected to realize in vivo long-acting circulation after bearing, and further strengthens the passive building-up effect of nano-carrier.
Summary of the invention
The objective of the invention is to basis and have the deficiency that exists in the ultrasonoscopy reagent now, a kind of nano level liquid fluorocarbon supported polymer ultrasonic imaging micelle is provided.
Another purpose of the present invention is to provide the method for preparing of above-mentioned polymer ultrasonic imaging micelle.
Above-mentioned purpose of the present invention is achieved through following technical scheme:
A kind of liquid fluorocarbon supported polymer nano ultrasonic imaging micelle is processed by the following component of meter by weight: the amphipathic copolymer 1 of Polyethylene Glycol and polylactide or polycaprolactone, liquid fluorocarbon class ultrasonoscopy reagent 1 ~ 20.
As a kind of preferred version; In the liquid fluorocarbon supported polymer nano ultrasonic imaging micelle of the present invention; The number-average molecular weight of Polyethylene Glycol section is preferably 2.0 ~ 6.0KD in the structure of the amphipathic copolymer of said Polyethylene Glycol and polylactide or polycaprolactone, and the number-average molecular weight of polylactide or polycaprolactone section is preferably 15.0 ~ 30.0KD respectively.
As a kind of preferred version, in the liquid fluorocarbon supported polymer nano ultrasonic imaging micelle of the present invention, said liquid fluorocarbon class ultrasonoscopy reagent is the hot bromine of perfluor.
The liquid fluorocarbon supported polymer nano ultrasonic imaging micelle that the present invention designed is by Polyethylene Glycol (Polyethyeneglycol; Can be abbreviated as PEG) and polylactide (poly (D; L-lactic acid); Can be abbreviated as PDLLA) or polycaprolactone (the amphipathic copolymer (can be abbreviated as PEG-PDLLA or PEG-PCL) of poly (-caprolactone), can be abbreviated as PCL) is processed.Wherein hydrophobic PDLLA or PCL section have excellent biological compatibility and biodegradability; Hydrophilic PEG section can prolong the blood circulation time of whole pharmaceutical carrier, is excreted out by the reticuloendothelium system avoiding.In self assembling process, PDLLA section or PCL section spontaneously form micellar hydrophobic cores, and the PEG section is positioned at the surface of this nuclear, and its kernel then wraps bears hydrophobic liquid fluorocarbon class ultrasonoscopy reagent---the hot bromine of perfluor.
The method for preparing of the polymer nano ultrasonic imaging micelle that the present invention is liquid fluorocarbon supported comprises the steps: that the amphipathic copolymer with Polyethylene Glycol and polylactide or polycaprolactone is a raw material; Adopt supersound method to coat liquid fluorine carbon ultrasonoscopy reagent, form nano ultrasonic imaging micelle through the self assembly of polymer molecular chain.
In the above-mentioned preparation process; The method for preparing of the amphipathic copolymer of said Polyethylene Glycol and polylactide or polycaprolactone is following: with the ring-opening polymerisation of Polyethylene Glycol trigger monomer lactide or caprolactone under the catalysis of stannous octoate, obtain the amphipathic copolymer of Polyethylene Glycol and polylactide or polycaprolactone.
In the above-mentioned preparation process, said supersound method is that the amphipathic copolymer of Polyethylene Glycol and polylactide or polycaprolactone and liquid fluorocarbon class ultrasonoscopy reagent are dissolved in carbon tetrachloride formation oil phase, under ultrasonication, in ice bath, is scattered in water again.
It is specific as follows that the present invention prepares the method for liquid fluorocarbon supported polymer nano ultrasonic imaging micelle: 1 weight portion copolymer and 1 ~ 20 weight portion liquid fluorocarbon class ultrasonoscopy reagent are dissolved in the carbon tetrachloride of 8 volumes altogether; (molecular weight is in 0.3 ~ 0.5KD) aqueous solution in ice bath, under ultrasonication, to be dispersed to 0.5 ~ 5.0wt% polyvinyl alcohol of 20 volumes; Volatilize through long-time the stirring, remove the carbon tetrachloride that desolvates and promptly get.
The research of the polymer nano ultrasonic imaging micelle that the present invention is liquid fluorocarbon supported has obtained the support of state natural sciences fund general project (30870717).
Compared with prior art, the present invention has following beneficial effect:
(1) the liquid fluorocarbon supported polymer nano ultrasonic imaging micelle of the present invention is processed by the amphipathic copolymer of Polyethylene Glycol and polylactide or polycaprolactone; Polyethylene Glycol can prolong micellar blood circulation time as hydrophilic section, and polylactide or polycaprolactone then have good biocompatibility and degradability as hydrophobic section;
(2) the liquid fluorocarbon supported polymer nano ultrasonic imaging micelle of the present invention is highly stable in water, and mean diameter is 200 ~ 700nm, helps micelle in the intravital passive gathering of people;
(3) the liquid fluorocarbon supported polymer nano ultrasonic imaging micelle of the present invention can carry out chemical modification with link targeting part at the Polyethylene Glycol end, thereby realizes the targeting effect of this video picture reagent, has improved local concentration and the imaging results of video picture reagent etc.;
(4) after the present invention coats into nano-micelle with liquid fluorocarbon, can significantly improve its stability and ultrasonic echo characteristic in water, lower with respect to the activatory liquid fluorocarbon contrast agent of surfactant desired concn, the produce effects effect is also better.
Description of drawings
Fig. 1 ~ 3 are respectively the dynamic light scattering histogram of particle size distribution of the polymer nano micelle of the hot bromine of load different volumes perfluor among the embodiment 3.Wherein, the perflenapent volume that Fig. 1, Fig. 2 and Fig. 3 are corresponding respectively is 0.025ml, 0.05ml and 0.1ml, and its particle size distribution is positioned between 400 ~ 500nm;
Fig. 4 is the transmission electron micrograph of the nano-micelle of load 0.1ml PFOB.Wherein the small spherosome of white is the PFOB drop, is wrapped the negative light grey globular micelle inside that is;
Fig. 5 ~ 7 are respectively the external supersonic video picture pictures of the polymer nano micelle of the hot bromine of load different volumes perfluor among the embodiment 4.Wherein, the hot bromine volume of the perfluor that Fig. 5, Fig. 6 and Fig. 7 are corresponding respectively is 0.025ml, 0.05ml and 0.1ml, and tangible ultrasonoscopy effect is all arranged;
Fig. 8 be the polymer nano micelle of load 0.1ml PFOB among the embodiment 5 at the hypodermic ultrasonoscopy picture of rabbit, its imaging results is obvious.
The specific embodiment
Come further to explain the present invention below in conjunction with embodiment, but embodiment does not do any type of qualification to the present invention.
The nano-micelle that the present invention is based on amphipathic copolymer p EG-PDLLA or PEG-PCL is used to the hot bromine of load perfluor; The micellar particle diameter of gained adopts dynamic light scattering to measure; And test through the animal skins injected and to estimate this nanoscale ultrasonoscopy reagent; Promptly insert ultrasonic probe and carry out video picture, and be subjects, in subcutaneous instant injection and video picture with the rabbit with ultrasonic imaging micelle solution to equal volume in the syringe.
Embodiment 1
1. the preparation of polymer nano ultrasonic imaging micelle carrier material PEG-PDLLA or PEG-PCL:
Under the argon shield with 0.2g terminal hydroxy group PEG (molecular weight 2.0 ~ 3.0Kg/mol) at 50 ℃ of left and right sides vacuum drying number hour postcooling to room temperature, inject the exsiccant lactide of 1.6 ~ 2.4g or-caprolactone and a small amount of stannous octoate then.Add dry toluene 20ml under the room temperature behind the vacuum drying 1h, 120 ℃ of 12 ~ 24h polymerizations that reflux.After the reaction end, in absolute ether, carry out reprecipitation, filter back reuse dichloromethane dissolving, in absolute ether, carry out the secondary reprecipitation, obtain the pure sample article through filtration and vacuum drying.
2. the preparation of the polymer nano ultrasonic imaging micelle of the hot bromine of load perfluor:
With 40mg copolymer (PEG-PDLLA or PEG-PCL) respectively with 0.025,0.05 and the hot bromine of 0.1ml perfluor be dissolved in altogether in the 8ml carbon tetrachloride; Under ultrasonication, in ice bath, be scattered in the 20ml 2wt% polyvinyl alcohol water solution; Volatilize through long-time the stirring, remove the carbon tetrachloride that desolvates and promptly get.
The polymer nano ultrasonic imaging micelle size of the hot bromine of embodiment 2 load perfluors and the test of form
The micellar size of gained adopts the dynamic light scattering system to measure, and its form is then observed definite through transmission electron microscope, and test result is seen Fig. 1 ~ 4.Fig. 1 (0.025ml PFOB), Fig. 2 (0.05mlPFOB) and Fig. 3 (0.1ml PFOB) are respectively the micellar dynamic light scattering histogram of particle size distribution of corresponding PFOB concentration.Can find out that the particle size distribution of the polymer nano micelle of the hot bromine of load perfluor is narrower, mainly is positioned between 400 ~ 500nm, is nanoscale.Fig. 4 is the transmission electron micrograph of load 0.1ml PFOB nano-micelle; Can find out significantly that from figure amphipathic nature polyalcohol is self-assembled into particle diameter solid sphere comparatively uniformly in aqueous solution; Wherein the small spherosome of white is the PFOB drop, is wrapped the negative globular micelle inside that is.
The polymer nano ultrasonic imaging micelle external supersonic video picture test of the hot bromine of embodiment 3 load perfluors
Be filled the ultrasonic imaging micelle solution that makes with the 2ml syringe, place water bath with thermostatic control and ultrasonic probe inserted and carry out video picture, write down its ultrasonoscopy image respectively, test result is seen Fig. 4 to 6.Fig. 4 to 6 has shown the ultrasonoscopy image of the polymer nano micelle of different PFOB concentration: 0.025ml PFOB (Fig. 5), 0.05ml PFOB (Fig. 6) and 0.1ml PFOB (Fig. 7).Can see that therefrom the polymer nano micelle of the hot bromine of load perfluor has a tangible imaging results external, its imaging results improves with the raising of the concentration of PFOB.
The polymer nano ultrasonic imaging micelle animal skins injected video picture test of the hot bromine of embodiment 4 load perfluors
Be filled the ultrasonic imaging micelle solution that makes load 0.1ml PFOB and be injected in experimental animal with the 2ml syringe---rabbit subcutaneous, to carry out instant ultrasonoscopy and observe, test result is seen Fig. 8.Can be clear that the nano-micelle that injection gets in the subcutaneous interval group tissue region in Fig. 7 top has tangible ultrasonoscopy effect.
Above test result shows that the micellar particle diameter of gained is 400 ~ 500nm, is nanoscale.External video picture experiment shows that the polymer nano micelle stable performance of the hot bromine of this load perfluor can be carried out intravital long-acting circulation, and this micelle has tangible ultrasonoscopy effect, and its imaging results improves with the raising of the hot bromine concentration of perfluor.Animal skins injected video picture experiment shows, this nano-micelle has a ultrasonoscopy effect preferably subcutaneous.
Claims (1)
1. liquid fluorocarbon supported polymer nano ultrasonic imaging micelle is characterized in that preparing gained by following method:
(1) preparation of polymer nano ultrasonic imaging micelle carrier material Polyethylene Glycol and polylactide copolymer or Polyethylene Glycol and polycaprolactone copolymer:
Under the argon shield with the 0.2g molecular weight at the terminal hydroxy group Polyethylene Glycol of 2.0～3.0Kg/mol at 50 ℃ of vacuum drying number hour postcooling to room temperature, inject exsiccant lactide of 1.6～2.4g or 6-caprolactone and a small amount of stannous octoate then; Add dry toluene 20ml under the room temperature behind the vacuum drying 1h, 120 ℃ of 12～24h polymerizations that reflux; After the reaction end, in absolute ether, carry out reprecipitation, filter back reuse dichloromethane dissolving, in absolute ether, carry out the secondary reprecipitation, obtain the pure sample article through filtration and vacuum drying;
(2) preparation of the polymer nano ultrasonic imaging micelle of the hot bromine of load perfluor:
With 40mg Polyethylene Glycol and polylactide copolymer or Polyethylene Glycol and polycaprolactone copolymer respectively with 0.025,0.05 and the hot bromine of 0.1ml perfluor be dissolved in altogether in the 8ml carbon tetrachloride; Under ultrasonication, in ice bath, be scattered in the 20ml 2wt% polyvinyl alcohol water solution; Volatilize through long-time the stirring, remove the carbon tetrachloride that desolvates and promptly get said liquid fluorocarbon supported polymer nano ultrasonic imaging micelle.
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| CN101773676A (en) | 2010-07-14 |
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