CN101773675A - Liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle and preparation method thereof - Google Patents
Liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle and preparation method thereof Download PDFInfo
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- CN101773675A CN101773675A CN 201010121734 CN201010121734A CN101773675A CN 101773675 A CN101773675 A CN 101773675A CN 201010121734 CN201010121734 CN 201010121734 CN 201010121734 A CN201010121734 A CN 201010121734A CN 101773675 A CN101773675 A CN 101773675A
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Abstract
The invention discloses a liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle and a preparation method thereof. The liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle comprises the following components in parts by weight: 1 part of amphiphilic copolymer of polyethylene glycol and poly lactide and 2-40 parts of liquid fluorocarbon ultrasonic imaging reagent. The liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle 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 and inside the heart after concentrating, is expected to be further applied in vivo and to other tissues and organs and has great research value and application prospect in the filed of diagnosis.
Description
Technical field
The present invention relates to polymer chemistry and biomedical engineering field, be specifically related to a kind of liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle and preparation method thereof.
Background technology
Ultrasonic be the most frequently used, also be one of most important iconography means, it 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, several microns have been reached, after in body is gone in intravenous injection, can arrive the microcirculation of body tissue's internal organs by pulmonary circulation, by 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 nanoscale acoustic contrast agent that adopts granule littler: 1) particle diameter reaches nanoscale and helps reducing that renal excretion is removed, reticuloendothelial system absorbs and cytophagous identification, thereby prolongs its circulation time in vivo; 2) can organize the target area by the arrival of capillary endothelial cell gap smoothly, and can pass through the high retention effect of high penetration (enhanced permeability andretention effect, EPR effect) and in lesion tissue, realize the passive target enrichment; 3) link with ligands specific easily, selectivity combines with the focus specific molecular, realizes initiatively targeted imaging.
Now both at home and abroad the nanoscale acoustic contrast agent of research mainly be divided into nanometer grade liposome contrast agent, nanoscale microbubble contrast agent and nanoscale liquid fluorocarbon Emulsion three classes, but exist processing technology immature at present, granule is bigger than normal, easily be eliminated, the body-internal-circulation time is shorter, be difficult for carrying out finishing, the limited deficiency that waits of echo reinforced effects.Wherein, the nanoscale microbubble contrast agent is owing to introducing gas at organization internal and may having a negative impact, nanoscale liquid fluorocarbon Emulsion is then because the activatory instability of surfactant, and high dilution and temperature condition with higher are easy to take place inactivation and precipitation in vivo to cause contrast agent.
In the efficient nano carrier, liposome vesicle is as a kind of biomembrane medicine carrying model, always be emphasis research direction partly be applied in the lump clinical, but its critical defect that has the targeting difference and can't realize controllable release.Therefore, the novel nano vesicle that is developed out by amphipathic nature block polymer is progressively rising and beginning to replace liposome becomes the focus model of studying and using.Parents' molecule is because its special dissolution properties can the spontaneous molecular assembly structure that is integrated in solution, wherein a kind ofly shows as double-deck configuration.Just formed a kind of new configuration when these bi-laminate curved and when being closed.If these parents' molecules are amphipathic block, then be referred to as polymer vesicle.It is raw materials used basic identical with micelle.
Than other nanoparticles, polymer nano vesicle has following advantage: 1) preparation process is simple, utilizes the self assembly in aqueous solution of amphipathic copolymer to form the nanoparticle of the relative homogeneous of particle diameter, and can wrap a year different content; 2) particle diameter is little and controlled, because similar in cell, has stronger tissue permeability, and is difficult for being eliminated; 3) wall of nano vesicle is thicker and can regulate, and the permeability of film is low, has better stability and certain retractility, has the long half-life in blood circulation; 4) carry out chemical modification and introducing targeting group easily, to prolong circulation time and to realize initiatively targeted imaging and treatment.Result of study shows, nano vesicle in vivo the circulation half-life be more than 2 times of hidden liposome vesicle, more help the enrichment of nano vesicle in lesion tissue.
On the other hand, the stable performance of liquid fluorocarbon class contrast agent, ultrasonic echo effect are 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, provide a kind of nanoscale liquid fluorocarbon supported polymer ultrasonic imaging vesicle.
Another purpose of the present invention is to provide the preparation method of above-mentioned polymer ultrasonic imaging vesicle.
Above-mentioned purpose of the present invention is achieved by the following technical programs:
A kind of liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle is made by following components in part by mass: the amphipathic copolymer 1 of Polyethylene Glycol and polylactide, liquid fluorocarbon class ultrasonoscopy reagent 2 ~ 40.
Wherein, in the structure of the amphipathic copolymer of described Polyethylene Glycol and polylactide, the number-average molecular weight of Polyethylene Glycol section is 1.0 ~ 3.0KD, and the number-average molecular weight of polylactide section is 8.0 ~ 45.0KD.
As a kind of preferred version, in the liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle of the present invention, described liquid fluorocarbon class ultrasonoscopy reagent is preferably the hot bromine of perfluor.
The designed nano vesicle of the present invention is made by the Polyethylene Glycol (Polyethyeneglycol can be abbreviated as PEG) and the amphipathic copolymer (can be abbreviated as PEG-PDLLA) of polylactide (poly (D, L-lactic acid) can be abbreviated as PDLLA).Wherein hydrophobic PDLLA section has good chain compliance, biocompatibility 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, the PDLLA section spontaneously forms the hydrophobic enclosure of vesicle, and the PEG section is positioned at the surfaces externally and internally of this shell, and its shell can wrap negative hydrophobic liquid fluorocarbon class ultrasonoscopy reagent---the hot bromine of perfluor.
The preparation method of the polymer nanometer ultrasonic imaging vesicle that the present invention is liquid fluorocarbon supported comprises the steps: that the amphipathic copolymer with Polyethylene Glycol and polylactide is a raw material, coat liquid fluorine carbon ultrasonoscopy reagent by ultrasonic pair of emulsion process, obtain liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle.
In the above-mentioned preparation method, the preparation method of the amphipathic copolymer of described Polyethylene Glycol and polylactide is as follows: 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.
As a kind of preferred version, preparation method of the present invention comprises the steps: the liquid fluorocarbon of 1 weight portion copolymer and 2 ~ 40 weight portions is dissolved in the carbon tetrachloride of 10 volumes altogether, under ultrasonication, in ice bath, drip the polyvinyl alcohol water solution of 1 volume, 0.0 ~ 5.0wt%, then this emulsion is dispersed under ultrasonication in the 200 volume 0.5wt% polyvinyl alcohol water solutions, promptly gets liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle.Wherein, preferably the emulsion after the ultrasonic end is stirred for a long time, to remove carbon tetrachloride wherein.Concentrate as need, then can adopt Rotary Evaporators to carry out distilling under reduced pressure, remove unnecessary water, ultimate density and cycles of concentration are decided on initial volume and final volume.
But the research of the polymer nanometer ultrasonic imaging vesicle of the hot bromine of the load perfluor of targetingization has obtained the support of state natural sciences fund general project (30870717) among the present invention.
Compared with prior art, the present invention has following beneficial effect:
(1) this vesicle is made by the amphipathic copolymer of Polyethylene Glycol and polylactide, and PEG can prolong the blood circulation time of vesicle as hydrophilic section, and polylactide then has good biocompatibility and degradability as hydrophobic section;
(2) this capsule ducks in drink highly stablely, and mean diameter is 200 ~ 800nm, helps vesicle in the intravital passive gathering of people;
(3) this vesicle can carry out chemical modification with link targeting part at the PEG end, thus realize this video picture reagent the targeting effect, improve the local concentration of video picture reagent and improve imaging results etc.;
(4) the hot bromine of perfluor by wrap bear can significantly improve behind this nano vesicle into its in water stability and improved the ultrasonic echo characteristic, lower with respect to the activatory liquid fluorocarbon contrast agent of surfactant desired concn, imaging results is better; Simultaneously, disperse more, further improved the echoing characteristic of the hot bromine of perfluor because the bag in the vesicle shell is negative, more obvious with respect to nano-micelle carrier imaging results with concentration PFOB.
Description of drawings
Fig. 1 ~ 3 are respectively the dynamic light scattering histogram of particle size distribution of the polymer nano vesicle 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 0.05ml, 0.1ml and 0.2ml, and its particle size distribution is positioned between 400 ~ 500nm;
Fig. 4 is the transmission electron micrograph of the nano vesicle of load 0.2ml PFOB.Wherein Bai Se small spherosome is the PFOB drop, is evenly wrapped the enclosure of being defeated by for the spherical vesicle of light gray;
Fig. 5 ~ 7 are respectively the external supersonic video picture pictures of the polymer nano vesicle of load different volumes PFOB 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 is that polymer nano vesicle and the micellar ultrasonoscopy gray value of load equal volume PFOB among the embodiment 4 compares, and the imaging results of vesicle is more obvious;
Fig. 9 is that the polymer nano vesicle through concentrating 12 times of back loading 0.2ml PFOB is at the hypodermic ultrasonoscopy picture of rabbit among the embodiment 5, and its imaging results is obvious;
Figure 10 is that the polymer nano vesicle through concentrating 12 times of back loading 0.2ml PFOB is at the ultrasonoscopy picture of rabbit ventricle injection among the embodiment 5, and its imaging results is obvious.
The specific embodiment
Further explain the present invention below in conjunction with embodiment, but embodiment does not do any type of qualification to the present invention.
The nano vesicle that the present invention is based on amphipathic copolymer p EG-PDLLA is used to the hot bromine of load perfluor, the particle diameter of gained vesicle adopts dynamic light scattering to measure, and by estimating this nanoscale ultrasonoscopy reagent with the ventricle test injection under the animal skins, promptly insert ultrasonic probe and carry out video picture with ultrasonic imaging vesicle solution to equal volume in the syringe, and be subjects with the rabbit, in subcutaneous and instant injection of ventricle and video picture.
Embodiment 1
1. the preparation of polymer nanometer ultrasonic imaging vesicle carrier material PEG-PDLLA:
Under the argon shield with 0.2g terminal hydroxy group PEG (molecular weight 1.0 ~ 3.0Kg/mol) at 50 ℃ of left and right sides vacuum drying a few hours postcooling to room temperature, inject the exsiccant lactide of 1.6 ~ 2.4g and a small amount of stannous octoate then.Vacuum drying adds dry toluene 20ml under the room temperature after one hour, 120 ℃ of 12 ~ 24h polymerizations that reflux.Reaction is carried out reprecipitation after finishing in absolute ether, filter back reuse dichloromethane dissolving, carries out the secondary reprecipitation in absolute ether, obtains the pure sample product with vacuum drying after filtration.
2. the preparation of the polymer nanometer ultrasonic imaging vesicle of the hot bromine of load perfluor:
With 10mg copolymer (PEG-PDLLA) respectively with 0.05,0.1 and the hot bromine of 0.2ml 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 and desolvate carbon tetrachloride promptly.
The polymer nanometer ultrasonic imaging vesicle size of the hot bromine of embodiment 2 load perfluors and the test of form
The size of gained vesicle adopts the dynamic light scattering system to measure, and its form is then observed definite by transmission electron microscope, and test result is seen Fig. 1 to 4.Fig. 1 (0.05ml PFOB), Fig. 2 (0.1mlPFOB) and Fig. 3 (0.2ml PFOB) are respectively the dynamic light scattering histogram of particle size distribution of corresponding PFOB concentration vesicle.As can be seen, the particle size distribution of the polymer nano vesicle of the hot bromine of load perfluor is narrower, mainly is positioned at 400 ~ 500nm, is nanoscale.Fig. 4 is the transmission electron micrograph of load 0.2ml PFOB nano vesicle, can find out significantly that from figure amphipathic nature polyalcohol is self-assembled into " hollow ball " that particle diameter has the center membranous wall comparatively uniformly in aqueous solution, wherein Bai Se small spherosome is the PFOB drop, is evenly wrapped the enclosure of being defeated by " hollow ball ".
The polymer nanometer ultrasonic imaging vesicle external supersonic video picture test of the hot bromine of embodiment 3 load perfluors
Be filled the ultrasonic imaging vesicle 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, and compare with the syringe interior zone gray value of the nano-micelle of identical PFOB concentration, test result is seen Fig. 5 to 8.Fig. 5 to 7 has shown the ultrasonoscopy image of the polymer nano vesicle of different PFOB concentration: 0.05ml PFOB (Fig. 5), 0.05ml PFOB (Fig. 6) and 0.1ml PFOB (Fig. 7).Can see that therefrom the polymer nano vesicle 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.Fig. 8 has shown the ultrasonoscopy gray value of micelle and vesicle under the identical PFOB concentration.Clearly, the ultrasonoscopy effect of the polymer nano vesicle of the hot bromine of this load perfluor is better.
Reach ventricle injection video picture test under the polymer nanometer ultrasonic imaging vesicle animal skins of the hot bromine of embodiment 4 load perfluors
Be filled the ultrasonic imaging vesicle solution of the load 0.2ml PFOB after concentrating 12 times and be injected in experimental animal with the 2ml syringe---the subcutaneous and ventricle of rabbit, to carry out instant ultrasonoscopy and observe, test result is seen Fig. 9 and Figure 10 respectively.Can be clear that the nano vesicle that injection enters in the subcutaneous interval group tissue region in Fig. 9 top has tangible ultrasonoscopy effect, nano vesicle has also shown stronger ultrasonoscopy effect among Figure 10 after injection enters ventricle inside.
Above test result shows that the particle diameter of gained vesicle is 400～500nm, is nanoscale, and the hot bromine of ultrasonoscopy reagent perfluor is wrapped the enclosure of being defeated by this vesicle equably.External video picture experiment shows, the polymer nano vesicle stable performance of the hot bromine of this load perfluor, can carry out intravital long-acting circulation, and this vesicle has than the more tangible ultrasonoscopy effect of the nano-micelle under the identical PFOB concentration, its imaging results improves with the raising of PFOB concentration.Show that with ventricle injection video picture experiment this nano vesicle all has ultrasonoscopy effect preferably at subcutaneous and ventricle after concentrating under the animal skins.
Claims (7)
1. a liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle is characterized in that being made by following components in part by mass: the amphipathic copolymer 1 of Polyethylene Glycol and polylactide, liquid fluorocarbon class ultrasonoscopy reagent 2 ~ 40.
2. according to the described liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle of claim 1, it is characterized in that in the structure of amphipathic copolymer of described Polyethylene Glycol and polylactide, the number-average molecular weight of Polyethylene Glycol section is 1.0 ~ 3.0KD, and the number-average molecular weight of polylactide section is 8.0 ~ 45.0KD.
3. according to the described liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle of claim 1, it is characterized in that described liquid fluorocarbon class ultrasonoscopy reagent is the hot bromine of perfluor.
4. the preparation method of the described liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle of any claim in the claim 1 ~ 3, it is characterized in that described method comprises the steps: that the amphipathic copolymer with Polyethylene Glycol and polylactide is a raw material, coat liquid fluorine carbon ultrasonoscopy reagent by ultrasonic pair of emulsion process, obtain liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle.
5. the preparation method of liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle according to claim 4, the preparation method of amphipathic copolymer that it is characterized in that described Polyethylene Glycol and polylactide is as follows: 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.
6. the preparation method of liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle according to claim 4, it is characterized in that comprising the steps: that the liquid fluorocarbon with 1 weight portion copolymer and 2 ~ 40 weight portions is dissolved in the carbon tetrachloride of 10 volumes altogether, under ultrasonication, in ice bath, drip the polyvinyl alcohol water solution of 1 volume, 0.0 ~ 5.0wt%, then this emulsion is dispersed under ultrasonication in the 200 volume 0.5wt% polyvinyl alcohol water solutions, promptly gets liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle after removing oil phase solvent carbon tetrachloride.
7. the preparation method of liquid fluorocarbon supported polymer nanometer ultrasonic imaging vesicle according to claim 6 is characterized in that the emulsion after the ultrasonication is stirred to remove carbon tetrachloride wherein.
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| CN102391446A (en) * | 2011-09-05 | 2012-03-28 | 同济大学 | Method for preparing biocompatible polymer nano-vesicle in pure water |
| CN102895680A (en) * | 2011-07-27 | 2013-01-30 | 戴志飞 | Theranostic agent and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102895680A (en) * | 2011-07-27 | 2013-01-30 | 戴志飞 | Theranostic agent and preparation method thereof |
| CN102391446A (en) * | 2011-09-05 | 2012-03-28 | 同济大学 | Method for preparing biocompatible polymer nano-vesicle in pure water |
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