CN110101879A - A kind of triggering type acoustic contrast agent and preparation method thereof - Google Patents
A kind of triggering type acoustic contrast agent and preparation method thereof Download PDFInfo
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- CN110101879A CN110101879A CN201910576669.8A CN201910576669A CN110101879A CN 110101879 A CN110101879 A CN 110101879A CN 201910576669 A CN201910576669 A CN 201910576669A CN 110101879 A CN110101879 A CN 110101879A
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/225—Microparticles, microcapsules
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- Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Acoustics & Sound (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention belongs to biomedicine fields, are related to a kind of contrast agent, and in particular to a kind of triggering type acoustic contrast agent and preparation method thereof.Acoustic contrast agent of the invention includes hud typed particle, and hud typed particle includes shell and core；Shell includes the shell membrane that filmogen is formed, and is inlaid with gold nano grain on shell membrane, core is liquid fluorocarbon.The triggering type acoustic contrast agent under normal conditions stablize by character, and photic phase transformation can safely and efficiently occur under laser action, to optimize the ultrasound enhancing imaging results of contrast agent in vivo.Acoustic contrast agent of the invention can be applied in the operation for accurately detecting tumor by local lymphatic metastasis, to tumor patient Staging of course of disease, progress, prognosis and formulate effective treatment plan with important clinical significance.
Description
Technical field
The invention belongs to biomedicine fields, are related to a kind of contrast agent, and in particular to a kind of triggering type acoustic contrast agent and
Preparation method.
Background technique
Accurate detection metastases in local lymph node is to tumor patient Staging of course of disease, progress, prognosis and formulates effective treatment plan
With important clinical significance.Regional nodes' Biopsy can accurately react tumour Staging of course of disease situation, and can be with one
Determine the generation that complication is avoided in degree, therefore, regional nodes' Biopsy is gradually instead of conventional Pulmonary resections.
However, regional nodes' biopsy still has great limitation.Lymph node biopsy itself is also a kind of invasive detection, and
During open operation, it usually needs injection dyestuff or radionuclide are with tracer, identification lymphnode metastatic.But it contaminates
Expect that the trace method operating time is long, subjectivity is strong, and dyestuff internal clearance rate is fast, photo and thermal stability is poor, signal strength is limited；Nucleic
Trace method is costly, can lead to radioactive pollution and operating technology is cumbersome.
Since Color Doppler ultrasound and ultrasonic contrast are applied to clinic, ultrasound is with non-invasive, accuracy is high, real-time
Dynamically, the preferred and main inspection method easy to operate and reproducible for being increasingly becoming detection tumor by local lymphatic metastasis.Companion
With the development of Molecular imaging techniques, set molecule detection and functional imaging more become a kind of in the ultrasound molecular imaging technique of one
The emerging biomedical imaging pattern that do not replace.In the prior art, researcher contains liquid fluorocarbon in filmogen
In, triggering inversion of phases particle is formed, character is stablized under the particle normal condition, is not easy to be destroyed during body-internal-circulation, can be with
It is changed into a kind of acoustic contrast agent under laser triggering, realizes the detection to metastases in local lymph node.Liquid fluorocarbon is pressed on surface
Under the conditions of power reduction and temperature are raised, it can be transformed into gaseous state (undergoing phase transition) by liquid, inversion of phases particle forms gassiness
Microvesicle, microvesicle can produce very high ultrasonic scattering signal, to enhance ultrasonic imaging capability.But liquid fluorocarbon needs the external world
Applying certain heat could gasify, the heat of application it is higher may to human body generate adverse effect, and apply heat
Measure it is lower liquid fluorocarbon may cannot be caused to undergo phase transition, and cannot generate enhancing imaging effect.Apply due to the external world
Energy is not easy to assemble and control, so that the temperature and pressure of liquid fluorocarbon kernel is relatively difficult to control, is unfavorable for realizing to local leaching
Fawn on the accurate detection of transfer.
Summary of the invention
The purpose of the present invention is to provide a kind of triggering type acoustic contrast agent, the triggering type acoustic contrast agent can swash
Photic phase transformation safely and efficiently occurs under light action, so that the ultrasound enhancing imaging effect of contrast agent in vivo is optimized,
So that imaging process is more controllable, it can be achieved that accurate detection to metastases in local lymph node.
In order to solve the above technical problems, technical solution of the present invention is as follows:
A kind of triggering type acoustic contrast agent, the triggering type acoustic contrast agent include hud typed particle, described hud typed micro-
Grain includes shell and core；The shell includes the shell membrane that filmogen is formed, and is inlaid with gold nano grain, the core on shell membrane
The heart is liquid fluorocarbon.
By adopting the above technical scheme, the main functional parts of the triggering type acoustic contrast agent are hud typed particle, contain liquid
The hud typed particle of state fluorine carbon recycles in vivo, and character is stablized, after being administered into purpose tissue, under the effect of the laser, Jenner
Rice grain and liquid fluorocarbon synergistic effect, gold nano grain absorbs and the energy of aggregation laser, and converts light energy into thermal energy, produces
The third contact of a total solar or lunar eclipse causes phase transformation effect, so that liquid fluorocarbon gasifies, changes acoustic enviroment, to enhance ultrasonic imaging.Gold nano grain
It is embedded on shell membrane, can preferably absorb laser energy, efficiently transfer energy to the liquid fluorocarbon positioned at core part,
When kernel temperature and pressure reaches the phase change conditions of liquid fluorocarbon, it is the micro- of gas that hud typed particle, which can be transformed into kernel,
Bubble.
The utility model has the advantages that
The prior art usually directly encapsulates liquid fluorocarbon with filmogen, is then injected into bio-tissue to realize
Enhancing development.But the scheme of the prior art can not achieve and be precisely controlled to liquid fluorocarbon heat absorption degree, and need
Outer bound pair human body purpose tissue, which applies stronger energy, can just promote liquid fluorocarbon to gasify.Therefore the scheme of the prior art generates
The demand of practical application is not achieved in technical effect.The technical program uses the shell packet that filmogen and gold nano grain are formed
The scheme for carrying liquid fluorocarbon can achieve the effect of the temperature of safe, accurate and efficient control liquid fluorocarbon core, to optimize
The imaging effect of contrast agent in vivo.Also, the scheme of core is respectively positioned on relative to gold nano grain and liquid fluorocarbon, we
The luminous energy that the particle of case applies laser is more sensitive, and photothermal conversion efficiency is higher.This programme avoids liquid fluorocarbon gasification pair
The inhibition of the photothermal conversion of gold nano grain, if gold nano grain and liquid fluorocarbon are located at core, liquid fluorocarbon
Partial gasification is generated, gaseous environment will hinder absorption of the gold nano grain to luminous energy.
Wherein, gold nano grain is a kind of novel multi-functional nanometer material, possesses continuously adjustable resonant wavelength, has
Good photothermal conversion efficiency and stability is good.Gold nano grain can absorb laser energy, and converts light energy into thermal energy, so that
Liquid fluorocarbon gasification is produced as microvesicle.When carrying out the preparation of particle type acoustic contrast agent usually using gold nano grain, need in gold
The materials such as silica are wrapped up outside nano particle, can avoid the aggregation of gold nano grain, to prevent size after aggregation from increasing,
The materials such as package silica can also increase the biocompatibility of gold nano grain.However dioxy is wrapped up outside gold nano grain
SiClx film, and the photothermal conversion efficiency of gold nano grain can be made to reduce, to increase the difficulty for being precisely controlled contrast agent phase transformation
Degree.Inventor studies discovery and uses filmogen as the shell membrane of hud typed particle, and gold nano grain is embedded on shell membrane, the knot
The hud typed particle of structure not only has preferable biocompatibility, and gold nano grain is partially exposed at shell membrane surface layer, facilitates pair
The absorption of laser energy and the conversion of photo-thermal.And gold nano grain, which is embedded on shell membrane, can equally reduce gold nano grain
Immunogenicity, the technical program, which overcomes gold nano grain and must be wrapped in filmogen, is just able to achieve it in tissue
The technology prejudice of middle transfer.
In conclusion the triggering type acoustic contrast agent of the technical program have the beneficial effect that can achieve safety, it is accurate and
The efficiently effect of the temperature of control liquid fluorocarbon core, to optimize the ultrasound enhancing imaging effect of contrast agent in vivo.
Further, the average grain diameter of the hud typed particle is 1.83-1.95 μm.
By adopting the above technical scheme, there is the hud typed particle of above-mentioned partial size preferable bioavailability and lymphoid tissue to seep
Permeability.
Further, the filmogen is poly lactic coglycolic acid；In the poly lactic coglycolic acid,
The mass ratio of lactic acid and hydroxyacetic acid is 2:1；The liquid fluorocarbon is perflexane.
By adopting the above technical scheme, poly lactic coglycolic acid (PLGA) is by two kinds of monomers (lactic acid and hydroxyacetic acid)
It is polymerized at random, is a kind of degradable functional polymer organic compound, there is good biocompatibility, nontoxic, good
The performance of good encystation and film forming.
The mass ratio of lactic acid and hydroxyacetic acid is 2:1, can make the lactic acid formed by lactic acid and hydroxyacetic acid-hydroxyl second
Acid copolymer has preferable filming performance, so as to efficiently wrap up perflexane (PFH), and inlays for gold nano grain
Support is provided on shell membrane, ensure that gold nano grain is embedded on shell membrane rather than is wrapped in hud typed particle by PLGA
At core, so that gold nano grain can efficiently absorb the energy of laser, and thermal energy is converted light energy into.
Further, a kind of preparation method of triggering type acoustic contrast agent, includes the following steps,
Step (1): poly lactic coglycolic acid and gold nano grain are added in chloroform, it is stirred well to
It is completely dissolved, obtains copolymer-goldc grains solution；
Step (2): being slowly added dropwise perflexane in copolymer-nanoparticle solution of step (1), obtains perflexane-altogether
Polymers-goldc grains solution；It is ultrasonically treated the perflexane-copolymer-goldc grains solution, obtains emulsion；
Step (3): being added poly-vinyl alcohol solution in the emulsion of step (2), and emulsion-is then obtained after homogenization
Polyvinyl alcohol mixture；
Step (4): the chloroform in the emulsion-polyvinyl alcohol mixture of step (3) is removed, it is heavy to be then centrifuged for taking
It forms sediment.
By adopting the above technical scheme, the hud typed particle of uniform particle sizes can be obtained.In step (1), PLGA is formed vertical
Body reticular structure, which adsorbs gold nano grain, to be fixed, so that gold nano grain is embedded in the surface of the membrane structure of PLGA formation,
The step ensure that in the hud typed particle eventually formed, gold nano grain is to be embedded on shell membrane, rather than be located at other
Position.The precipitating obtained in step (4) is exactly the triggering type acoustic contrast agent of this programme, is contained in the triggering type acoustic contrast agent
There is the hud typed particle of this programme.
Further, in step (1), the mass ratio of the poly lactic coglycolic acid and the gold nano grain is
100:1, the partial size of gold nano grain are 10nm.
By adopting the above technical scheme, the mass ratio of PLGA and gold nano grain is 100:1, both can guarantee that PLGA wraps up PFH
Efficiency, and photothermal conversion needed for can guaranteeing to have enough gold nano grains to carry out PFH phase transformation.The partial size of gold nano grain is
10nm, size properly can guarantee that gold nano grain is more firm and be embedded on shell membrane.
Further, in step (2), in ultrasonication, the perflexane-copolymer-goldc grains solution is set
In 5 DEG C of environment.
By adopting the above technical scheme, in ultrasonic procedure, by the way of low-temperature treatment, it can prevent PFH is heated to occur in advance
Gasify phenomenon.
Further, in step (2), sonication treatment time 45s, ultrasonic power 130W.
By adopting the above technical scheme, above-mentioned parameter can guarantee the fully emulsified of perflexane-copolymer-goldc grains solution, again
Can prevent ultrasonic time is too long, ultrasonic power it is excessive caused by PFH gasification.Because the hud typed particle of this programme uses micro-
Alveolitoid contrast agent liquid fluorocarbon (perflexane), when ultrasonic disperse is handled, overlong time or intensity are excessive, ultrasonic cavitation
Meeting influences the homogeneity of nanoparticle so that generate bubble in liquid fluorocarbon.The partial size of particle is larger to be will affect its infiltration and penetrates
Vasculolymphatic ability reduces the lymph node imaging effect of phase transformation generation.
Further, in step (3), the concentration of poly-vinyl alcohol solution is 5 weight %.
By adopting the above technical scheme, the poly-vinyl alcohol solution of above-mentioned concentration can relatively efficiently make hud typed particle from cream
Change in liquid and forms and be precipitated.
Further, in step (3), the volume ratio of emulsion and poly-vinyl alcohol solution is 1:5.
By adopting the above technical scheme, above-mentioned volume ratio, excessive polyvinyl alcohol can guarantee that hud typed particle is sufficiently precipitated.
Further, in step (4), emulsion-polyethylene is removed using the method for aqueous isopropanol extraction chloroform
Chloroform in alcohol mixture.
By adopting the above technical scheme, chloroform has certain toxicity to bio-tissue, with aqueous isopropanol extraction three
Chloromethanes can reach the effect for sufficiently removing chloroform.
Detailed description of the invention
Fig. 1 is the structural schematic diagram of the hud typed particle prepared in embodiment 1；
Fig. 2 is the form of the hud typed particle for preparing in embodiment 1 under scanning electron microscope (scale bar is 10 μm)；
Fig. 3 is the form of the hud typed particle for preparing in embodiment 1 under scanning electron microscope (scale bar is 1 μm)；
Fig. 4 is the absorption photometric that the triggering type acoustic contrast agent prepared in embodiment 1 is measured using ultraviolet specrophotometer
Value；
Fig. 5 is the absorption photometric value that gold nano grain is measured using ultraviolet specrophotometer；
Fig. 6 is the absorption photometric value that the PLGA particle of package PFH is measured using ultraviolet specrophotometer；
Fig. 7 is the external conventional Ultrasound visualising image (B-Mode) of the physiological saline group in experimental example 2, and a left side is predose,
After irradiation is in the right side；
Fig. 8 is the external conventional Ultrasound visualising image (B-Mode) of the PLGA particle group in experimental example 2, and a left side is predose,
After irradiation is in the right side；
Fig. 9 is the external conventional Ultrasound visualising image (B-Mode) of the triggering type acoustic contrast agent group in experimental example 2, Zuo Wei
Predose, after irradiation is in the right side；
Figure 10 is the external Enhance ultrasonography image (CEUS) of the physiological saline group in experimental example 2, and a left side is predose, right
After irradiation；
Figure 11 is the external Enhance ultrasonography image (CEUS) of the PLGA particle group in experimental example 2, and a left side is predose, right
After irradiation；
Figure 12 is the external Enhance ultrasonography image (CEUS) of the triggering type acoustic contrast agent group in experimental example 2, Zuo Wei
Predose, after irradiation is in the right side；
Figure 13 is the internal conventional Ultrasound visualising image (B-Mode) of the physiological saline group in experimental example 3, and a left side is predose,
After irradiation is in the right side；
Figure 14 is the internal conventional Ultrasound visualising image (B-Mode) of the PLGA particle group in experimental example 3, and a left side is predose,
After irradiation is in the right side；
Figure 15 is the internal conventional Ultrasound visualising image (B-Mode) of the triggering type acoustic contrast agent group in experimental example 3, left
For predose, the right side is after irradiating；
Figure 16 is the internal Enhance ultrasonography image (CEUS) of the physiological saline group in experimental example 3, and a left side is predose, right
After irradiation；
Figure 17 is the internal Enhance ultrasonography image (CEUS) of the PLGA particle group in experimental example 3, and a left side is predose, right
After irradiation；
Figure 18 is the internal Enhance ultrasonography image (CEUS) of the triggering type acoustic contrast agent group in experimental example 3, Zuo Wei
Predose, after irradiation is in the right side.
Specific embodiment
It is further described below by specific embodiment:
Embodiment 1: the preparation of triggering type acoustic contrast agent
1. main agents and instrument
Poly lactic coglycolic acid (mass ratio of PLGA, lactic acid and hydroxyacetic acid is 2:1, a Jinan Mount Tai handle of the Big Dipper), gold nano
Particle (GNPs, 10nm, 10mg/ml, Ocean), perflexane (PFH, Sigma Co., USA), polyvinyl alcohol (PVA, the U.S.
Sigma company).
VCX130 sound and vibration instrument (SONICS company, the U.S.), magnetic stirring apparatus (German IKA company), FJ-200 high speed dispersion is equal
Matter machine (Shanghai Sample Model Factory), high speed freezing centrifuge (German Eppendorf company), Malvern particle instrument (Britain Ma Er
Literary instrument company), LAZR photoacoustic imager (Canadian VisualSonics company), ultraviolet specrophotometer (UV-Vis,
CARY50, Thermo company, the U.S.).
2. preparation process
(1) tri- chloromethane of 20ml is added in 1g poly lactic coglycolic acid (PLGA) and 10mg gold nano grain (GNPs)
It in alkane, is stirred well to it and is completely dissolved, obtain copolymer-nanoparticle solution.
(2) in above-mentioned copolymer-nanoparticle solution, perflexane 5ml (PFH) is slowly added dropwise, obtains perflexane-copolymerization
Object-goldc grains solution.Perflexane-copolymer-goldc grains solution, ultrasonication are then ultrasonically treated using VCX130 sound and vibration instrument
In carried out under 5 DEG C of environment, ultrasonic power 130W, ultrasonic time 45s.And in ultrasonication, intermittent oscillation institute
State perflexane-copolymer-nanoparticle solution.Emulsion is obtained after perflexane-copolymer-goldc grains solution is sonicated.
(3) polyvinyl alcohol is dissolved in the polyethylene for being configured to that polyvinyl alcohol weight percentage is 5 weight % in distilled water
Alcohol (PVA) solution.It is by volume that 1:5 is mixed by above-mentioned emulsion and 5 weight % poly-vinyl alcohol solutions, then in 5 DEG C of environment
In, using high speed dispersion homogenizer (FJ300-SH, Shanghai) homogeneous 5min, obtain emulsion-polyvinyl alcohol mixture.
(4) magnetic stirrer 2h is used to emulsion-polyvinyl alcohol mixture, is extracted using 20ml aqueous isopropanol
Chloroform in emulsion-polyvinyl alcohol mixture.Then, emulsion-polyvinyl alcohol of chloroform will have been removed
Object centrifugation, centrifugal rotational speed 3500rpm stand 3min after centrifugation, discard supernatant liquid, sediment is washed with deionized.Go from
Centrifuging and taking precipitates after sub- water washing and precipitating object, and washing process is in triplicate.Finally collection sediment, which places it in 4 DEG C of refrigerators, saves
Spare, sediment is triggering type acoustic contrast agent of the invention, contains hud typed particle in triggering type acoustic contrast agent.
3. the feature and physical property of triggering type acoustic contrast agent
The hud typed particle of obtained triggering type acoustic contrast agent be shell-caryogram structure, it is rounded, including PLGA with
And the contrast agent shell that GNPs is formed, wherein GNPs is embedded on shell membrane, and core wraps up PFH, hud typed micrograined texture schematic diagram
As shown in Figure 1, figure label 1 is gold nano grain (GNPs), figure label 2 is liquid fluorocarbon (PFH), and figure label 3 is
PLGA shell membrane.
(1) the hud typed particle of the triggering type acoustic contrast agent obtained by uses after phosphate buffer (PBS) dilution
Ordinary optical microscope and scanning electron microscope carry out morphological observation to it, under optical microscopy, hud typed particulate form rule, greatly
Small to be evenly distributed, nothing significantly builds up phenomenon.Under scanning electron microscope due to high temperature and pressure act on, hud typed particle deformation occurs cause form
Irregularly, size is owed uniformly, as shown in Figure 2 and Figure 3.
(2) it hud typed diameter of particle size, distribution and the surface potential of Malvern laser diameter measuring instrument contrast agent detection: makes
The hud typed particle average grain diameter of shadow agent is 1.83-1.95 μm, and distribution and dispersion degree are uniform；Zeta potential is -27.2--
20.0mv。
(3) in the hud typed particle of transmission electron microscope observing contrast agent gold nano grain distribution situation, make under transmission electron microscope
Shadow agent is at spherical shape, and GNPs more uniform distribution is in contrast agent shell mechanism.
(4) absorption photometric value of triggering type acoustic contrast agent manufactured in the present embodiment is measured using ultraviolet specrophotometer,
Acoustic contrast agent (acoustic contrast agent i.e. manufactured in the present embodiment for carrying gold nano grain) (Fig. 4) and individual gold nano of preparation
Particle (Fig. 5) has obvious absorption wave crest at 532nm wavelength, and only wraps up the PLGA particle (Fig. 6) of PFH in 532nm wavelength
And not observing obvious absorption wave crest in detection wave band, it was demonstrated that GNPs is successfully loaded into triggering type acoustic contrast agent, and
The subsequent premise for carrying out photic phase transformation ultrasonoscopy.
Embodiment 2:
Substantially with embodiment 1, difference is the present embodiment: in the poly lactic coglycolic acid (PLGA) of use, cream
The mass ratio of acid and hydroxyacetic acid is 1:1.Compared with the triggering type acoustic contrast agent prepared in embodiment 1, under transmission electron microscope
Triggering type acoustic contrast agent manufactured in the present embodiment is observed, distribution of the GNPs on contrast agent shell owes uniform.Lactic acid and hydroxyl
The mass ratio of acetic acid plays important effect to distribution of the GNPs on shell membrane and attachment.The quality of lactic acid and hydroxyacetic acid
Than that for 2:1, can make the poly lactic coglycolic acid formed by lactic acid and hydroxyacetic acid that there is preferable filming performance,
It so as to efficiently wrap up perflexane (PFH), and is embedded on shell membrane for gold nano grain and support is provided, ensure that gold
Nano particle is embedded on shell membrane rather than is wrapped at the core of hud typed particle by PLGA, so that gold nano grain can
Efficiently to absorb the energy of laser, and convert light energy into thermal energy.According to experimental result it is found that in lactic acid and hydroxyacetic acid
Under conditions of mass ratio is 1:1, the PLGA shell membrane of formation does not obviously have the effect that GNPs is fixed.
Experimental example 1: the cytotoxicity experiment of the triggering type acoustic contrast agent prepared in embodiment 1
Using the further contrast agent detection of mtt assay to cytotoxic effect, detailed process is as follows:
The MDA-MB-231 cell (human breast cancer cell, deposit number: ATCC CRM-HTB-26) of logarithmic growth phase, with 1
×104The density in/hole is inoculated in 96 orifice plates, is placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in constant incubator.By postdose sterilizing
It is respectively 25 μ that triggering type acoustic contrast agent (the triggering type acoustic contrast agent prepared in embodiment 1), which is diluted to concentration with culture solution,
G/ml, 50 μ g/ml, 75 μ g/ml, 100 μ g/ml, 200 μ g/ml are added in each hole, and cellular control unit is added without contrast agent
Equivalent fresh medium, every group sets 4 multiple holes in parallel.After cell processing, it is put in constant incubator and is incubated for for 24 hours.Discard culture
Liquid, after PBS liquid repeated flushing, 20 μ l (5mg/ml) of MTT solution is added in every hole, is incubated for 4h.Culture cell is terminated, is carefully discarded
Clear liquid, every hole are added 150 μ lDMSO, tissue culture plate are put in low-speed oscillation 10min on constant temperature oscillator.Existed with microplate reader
Absorbance (OD) value that each hole is detected at 490nm wavelength, is returned to zero with blank.
Testing result (being shown in Table 1) confirms the absorbance value group difference for the experimental group and control group that mtt assay measures without statistics
Meaning is learned, toxic effect is not generated to MDA-MB-231 cell, further illustrates the triggering type ultrasonic contrast prepared in embodiment 1
Agent safety is good.
Table 1: influence of the various concentration contrast agent to MDA cell activity
Note: compared two-by-two between each processing group, P > 0.05, difference is not statistically significant
Experimental example 2: photic Phase Change Experiment and the external supersonic imaging of the triggering type acoustic contrast agent prepared in embodiment 1
1. experimental method
In order to evaluate the ultrasound of the triggering type acoustic contrast agent prepared in embodiment 1 (i.e. photic inversion of phases acoustic contrast agent)
Enhance imaging results, specifically use following test method: the test agent prepared (100 μ g/mL) being placed in gel system first
In standby models holes.Gelinite mould is prepared using 1% agar (w/v) of dissolution in deionized water, and imaging bore dia is
0.5cm.Then using Nd:YAG Q5 Laser emission instrument with wavelength 532nm, pulse recurrence frequency 4MHz, energy 120mJ/cm2's
Pulse laser irradiation contrast agent, irradiation time 5s.Using diasonograph (Mylab 90, Esaote, Italy), in conventional B
Emit and receive the centre frequency of 5.0MHz and 12MHz under mode, that is, Fundamental Imaging mode and harmonic mode with linear array probe,
Scanning acoustic beam is vertical with hole long axis, and using physiological saline and the particle without gold nano grain as control, acquire in each hole
Ultrasound image.And the echo intensity value of each sample is measured with DFY type ultrasonic image quantitatively analyzing instrument.Three groups of samples are carried out altogether
Experiment detection, sample is the touching prepared in physiological saline group (saline), PLGA particle group (PLGA/PFH) and embodiment 1 respectively
Hair style acoustic contrast agent group (GNPs-PLGA/PFH).Wherein PLGA particle group is to wrap up the particle that PFH is formed with PLGA, is existing
There is the known particle in technology.
2. experimental result
External supersonic image results show that three groups of sample ultrasonoscopies before laser irradiation are in echoless.With wavelength
532nm, pulse recurrence frequency 4MHz, 120mJ/cm2Pulse laser irradiation 5s after, embodiment 1 prepare triggering type ultrasound make
Shadow agent and converts light energy into thermal energy due to the GNPs specificabsorption 532nm wave band luminous energy of case surface, promotes contrast agent local
Temperature increases, and after temperature is more than the threshold value that liquid-gas phase transition occurs for PFH, liquid-gas phase transition occurs for PFH, i.e. the triggering of realization light
Phase transformation forms the internal acoustic contrast agent for bubble, so that fundamental wave and harmonic signal intensity on ultrasound image be made to obviously increase, increases
Strong ultrasonoscopy (see Fig. 7-12).And other two groups of control groups are not due to having the synergistic effect of gold nano grain and PFH, ultrasound letter
Number nothing is remarkably reinforced.Meanwhile the echo intensity variation of DFY Ultrasonic Quantitative Analysis instrument detection is also consistent with ultrasound enhancing imaging results
(being shown in Table 2).
Acoustic contrast agent compares in two dimension and contrast mode echo intensity (EI) before and after 2 laser irradiation of table
Note: reagent used in acoustic contrast agent group is triggering type acoustic contrast agent prepared by embodiment 1, with other two groups
Comparing difference is statistically significant, P < 0.05
Experimental example 3: the rabbit Zhong Liu popliteal nest lymphatic metastasis ultrasonoscopy of the triggering type acoustic contrast agent prepared in embodiment 1
Experiment
1. test method
(1) establish Tu popliteal nest VX2 metastases lymph node model: (selective body focuses between 2.0-2.5kg New Zealand White Rabbit
Experimental rabbit tested) by ear vein injection 3% yellow Jackets (0.8mL/kg) anesthesia, and with 8% vulcanized sodium will after
Leg depilation.From inoculation VX2 tumour (VX2 squamous cell carcinoma line；Funabashi FarmCo, Kyoto, Japan) lotus knurl
Removing tumor tissues are taken the eugonic flesh of fish sample tissue of borderline tumor, are cut into 1mm with brine in kind rabbit body3Greatly
Small tumor mass is spare.By the fixed simultaneously routine disinfection of postanesthetic rabbit, tumor tissues are inoculated by back leg by intramuscular heeling-in, and
It carries out disinfection to the inoculation position on skin.After tumor inoculation, experimental rabbit During Intramuscular Injection of Penicillin (120mg, 1670U/ are given
Mg) prevention infection.
(2) ultrasonoscopy was carried out to experimental rabbit in 3 weeks after tumor inoculation, only forms tumor lympha knot metastasis model for 18
Experimental rabbit is randomly divided into 3 groups.The anesthesia of 3% yellow Jackets is given before ultrasonic development, then makes 2mL (100 μ g/mL) ultrasound
Shadow agent (or substitute) is injected through rabbit tumor inoculation parapodum pad, and carries out part massage 5min in injection site, and stimulation accelerates to make
Shadow agent enters in lymphatic and lymph node.After 30min, Wei popliteal nest lymph node is Dinged with conventional Ultrasound, frequency is then repeated with pulse
Rate is 4MHz, 120mJ/cm2Pulse laser irradiation 10s, the fundamental wave and harmonic mode of acquisition irradiation Qian Hou popliteal nest lymph node be super
Acoustic image, and become with the echo intensity value of lymphnode metastatic before and after DFY type ultrasonic image quantitatively analyzing instrument detection laser irradiation
Change.Using physiological saline and the particle without gold nano grain (PLAG particle group) is compareed as between group.Three groups of samples are carried out altogether
Experiment detection, sample is the touching prepared in physiological saline group (saline), PLGA particle group (PLGA/PFH) and embodiment 1 respectively
Hair style acoustic contrast agent group.Wherein the PLGA particle in PLGA particle group (GNPs-PLGA/PFH) is directly to wrap up PFH with PLGA
The particle of formation, for known particle in the prior art.
2. experimental result
As shown in figures 13-18, after localization by ultrasonic lymphnode metastatic, lymph node is irradiated with local laser, it is seen that implementing
In the triggering type acoustic contrast agent group prepared in example 1, lymph node fundamental wave and harmonic signal intensity are obviously increased, and are greatly improved
To the accuracy of lymphnode metastatic identification, and imaging is remarkably reinforced in other two groups of control group lymph nodes nothing.Meanwhile DFY is super
Echo intensity variation also enhances imaging results with ultrasound in lymphnode metastatic before and after the laser irradiation of sound quantitative analysis instrument detection
Unanimously (table 3).
Lymphnode metastatic compares in two dimension and contrast mode echo intensity (EI) before and after 3 laser irradiation of table
Note: reagent used in acoustic contrast agent group is triggering type acoustic contrast agent prepared by embodiment 1, with other two groups
Comparing difference is statistically significant, P < 0.05
The data of 1 and experimental example 1-3 are it is found that triggering type acoustic contrast agent prepared by embodiment 1 has light in conjunction with the embodiments
The property of phase transformation is caused, and the hud typed particle size in triggering type acoustic contrast agent is more uniform, good dispersion, sees under transmission electron microscope
It examines, gold nano grain more uniform distribution is in microparticle shell structure.MTT experiment illustrates the triggering type prepared in embodiment 1 ultrasound
Contrast agent safety is good, and the toxic effect generated to cell is lower.Triggering type acoustic contrast agent prepared by embodiment 1 is due to shell
The gold nano grain on surface has specificity to absorb the property of specific wavelength luminous energy and photothermal conversion, promotes contrast agent local temperature liter
Height can form the internal acoustic contrast agent for bubble, it can be achieved that light triggering phase transformation.Gold nano grain can be real due to above-mentioned characteristic
Hud typed particle phase transition process is now accurately controlled, and does not need to carry out bio-tissue excessive laser or other processing, more
Add safety.Rabbit lymph node is handled using triggering type acoustic contrast agent prepared by embodiment 1, lymph node fundamental wave and harmonic wave can be made to believe
Number intensity obviously increases, and greatly improves the accuracy to lymphnode metastatic identification, to realize the leaching of accurate detection part
Fawn on transfer.
What has been described above is only an embodiment of the present invention, and the common sense such as well known specific structure and characteristic are not made herein in scheme
Excessive description.It, without departing from the structure of the invention, can be with it should be pointed out that for those skilled in the art
Several modifications and improvements are made, these also should be considered as protection scope of the present invention, these all will not influence what the present invention was implemented
Effect and patent practicability.The scope of protection required by this application should be based on the content of the claims, in specification
The records such as specific embodiment can be used for explaining the content of claim.
Claims (10)
1. a kind of triggering type acoustic contrast agent, which is characterized in that the triggering type acoustic contrast agent includes hud typed particle, described
Hud typed particle includes shell and core；The shell includes the shell membrane that filmogen is formed, and is inlaid with gold nano on shell membrane
Grain, the core are liquid fluorocarbon.
2. a kind of triggering type acoustic contrast agent according to claim 1, which is characterized in that the hud typed particle is averaged
Partial size is 1.83-1.95 μm.
3. a kind of triggering type acoustic contrast agent according to claim 2, which is characterized in that the filmogen is lactic acid-
Co-glycolic acid；In the poly lactic coglycolic acid, the mass ratio of lactic acid and hydroxyacetic acid is 2:1；The liquid
State fluorine carbon is perflexane.
4. a kind of preparation method of triggering type acoustic contrast agent according to claim 3, which is characterized in that including following step
Suddenly,
Step (1): poly lactic coglycolic acid and gold nano grain are added in chloroform, are stirred well to it completely
Dissolution, obtains copolymer-goldc grains solution；
Step (2): perflexane is slowly added dropwise in copolymer-goldc grains solution of step (1), obtains perflexane-copolymer-gold
Grain solution；It is ultrasonically treated the perflexane-copolymer-goldc grains solution, obtains emulsion；
Step (3): being added poly-vinyl alcohol solution in the emulsion of step (2), and the poly- second of emulsion-is then obtained after homogenization
Enol mixture；
Step (4): the chloroform in the emulsion-polyvinyl alcohol mixture of step (3) is removed, is then centrifuged for taking precipitating.
5. preparation method according to claim 4, which is characterized in that in step (1), the lactic-co-glycolic acid
The mass ratio of copolymer and the gold nano grain is 100:1, and the partial size of gold nano grain is 10nm.
6. preparation method according to claim 4, which is characterized in that in step (2), in ultrasonication,
Perflexane-copolymer-goldc grains the solution is placed in 5 DEG C of environment.
7. preparation method according to claim 4, which is characterized in that in step (2), sonication treatment time 45s,
Ultrasonic power is 130W.
8. preparation method according to claim 4, which is characterized in that in step (3), the concentration of poly-vinyl alcohol solution
For 5 weight %.
9. preparation method according to claim 4, which is characterized in that in step (3), emulsion and polyvinyl alcohol are molten
The volume ratio of liquid is 1:5.
10. preparation method according to claim 4, which is characterized in that in step (4), extracted using aqueous isopropanol
The method for taking chloroform removes the chloroform in emulsion-polyvinyl alcohol mixture.
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