CN108671231A - A kind of multifunctional nano-carrier and preparation method for tumor photo-thermal synergy treatment and ultrasonic imaging - Google Patents
A kind of multifunctional nano-carrier and preparation method for tumor photo-thermal synergy treatment and ultrasonic imaging Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical Kinetics & Catalysis (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
The invention discloses a kind of multifunctional nano-carriers and preparation method for tumor photo-thermal synergy treatment and ultrasonic imaging, it is characterised in that：Nano-carrier is nucleocapsid, is using Soluble Polypyrrole as shell mechanism, kernel is filled with phase-change material and micromolecular inhibitor drug.The nano-carrier of the present invention has the function of ultrasonic contrast diagnosis and photo-thermal synergy treatment simultaneously, the contrast and clarity of the phase-change material mounted gas-bubble enhanced ultrasound image that phase transformation generates under outside stimulus, the drug discharged acts on the level for reducing thermostable protein in cancer cell by a series of cascades, to significantly improve cancer cell to the sensibility of heat, enhance the effect of photo-thermal therapy.
Description
Technical field
The invention belongs to technical field of nano material, and in particular to one kind being used for tumor photo-thermal synergy treatment and ultrasonic imaging
Multifunctional nano-carrier and preparation method.
Background technology
Annual cancer neopathy number is in rising trend according to the statistics of the World Health Organization, and cancer, which becomes current serious, influences people
Class health, one of the principal disease for threatening human life.In treatment of cancer, primary treatments have operation, radiotherapy, change
Treat three big means, but clinical discovery these means all have certain limitation, keep final therapeutic effect unsatisfactory.Therefore
Developing a kind of safe and efficient, Small side effects novel therapeutic means has very important practical significance.Research is found using close
Infrared light region (650nm~950nm) is used as exciting light, can must not only obtain good tissue penetration depths, and with
The nano-particle of photothermal conversion ability is simultaneously using the requirement that can meet new therapeutic agent.Particle is injected after human body using receiving
The infiltration retention effect (enhanced permeability and retention effect, EPR) of rice corpuscles, makes its selection
Property be enriched near tumor tissues, convert light energy into thermal energy under excitation light source irradiation and make tumor by local temperature rise to cell
Tolerable temperature (>42 DEG C) and normal cell is unaffected.
It, can be by the means of imaging toward contact to ensure the accuracy for the treatment of during treatment of cancer.Therefore make light
Also it is one with imaging capability while heat cure agent acts on more than playing and is rich in the target challenged and meant a great.At present
Common imaging means have：Magnetic resonance imaging (Magnetic Resonance Imaging, MIR), ultrasonic imaging
(Ultrasound Imaging, US), fluorescence imaging etc., wherein ultrasonic imaging utilize ultrasonic scanning destination organization, believe echo
Number it is collected processing, to obtain the image of pathological tissues, to provide more foundations for the Precise Diagnosis of disease and treatment.For
The better ultrasonic imaging of acquisition is sharp as a result, the clinical drop for being often used a diameter of several microns of bubble is used as acoustic contrast agent
There is the characteristic of strong scattering to ultrasonic wave with bubble to enhance the contrast and clarity of image.By photo-thermal therapy agent and ultrasonic contrast
Agent, which is combined together to prepare, has the function of ultrasonic contrast enhancing in the photo-thermal therapy agent of one, can detect photo-thermal in real time and control
Treat the enrichment degree of agent distribution in vivo and target area.
Current research finds solely cell can be caused to generate heat resistance using photo-thermal therapy, if improving laser power
Or reirradiation can lead to inflammation, metastases equivalent risk.And solely use photo-thermal therapy that cannot thoroughly eradicate depths
Tumor tissues, because when need photo-thermal therapy being combined with other treatment method.Studies have shown that by with good photo-thermal effect
Nano-medicament carrier and micromolecular inhibitor combine, and can overcome the limitation of single photo-thermal therapy, achieve the purpose that thermotherapy synergy.
During photo-thermal therapy, tumor by local temperature increases, and membrane passage increases and the metabolic rate of cell is accelerated, meeting
So that tumour cell improves the uptake rate of drug, the micromolecular inhibitor drug of release is acted on by a series of cascades and being reduced
The level of thermostable protein in cancer cell enhances the effect of photo-thermal therapy to significantly improve cancer cell to the sensibility of heat.
Polypyrrole (Polypyrrole, PPy) has good photo and thermal stability, higher photothermal conversion efficiency and very
Good biocompatibility prepares using polypyrrole while having compound the examining of ultrasonic contrast diagnosis and photo-thermal synergy treatment function
Disconnected preparation so that only need a kind of compound formulation that two kinds of functions of diagnosing and treating can be achieved at the same time, reach photo-thermal synergy treatment
With the purpose of metabolism treatment combination therapy.
Invention content
The purpose of the invention is to provide a kind of multifunctional nanos for tumor photo-thermal synergy treatment and ultrasonic imaging
Carrier solves to diagnose in traditional clinical practice to make it have the function of ultrasonic contrast diagnosis and photo-thermal synergy treatment
Or the limitation for the treatment of single use, realize two kinds of functions of diagnosing and treating simultaneously with a kind of compound formulation.
The present invention is to solve technical problem, is adopted the following technical scheme that：
The invention discloses a kind of multifunctional nano-carrier for tumor photo-thermal synergy treatment and ultrasonic imaging, features
It is：The nano-carrier is nucleocapsid (capsule structure), is using Soluble Polypyrrole as shell mechanism, kernel is filled with phase
Become material and micromolecular inhibitor drug；80~200 nanometers of the diameter of the nano-carrier.
The nano-carrier has the function of ultrasonic contrast diagnosis and photo-thermal synergy treatment simultaneously.Utilize the phase-change material
With micromolecular inhibitor drug, realize that the mode of tumor photo-thermal synergy treatment and ultrasonic imaging is：Outside stimulus acts on described
When nano-carrier, the Soluble Polypyrrole generates heat, so that the temperature of kernel is reached phase-change material fusing point or more, makes phase transformation
Material generates the echo signal that bubble enhances ultrasound, realizes ultrasonic contrast diagnosis；The heat generated simultaneously makes tumor by local group
Necrosis is knitted, a portion cell, which generates tolerance protein, enhances its tolerance, and the drug discharged reduces the base of cell GLUT-1
Because of expression, the glucose that cell absorbs is caused to reduce, the ATP that glycolysis generates is reduced, and then is made dependency ATP and generated
Heat shock protein cluster HSP70/90 levels reduce, to realize that tumor photo-thermal synergy is treated.
The preparation-obtained preparation of the present invention has the function of ultrasonic contrast diagnosis and photo-thermal synergy treatment simultaneously, is wrapped up
Phase-change material under outside stimulus phase transformation generate gas-bubble enhanced ultrasound image contrast and clarity, the drug discharged
Being acted on by a series of cascades reduces the level of thermostable protein in cancer cell, to significantly improve sensibility of the cancer cell to heat,
Enhance the effect of photo-thermal therapy.
Preferably, the micromolecular inhibitor drug is everolimus, chloroquine, Diclofenac or anti-farnesyl thiosalicylic
Acid.
The phase-change material is menthol, perfluocarbon or perflexane.
The outside stimulus is the thermostimulation that light stimulus, microwave stimulation, magnetic stimulation, ultrasound stimulation or body heat cause.
The preparation method of the above-mentioned multifunctional nano-carrier for tumor photo-thermal synergy treatment and ultrasonic imaging, including it is as follows
Step：
(1) Soluble Polypyrrole and phase-change material are dissolved in volatile organic solvent；
(2) it is added in step (1) acquired solution after dissolving drug, obtains mixed solution；
(3) ultrasound after surfactant solution mixes is added in the mixed solution, micro emulsion method forms nucleocapsid, obtains
Soluble nano-particle；Then being stirred at room temperature keeps organic solvent volatilization complete, obtains the aqueous dispersions of nano-particle；
(4) aqueous dispersions of the nano-particle are centrifuged, centrifugal rotational speed 9500rpm, centrifugation time 8min,
Gained medicament-carried nano carrier, is as used for the multifunctional nano of tumor photo-thermal synergy treatment and ultrasonic imaging after multiple centrifuge washing
Carrier.
By taking menthol, Diclofenac as an example, above-mentioned preparation method includes the following steps：
(1) that 100~500mg Soluble Polypyrroles and 30~150mg phase-change materials are dissolved in 4mL volatility first is organic molten
In agent；
(2) it after 30~200mg drugs being dissolved in 800 μ L dimethyl sulfoxide (DMSO)s, is added in step (1) acquired solution, obtains
Obtain mixed solution；
(3) aqueous solution (1~1.5g containing surfactant) that the mixed solution is added to 20mL surfactants mixes
It is ultrasonic afterwards, keep oil phase not stratified with water phase, obtains the nano-particle of good dispersion in water；Then being stirred at room temperature makes organic solvent wave
It distributes entirely, obtains the aqueous dispersions of nano-particle；
(4) aqueous dispersions of the nano-particle are centrifuged, centrifugal rotational speed 9500rpm, centrifugation time 8min,
Gained medicament-carried nano carrier, is as used for the multifunctional nano of tumor photo-thermal synergy treatment and ultrasonic imaging after multiple centrifuge washing
Carrier.
Beneficial effects of the present invention are embodied in：
1, nano-carrier of the invention has the ability of photo-thermal therapy synergy, is that photo-thermal synergy treatment is combined with metabolism treatment
A kind of form.
2, nano-carrier of the invention can be used for enhancing ultrasonic imaging, improve the clarity of imaging.
3, preparation process of the present invention is simple, mild condition, has the possibility of large-scale production, has industry and practical application
Potentiality.
4, material used in the present invention has good biocompatibility, to human body without direct or indirect toxic action,
Without genotoxic potential.
5, nano-carrier of the invention has good dispersibility and stability, is conducive to Clinical practice.
6, the nano-carrier of thermostimulation of the invention response release drug, external source sexual stimulus used can be that 808nm is closely red
Outer light, the response made are that temperature increases generation bubble and carries out drug release, and such mode reduces drug to other groups
The injury for knitting cell realizes the Targeting delivery of drug, improves the utilization rate of drug.
Description of the drawings
Fig. 1 is the principle of the present invention schematic diagram；
Fig. 2 is ultra-violet absorption spectrum of the nano-carrier of the carrying phase-change material prepared in embodiment 2 under various concentration
Scheme (Fig. 2 b)；
Fig. 3 is the nano-carrier of blank nano-carrier prepared by embodiment 1 and carrying phase-change material prepared by embodiment 2
Thermogravimetric analysis figure.
Fig. 4 is the hemolysis rate point that 2 various concentration of embodiment carries the nano-carrier of phase-change material and red cell suspension is incubated
Analysis figure.
Fig. 5 a are the heating curve figure of the nano-carrier aqueous dispersions of the carrying phase-change material of various concentration in embodiment 2,
The corresponding heating stability curve figure of the nano-carrier aqueous dispersions for the carrying phase-change material that Fig. 5 b are 50 μ g/mL of concentration.
Fig. 6 is physiological saline, blank nano-carrier and carries the nano-carrier of phase-change material in blank, heating and illumination item
Ultrasonic imaging figure under part.
Fig. 7 is the 3 gained medicament-carried nano of nano-carrier and embodiment of free drug, 2 gained carrying phase-change material of embodiment
The uv absorption spectra of carrier.
Fig. 8 a are the drug release patterns of medicament-carried nano carrier at different temperatures made from embodiment 3, and Fig. 8 b are to implement
Drug release patterns of the medicament-carried nano carrier made from example 3 in the case where being interrupted laser irradiation.
When Fig. 9 a are without laser irradiation, the nano-carrier of the carrying phase-change material in free drug, embodiment 2 and implementation
For the medicament-carried nano carrier of example 3 to the fragmentation effect of 4t1 cells, Fig. 9 b are by three couple when 808nm 1W laser irradiation 3min
The fragmentation effect of 4t1 cells.
When Figure 10 a are without laser irradiation, the nano-carrier and reality of the carrying phase-change material in free drug, embodiment 2
Fragmentation effect of the medicament-carried nano carrier to HeLa cells of example 3 is applied, Figure 10 b are by three when 808nm 1W laser irradiation 3min
To the fragmentation effect of HeLa cells.
Specific implementation mode
In order to make the foregoing objectives, features and advantages of the present invention clearer and more comprehensible, with reference to embodiment to this hair
Bright specific implementation mode is described in detail.The following contents is only the design example and explanation to the present invention, institute
Belong to those skilled in the art to make various modifications or additions to the described embodiments or using similar
Mode substitutes, and as long as it does not deviate from the concept of invention or beyond the scope defined by this claim, should all belong to the present invention
Protection domain.
Embodiment 1
The present embodiment is prepared as follows blank nano-carrier：
(1) Soluble Polypyrrole is prepared first：
Bis- (the 2- second hexyl) sodium sulfo-succinates (NaDEHS) for weighing 6.6684g are added in 90mL deionized waters, set
The stirring and dissolving in ice-water bath.After it is completely dissolved, the pyrrole monomer of 2.769mL is added into system, persistently stirs 5min
Afterwards, then 10mL ammonium persulfate solutions (containing ammonium persulfate 2.282g) are charged with, whole system reacts 20h in ice-water bath.
After reaction, it is centrifugally separating to obtain Soluble Polypyrrole [(Py)3 +(DEHS)-]x；
(2) 100mg Soluble Polypyrroles are weighed to be dissolved in 4mL dichloromethane solutions, are stirred at room temperature to uniformly mixed；
(3) 1.2g polyvinylpyrrolidones (PVP) are weighed to be dissolved in 20mL deionized waters as surfactant solution, it will
Step (2) acquired solution is added in PVP solution, obtains mixed solution；
(4) utilize ultrasonic cell disruptor under the conditions of ice-water bath, by mixed solution interval ultrasound 3min, make oil phase and
Water phase is not stratified, obtains the good nano-carrier of dissolubility；Then 4h is stirred at room temperature, dichloromethane is made to volatilize, obtains blank nanometer
The aqueous dispersions of carrier；
(5) aqueous dispersions of blank nano-carrier are centrifuged, centrifugal rotational speed 9500rpm, centrifugation time 8min,
Gained precipitation is finally dispersed in water up to blank nano-carrier solution by multiple centrifuge washing.
Embodiment 2
The present embodiment is prepared as follows the nano-carrier for carrying phase-change material：
(1) it presses 1 identical method of embodiment and prepares Soluble Polypyrrole；
(2) 100mg Soluble Polypyrroles are weighed and 50mg menthols are dissolved in 4mL dichloromethane solutions, are stirred at room temperature
It mixes to uniformly mixed；
(3) 1.2g polyvinylpyrrolidones (PVP) are weighed to be dissolved in 20mL deionized waters as surfactant solution, it will
Step (2) acquired solution is added in PVP solution, obtains mixed solution；
(4) utilize ultrasonic cell disruptor under the conditions of ice-water bath, by mixed solution interval ultrasound 3min, make oil phase and
Water phase is not stratified, obtains the good nano-particle of dissolubility；Then 4h is stirred at room temperature, dichloromethane is made to volatilize, obtains nano-carrier
Aqueous dispersions；
(5) aqueous dispersions of nano-carrier are centrifuged, centrifugal rotational speed 9500rpm, centrifugation time 8min, repeatedly
Gained precipitation is finally dispersed in water to get the aqueous dispersions for the nano-carrier for carrying phase-change material by centrifuge washing.
Fig. 2 is the ultra-violet absorption spectrum for the nano-carrier for carrying phase-change material, and characterizing method is：Gained is carried into phase transformation
The aqueous dispersions of the nano-carrier of material are diluted to various concentration (10 μ g/mL, 20 μ g/mL, 40 μ g/mL, 60 μ g/mL, 80 μ g/
ML, 100 μ g/mL), and test its UV-visible absorption spectrum, it can be seen that its absorption is concentration dependent, with dense
Its UV absorption of the raising of degree also increases.
Fig. 3 is the heat for the nano-carrier that phase-change material is carried obtained by 1 gained blank nano-carrier of embodiment and the present embodiment
Weight analysis figure, characterizing method are：After the nano-carrier freeze-drying of blank nano-carrier obtained and carrying phase-change material, utilize
Particle to be measured is placed under air atmosphere by thermogravimetric analyzer, is stepped up to 400 DEG C by room temperature, is measured mass particle in real time,
As shown, the decline degree that blank nano-carrier mass ratio carries the nano-carrier quality of phase-change material is small, show menthol
It is removed from particle.
Fig. 4 is to characterize carrier biocompatibility in vitro, and the nano-carrier of phase-change material and red is carried with various concentration
Cell suspension, which is incubated, surveys its hemolysis rate, and characteristic manner is：Blood sample is red to be obtained after 2000rpm centrifugations 10min
Cell, normal saline dilution erythroblast suspension.Make negative control with physiological saline, positive control is made with deionized water, 800
μ L physiological saline, 800 μ L deionized waters and 800 μ L various concentration medicament-carried nanos carriers (50 μ g/mL, 75 μ g/mL, 100 μ g/mL,
150 μ g/mL, 200 μ g/mL) aqueous solution in, it is each be added 200 μ L red cell suspensions (in figure upper row's centrifuge tube be add it is red thin
Sample after born of the same parents' suspension, since carrier has higher dissolubility, centrifugation that cannot completely remove in water, therefore following row is not plus red
The sample of cell suspension is as ground control), 37 DEG C of incubation 6h, then 3000rpm centrifugations 10min, uses ultravioletvisible spectroscopy
Absorbance of the survey supernatant in 541nm.As shown, after various concentration carrier is incubated with red cell suspension, the purple of supernatant
Outer absorption is very low, illustrates that the biocompatibility of the carrier is good.
Fig. 5 a are the temperature rise effect figure of the nano-carrier aqueous dispersions of the carrying phase-change material of various concentration, characteristic manner
For：3mL solution to be measured is taken to be irradiated in 808nm laser irradiation devices, irradiation time 10min, laser intensity 2W, interval 10s notes
Record a temperature.As a result illustrate that the raising with medicament-carried nano carrier concn, temperature rise effect increase.Fig. 5 b are 50 μ g/mL of concentration
Carry the corresponding heating stability test figure of the nano-carrier aqueous dispersions of phase-change material, it can be seen that carry phase-change material
Nano-carrier has good photo and thermal stability.
Fig. 6 is physiological saline, blank nano-carrier and carries the nano-carrier of phase-change material in blank, heating and illumination item
Ultrasonic imaging figure under part.Its characterizing method is：Physiological saline is placed in silicone tube to do respectively and is heated to without processing, from room temperature
Under the conditions of 40 DEG C and 808nm, 2W illumination 30min, with ultrasonic probe detection image；Equally by blank nano-carrier, carrying phase transformation
The nano-carrier of material does no processing respectively, under the conditions of room temperature is heated to 40 DEG C and 808nm, 2W illumination 30min, is visited with ultrasound
Head detection image variation.As can be seen that compared to blank control group, the condition of heating and illumination all makes the phase transformation that menthol continues
The contrast and clarity of ultrasonoscopy are enhanced, and the ability of illumination condition generation bubble is slightly stronger than heating condition, it was demonstrated that
Nano-carrier has a good ultrasonic contrast diagnostic function under external source stimulating.
Embodiment 3
The present embodiment is prepared as follows medicament-carried nano carrier：
(1) it presses 1 identical method of embodiment and prepares Soluble Polypyrrole；
(2) 100mg Soluble Polypyrroles are weighed, 50mg menthols are dissolved in 4mL dichloromethane solutions, weigh 100mg
Diclofenac is dissolved in 800 μ L dimethyl sulfoxide (DMSO)s (DMSO), and is added in dichloromethane, and stirring is equal to mixing at room temperature
It is even；
(3) 1.2g polyvinylpyrrolidones (PVP) are weighed to be dissolved in 20mL deionized waters as surfactant solution, it will
Above-mentioned solution is added in PVP solution, obtains mixed solution；
(4) utilize ultrasonic cell disruptor under the conditions of ice-water bath, by mixed solution interval ultrasound 3min, make oil phase and
Water phase is not stratified, obtains the good nano-particle of dissolubility；Then 4h is stirred at room temperature, dichloromethane is made to volatilize, obtains nano-carrier
Aqueous dispersions；
(5) aqueous dispersions of nano-carrier are centrifuged, centrifugal rotational speed 9500rpm, centrifugation time 8min, repeatedly
Gained precipitation is finally dispersed in water the aqueous dispersions up to medicament-carried nano carrier by centrifuge washing.
Fig. 7 is medicament-carried nano obtained by the nano-carrier and the present embodiment of free drug, 2 gained carrying phase-change material of embodiment
The uv absorption spectra of carrier, characterizing method are：Ensure free drug used and the nano-carrier of carrying phase-change material
Quality, respectively with wrapped up in medicament-carried nano carrier drug quality, outer cover quality equivalent；Therefore, it is used when the present embodiment is tested
The nano-carrier concentration of aqueous solution for carrying phase-change material is 60 μ g/mL, a concentration of 18 μ g/mL of DMSO solution of free drug, carries
Medicine nano-carrier concentration of aqueous solution is 78 μ g/mL.As shown in Figure 7, within the scope of 250-300nm, there are one absorption peaks for drug, together
When within the scope of this, the absorption of medicament-carried nano carrier accordingly improves, this shows that drug is successfully loaded in blank nano-carrier, and
So that its absorption under identical mass concentration is equal to drug and carries the absorption of the nano-carrier of phase-change material.
Fig. 8 a are the drug release patterns of medicament-carried nano carrier at different temperatures made from the present embodiment, characteristic manner
For：Medicament-carried nano carrier is dissolved in deionized water (concentration 2mg/mL), then 3mL is taken to be placed in the bag filter of 5000Da, then
Bag filter is placed in the deionized water of 30mL, different temperatures (25 DEG C, 37 DEG C, 42 DEG C, 45 DEG C, 60 DEG C) is heated to and is stirred.
After the variation of release profiles can be seen that temperature reaches menthol transformation temperature, starts a large amount of release drugs, illustrate menthol
With good temperature-responsive ability.
Fig. 8 b are drug release patterns of the medicament-carried nano carrier in the case where being interrupted laser irradiation made from the present embodiment, characterization
Mode is：Medicament-carried nano carrier is dissolved in deionized water (concentration 2mg/mL), 3mL is taken to be placed in the cell of 37 DEG C of silica dish constant temperature
(the laser pass) 10min in incubator is subsequently placed in the bag filter of 5000Da the 1h that dialyses, and acquires dialyzate and tests accumulative release
Amount；Particle in bag filter is again placed in silica dish and is placed in again in the cell incubation case of 37 DEG C of constant temperature, laser irradiation is opened
10min dialyses and acquires dialyzate, test Cumulative release amount again.It is multiple to repeat laser switch.Results showed that medicament-carried nano
Carrier has good light stimulus response medicine releasability.
When Fig. 9 a are without laser irradiation, the nano-carrier and this reality of the carrying phase-change material in free drug, embodiment 2
Fragmentation effect of the medicament-carried nano carrier to 4t1 cells of example is applied, Fig. 9 b are by three couple when 808nm 1W laser irradiation 3min
The fragmentation effect of 4t1 cells.It can be seen that：When without laser irradiation, free drug there is certain killing to imitate 4t1 cells
Fruit, but the medicament-carried nano carrier of the nano-carrier of carrying phase-change material and the present embodiment is to the injury very little of cell；Through too drastic
After light irradiation, free drug, without significant changes, but carries nano-carrier and this implementation of phase-change material to the fragmentation effect of cell
The medicament-carried nano carrier of example is remarkably reinforced Cell killing efficacy and more than effect caused by free drug, medicament-carried nano carrier
Fragmentation effect is better than the fragmentation effect for the nano-carrier for carrying phase-change material.
When Figure 10 a are without laser irradiation, the nano-carrier and sheet of the carrying phase-change material in free drug, embodiment 2
For the medicament-carried nano carrier of embodiment to the fragmentation effect of HeLa cells, Figure 10 b are by when 808nm 1W laser irradiation 3min three
Fragmentation effect of the person to HeLa cells.It can be seen that：When without laser irradiation, free drug has certain kill to HeLa cells
Hinder effect, but the medicament-carried nano carrier of the nano-carrier of carrying phase-change material and the present embodiment is to the injury very little of cell；It is passing through
After crossing laser irradiation, free drug to the fragmentation effect of cell without significant changes, but carry phase-change material nano-carrier and this
The medicament-carried nano carrier of embodiment is remarkably reinforced Cell killing efficacy and more than effect caused by free drug, and medicament-carried nano carries
The fragmentation effect of body is better than the fragmentation effect for the nano-carrier for carrying phase-change material.
Claims (7)
1. a kind of multifunctional nano-carrier for tumor photo-thermal synergy treatment and ultrasonic imaging, it is characterised in that：
The nano-carrier is nucleocapsid, is using Soluble Polypyrrole as shell mechanism, kernel is filled with phase-change material and small
Molecule inhibitor drug；A diameter of 80~200nm of the nano-carrier.
2. a kind of multifunctional nano-carrier for tumor photo-thermal synergy treatment and ultrasonic imaging according to claim 1,
It is characterized in that：The nano-carrier has the function of ultrasonic contrast diagnosis and photo-thermal synergy treatment simultaneously.
3. a kind of multifunctional nano-carrier for tumor photo-thermal synergy treatment and ultrasonic imaging according to claim 1,
It is characterized in that：The micromolecular inhibitor drug is everolimus, chloroquine, Diclofenac or anti-farnesyl thiosalicylic acid.
4. a kind of multifunctional nano-carrier for tumor photo-thermal synergy treatment and ultrasonic imaging according to claim 1,
It is characterized in that：The phase-change material is menthol, perfluocarbon or perflexane.
It a kind of is received for tumor photo-thermal synergy treatment and the multi-functional of ultrasonic imaging 5. according to claim 1,2,3 or 4
Meter Zai Ti, it is characterised in that：
Using the phase-change material and micromolecular inhibitor drug, the mode of tumor photo-thermal synergy treatment and ultrasonic imaging is realized
For：When outside stimulus acts on the nano-carrier, Soluble Polypyrrole generates heat, and the temperature of kernel is made to reach phase-change material
Fusing point or more makes phase-change material generate the echo signal that bubble enhances ultrasound, realizes ultrasonic contrast diagnostic function；It produces simultaneously
Raw heat makes tumor by local tissue necrosis, and a portion cell, which generates tolerance protein, enhances its tolerance, and the medicine discharged
Object reduces the gene expression dose of cell GLUT-1, and the glucose that cell absorbs is caused to reduce, and the ATP that glycolysis generates is reduced,
And then the heat shock protein cluster HSP70/90 levels for making dependency ATP and generating reduce, to realize that tumor photo-thermal synergy is treated.
6. a kind of multifunctional nano-carrier for tumor photo-thermal synergy treatment and ultrasonic imaging according to claim 5,
It is characterized in that：The outside stimulus is the thermostimulation that light stimulus, microwave stimulation, magnetic stimulation, ultrasound stimulation or body heat cause.
7. a kind of for the more of tumor photo-thermal synergy treatment and ultrasonic imaging described in a kind of any one of claim 1~6
The preparation method of function nano carrier, which is characterized in that include the following steps：
(1) Soluble Polypyrrole and phase-change material are dissolved in volatile organic solvent；
(2) it is added in step (1) acquired solution after dissolving drug, obtains mixed solution；
(3) ultrasound after surfactant solution mixes is added in the mixed solution, micro emulsion method forms nucleocapsid, obtains solvable
The nano-particle of property；Then being stirred at room temperature keeps organic solvent volatilization complete, obtains the aqueous dispersions of nano-particle；
(4) aqueous dispersions of the nano-particle are centrifuged, centrifugal rotational speed 9500rpm, centrifugation time 8min, repeatedly
Gained medicament-carried nano carrier after centrifuge washing, the multifunctional nano for being as used for tumor photo-thermal synergy treatment and ultrasonic imaging carry
Body.
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| CN109288816A (en) * | 2018-12-04 | 2019-02-01 | 广州凯普医药科技有限公司 | A kind of chloroquine gel and its preparation method and application |
| CN112933229A (en) * | 2021-03-17 | 2021-06-11 | 山东大学 | Carrier-free self-assembly nanoparticle of IR820 and atovaquone and preparation method and application thereof |
| CN113332619A (en) * | 2021-05-28 | 2021-09-03 | 西安交通大学 | Ultrasonic conformal activation and monitoring imaging method and system for phase-change nano-droplet drug carrier |
| CN113355056A (en) * | 2021-06-22 | 2021-09-07 | 广西民族大学 | Preparation method of photo-thermal phase change energy storage micro-nano super-hydrophobic anti-freezing particle material |
| CN113462363A (en) * | 2021-06-22 | 2021-10-01 | 广西民族大学 | Preparation method of photo-thermal phase change energy storage micro-nano multi-scale super-hydrophobic anti-freezing particle material |
| CN113975247A (en) * | 2021-12-17 | 2022-01-28 | 合肥工业大学 | PLGA nano-particles encapsulating DL-menthol and diclofenac as well as preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109288816A (en) * | 2018-12-04 | 2019-02-01 | 广州凯普医药科技有限公司 | A kind of chloroquine gel and its preparation method and application |
| CN109288816B (en) * | 2018-12-04 | 2019-11-22 | 广州凯普医药科技有限公司 | A kind of chloroquine gel and its preparation method and application |
| CN112933229A (en) * | 2021-03-17 | 2021-06-11 | 山东大学 | Carrier-free self-assembly nanoparticle of IR820 and atovaquone and preparation method and application thereof |
| CN113332619A (en) * | 2021-05-28 | 2021-09-03 | 西安交通大学 | Ultrasonic conformal activation and monitoring imaging method and system for phase-change nano-droplet drug carrier |
| CN113355056A (en) * | 2021-06-22 | 2021-09-07 | 广西民族大学 | Preparation method of photo-thermal phase change energy storage micro-nano super-hydrophobic anti-freezing particle material |
| CN113462363A (en) * | 2021-06-22 | 2021-10-01 | 广西民族大学 | Preparation method of photo-thermal phase change energy storage micro-nano multi-scale super-hydrophobic anti-freezing particle material |
| CN113975247A (en) * | 2021-12-17 | 2022-01-28 | 合肥工业大学 | PLGA nano-particles encapsulating DL-menthol and diclofenac as well as preparation method and application thereof |
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