CN104623698B - Liposome base nanometer diagnosis and treatment agent for multi-modal imaging and photo-thermal therapy and preparation method thereof - Google Patents
Liposome base nanometer diagnosis and treatment agent for multi-modal imaging and photo-thermal therapy and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to liposome base nanometer diagnosis and treatment agent for multi-modal imaging and photo-thermal therapy and preparation method thereof, the liposome base nanometer diagnosis and treatment agent includes airborne body fat plastid, the hydrophobic nano copper sulfide being wrapped between the bilayer of the liposome and the organic liquid-gas phase transition medium fluorocarbons being wrapped in the liposome kernel.The liposome base nanometer diagnosis and treatment agent of the present invention can be under near infrared light induction, while is used as ultrasound/near-infrared heat/optoacoustic multi-modal imaging contrast agent and photo-thermal therapy agent.
Description
Technical field
The invention belongs to technical field of nano material, and in particular to a kind of for multi-modal imaging and the lipid of photo-thermal therapy
Body base nanometer diagnosis and treatment agent and preparation method thereof.
Background technology
Cancer is to have a strong impact on one of human health, the major disease for threatening human life at present.If can be early in cancer
Phase diagnoses and treated in time will substantially reduce cancer mortality.And this depends on modern medicine imaging technique and cancer treatment method
Development.
The joint of multi-modal imaging means can make up the deficiency of single imaging pattern, so as to provide abundant and comprehensively examine
Disconnected information.Ultrasonic imaging, near infrared imaging and photoacoustic imaging are obtained due to its respective imaging advantage in cancer diagnosis
Be widely applied and pay close attention to, the joints of these three imaging means can provide that resolution ratio, sensitivity is higher and image taking speed faster
Imaging picture.
However, current imaging technique each uses different contrast agent, the joint of multi-modal imaging means needs one
The multi-functional contrast agent of kind.In addition, it is intended that contrast agent can be used as a kind of therapeutic agent while diagnosis, be examined so as to realize
Treat integration.This proposes new requirement for the development of following nanometer diagnosis and treatment agent.
The photo-thermal therapy of near infrared light induction enjoys in recent years as a kind of excellent Noninvasive cancer treatment method to be looked steadily
Mesh.It absorbs near infrared light luminous energy using photothermal deformation agent, and is translated into local heat energy so as to raise the temperature of tumor region
Degree directly burns cancer cell to death.Meanwhile the photo-thermal therapy under guiding is imaged due to being obtained which raises therapeutic efficiency and security
Extensive concern is arrived.
The liposome of parcel fluorocarbons has been widely used as ultrasonic imaging contrast agent.And copper sulfide due to surface etc. from
Daughter resonance effects and there is strong optical absorption characteristic near infrared region, can simultaneously as a kind of near-infrared heat/optoacoustic into
As contrast agent and photo-thermal therapy agent.If the liposome comprising fluorocarbons combined with copper sulfide, can not only overcome simple
The shortcomings that unstability and inorganic sulphide copper poor biocompatibility of organic liposome, and the energy under Same Wavelength laser excitation
The photo-thermal therapy under ultrasound/near-infrared heat/optoacoustic multi-modal imaging guiding is realized, and then realizes more accurate and efficient cancer
Diagnosis and treatment.Therefore, developing method for preparing lipidosome that is a kind of while wrapping up fluorocarbons and copper sulfide has important clinical significance.
The content of the invention
For above demand, it is an object of the invention to overcome the unstability and inorganic sulphide copper of simple organic liposome
The shortcomings that poor biocompatibility, there is provided a kind of to be used for multi-modal imaging and the liposome base nanometer diagnosis and treatment agent of photo-thermal therapy and its system
Preparation Method.
Herein, on the one hand, the present invention provides a kind of liposome base nanometer diagnosis and treatment for multi-modal imaging and photo-thermal therapy
Agent, the liposome base nanometer diagnosis and treatment agent include airborne body fat plastid, are wrapped between the bilayer of the liposome
Hydrophobic nano copper sulfide and the organic liquid-gas phase transition medium fluorocarbons being wrapped in the liposome kernel.
The liposome base nanometer diagnosis and treatment agent of the present invention has following characteristic：Using organic liposome as carrier, greatly improve
To fluorocarbons and the envelop rate of nano-copper sulfide, while improve the biocompatibility of nano-copper sulfide；Copper sulfide is near
There are strong Optical Absorption Characteristics at infrared light, near-infrared heat/photoacoustic imaging contrast agent and photo-thermal therapy agent can be used as simultaneously；Sulphur
Change Copper uptakie luminous energy and be translated into heat energy, fluorocarbons is changed into gas from liquid during the phase transition temperature for reaching fluorocarbons
State, caused bubble can strengthen ultrasonic imaging contrast ability.
The liposome base nanometer diagnosis and treatment agent of the present invention can be under near infrared light induction, while is used as ultrasound/near-infrared heat/light
Sound multi-modal imaging contrast agent and photo-thermal therapy agent.The photo-thermal therapy under multi-modal imaging guiding is realized, greatly improves treatment
Efficiency and security.
It is preferred that the particle diameter of the liposome base nanometer diagnosis and treatment agent is 50~120nm.The enhancing of tumor tissues can be passed through
Infiltration and delay effect (EPR), effectively gather tumor tissues.
It is preferred that in the liposome base nanometer diagnosis and treatment agent, mole of liposome, nano-copper sulfide and fluorocarbons
The ratio between amount is (60~150)：(1~2)：(6~12).
It is preferred that the liposome includes phosphatide and cholesterol, wherein the ratio between mole of phosphatide and cholesterol for (11~
15)：1.The ratio between mole by adjusting phosphatide and cholesterol, the phase transition temperature of liposome can be adjusted, so as to improve film
Permeability and circulation.
It is preferred that the fluorocarbons is liquid fluorocarbon, including in perflenapent, perflexane and the pungent bromine of perfluor
It is at least one.By using the fluorocarbons not undergone phase transition at a temperature of with suitable boiling point and in vivo, can vulcanize
Copper uptakie luminous energy easily reaches the phase transition temperature of fluorocarbons and it is changed into gaseous state from liquid when being translated into heat energy, production
Raw bubble can strengthen ultrasonic imaging contrast ability.It is highly preferred that the fluorocarbons is perflenapent.
It is preferred that the particle diameter ＜ 10nm of the nano-copper sulfide kernel of the hydrophobic nano copper sulfide.Because nanometer vulcanizes
Copper particle footpath ＜ 10nm, therefore can be completely exhausted out by liver and renal metabolism within the short time external, it is suppressed that it is long in vivo
Phase risk of toxicity, there is good biological safety.
On the other hand, the preparation method of the invention for also providing above-mentioned liposome base nanometer diagnosis and treatment agent comprises the following steps：
1) phosphatide, cholesterol and hydrophobic nano copper sulfide are dissolved in hydrophobic solvent, institute is removed after well mixed
Hydrophobic solvent is stated, water or the aqueous solution is added, vibration, obtains the liposome aqueous solution of parcel copper sulfide；
2) fluorocarbons is added in the liposome aqueous solution of the parcel copper sulfide of gained, homogeneous stirring, is obtained described
Liposome base nanometer diagnosis and treatment agent.
It is preferred that the preparation method of the hydrophobic nano copper sulfide includes：By the organic solvent with reproducibility, simple substance
Sulphur and Cu sources are mixed, and redox reaction is carried out at 40~100 DEG C and obtains the hydrophobic nano copper sulfide.
It is preferred that the Cu sources are at least one of acetylacetone copper, copper nitrate and copper acetate, it is described that there is reduction
Property organic solvent at least one of for oleyl amine, ethylenediamine and aniline, the elemental sulfur, the Cu sources and described have also
The ratio between mole of organic solvent of originality is (1~4)：(1~2)：(18~26).
It is preferred that in step 1), it is dissolved in by phosphatide, cholesterol and hydrophobic nano copper sulfide in hydrophobic solvent
When, it is additionally added surfactant, the ratio between the surfactant and mole of the phosphatide are (1~3)：(17~55), institute
It is F68-68, Tween-80, and/or F123 to state surfactant.
The advantages of liposome base nanometer diagnosis and treatment agent of the present invention combines organic and inorganic nano material each, preparation technology
Simply, pollution is small, reproducible, can be widely applied to the Clinics and Practices of multiple disease especially cancer, realizes diagnosis and treatment one
Body.This has extremely important meaning in clinical medicine application.
Brief description of the drawings
Fig. 1 a are the scanning transmission electron microscope photo for the liposome that fluorine carbon and copper sulfide are wrapped up while embodiment 1 is made, its
Middle illustration is high power scanning transmission electron microscope photo；
The ultraviolet-visible absorption spectroscopy of the liposome aqueous solution of fluorine carbon and copper sulfide is wrapped up while Fig. 1 b are various concentrations；
Fig. 2 is only to wrap up fluorine carbon liposome (a made from embodiment 11：Pre-irradiation, a2：After irradiation) and wrap up fluorine carbon simultaneously
With the liposome (b of copper sulfide1：Pre-irradiation, b2：After irradiation) ultrasonoscopy after near-infrared laser pre-irradiation；
Fig. 3 is the near infrared imaging picture for the liposome that fluorine carbon and copper sulfide are wrapped up while embodiment 1 is made；
Fig. 4 is the external photoacoustic imaging signal graph for the liposome that fluorine carbon and copper sulfide are wrapped up while embodiment 1 is made, its
In, optoacoustic of the liposome aqueous solution of parcel fluorine carbon and copper sulfide under 1064nm laser excitations while straight line is various concentrations
With concentration curve, the liposome aqueous solution that fluorine carbon and copper sulfide are wrapped up while illustration is various concentrations embeds signal value
Photoacoustic signal figure in agar gel；
Fig. 5 is the heating curve for the liposome that fluorine carbon and copper sulfide are wrapped up while embodiment 1 is made.Wherein, a is difference
Concentration wraps up the liposome aqueous solution of fluorine carbon and copper sulfide in 1064nm laser simultaneously, and power density is 1.41w cm-2Under effect
Ramp case, b is that to wrap up the liposome aqueous solution concentration of fluorine carbon and copper sulfide simultaneously be 50ppm in different capacity density laser
Ramp case under irradiation.
Embodiment
The present invention is further illustrated below in conjunction with accompanying drawing and following embodiments, it should be appreciated that accompanying drawing and following embodiments
The present invention is merely to illustrate, is not intended to limit the present invention.
The liposome base nanometer diagnosis and treatment agent for multi-modal imaging and photo-thermal therapy of the present invention includes machine carrier lipid
Body, organic liquid-gas phase transition medium fluorocarbons and inorganic active component copper sulfide three parts.That is, the lipid of the present invention
Body base nanometer diagnosis and treatment agent is a kind of organic mineral complex system.Wherein, using organic liposome as carrier, kernel parcel organic liquor gas
Phase change medium fluorocarbons, hydrophobic nano copper sulfide is wrapped up between liposome bilayers.Fig. 1 shows that the present invention one shows
The liposome base nanometer diagnosis and treatment agent of example, it will be seen from figure 1 that the liposome base nanometer diagnosis and treatment agent is spherical, particle diameter is 50~
120nm.Therefore, liposome base nanometer diagnosis and treatment agent of the invention is suitable for injection into human body.
In the liposome base nanometer diagnosis and treatment agent of the present invention, the mole of liposome, nano-copper sulfide and fluorocarbons it
Than that can be (60~150)：(1~2)：(6~12).By selecting the ratio of suitable each composition, can obtain suitable ultrasound/
Near-infrared heat/photoacoustic imaging intensity and photothermal deformation effect.
Liposome may include phosphatide and cholesterol, and the ratio between phosphatide and cholesterol mole can be (11~15)：1.Pass through tune
The ratio between mole of phosphatide and cholesterol is saved, the phase transition temperature of liposome can be adjusted, so as to improve the permeability of film and circulation
Property.Phosphatide in liposome can use the known phosphatide for being suitable to liposome, including but not limited to two palmityl phosphatidyl courages
Alkali, DSPC, DSPE, soybean lecithin, egg yolk lecithin, cephalin, hydrogenation
At least one of lecithin, hydrogenated soya phosphatide, phosphatidic acid, phosphatidylserine and phosphatidyl glycerol.
Fluorocarbons is liquid fluorocarbon, including but not limited to one kind in the pungent bromine of perflenapent, perflexane, perfluor or
It is a variety of.Preferably, using perflenapent.The boiling point of perflenapent is 29 DEG C, when copper sulfide absorber luminous energy is converted into heat energy, easily
Gaseous state is changed into from liquid in reaching phase transition temperature, caused bubble can strengthen ultrasonic imaging contrast ability.
Hydrophobic nano copper sulfide is the nano-copper sulfide wrapped up by hydrophobic molecule.Hydrophobic molecule therein for example may be used
For oleyl amine, ethylenediamine, aniline, nitroaniline etc., preferably oleyl amine.The particle diameter of nano-copper sulfide kernel is preferably ＜ 10nm.This
Sample can be completely exhausted out by liver and renal metabolism in a short time, suppress its internal long term toxicity, have good life
Thing security.
In addition, the surface of the liposome base nanometer diagnosis and treatment agent of the present invention can also connect has special affinity to target molecule
Part, such as monoclonal antibody, polypeptide, polysaccharide etc..Its active targeting can be so set to strengthen treatment effect to tumor locus.
The characteristics of liposome base nanometer diagnosis and treatment agent of the present invention, is：First, liposome can be enclosed with as organic carrier
Machine and inorganic active component, the biocompatibility that enhancing inorganic component is applied in vivo；Second, organic liquid-gas phase transition medium fluorine carbon
Compound can be changed into gaseous state from liquid when reaching phase transition temperature, caused bubble can strengthen ultrasonic imaging image contrast's degree；Third,
Inorganic active component nano-copper sulfide has strong optical absorption characteristic near infrared light, can strengthen near-infrared heat/photoacoustic imaging
Contrast and as a kind of excellent photo-thermal therapy agent；Fourth, the system can be achieved to surpass under the induction of Same Wavelength near infrared light
Photo-thermal therapy under sound/near-infrared heat/optoacoustic multi-modal imaging guiding, realizes diagnosis and treatment integration, substantially increases treatment effect
Rate and security.Therefore, liposome base nanometer diagnosis and treatment agent of the invention has good ultrasound/near-infrared heat/optoacoustic multi-mode
Imaging contrast ability and excellent photo-thermal therapy performance, achievable ultrasound/near-infrared heat/optoacoustic multi-mode under near infrared light induction
Photo-thermal therapy under imaging guiding.
＜ preparation methods ＞
The preparation of the liposome base nanometer diagnosis and treatment agent of the present invention can include：Step 1：Prepare hydrophobic nano copper sulfide；
Step 2：Prepare the liposome of parcel copper sulfide；And step 3：Prepare the lipid for wrapping up fluorocarbons and copper sulfide simultaneously
Body.
Hydrophobic nano copper sulfide can be by the way that the organic solvent with reproducibility, elemental sulfur and Cu sources are mixed,
Redox reaction is carried out at 40~100 DEG C and is made.Wherein, Cu sources can be in acetylacetone copper, copper nitrate and copper acetate
At least one.Organic solvent with reproducibility is at least one of oleyl amine, ethylenediamine, aniline, nitroaniline.It is also, single
The ratio between matter sulphur, Cu sources and mole of organic solvent with reproducibility can be (1~4)：(1~2)：(18~26).
In one example, the preparation of hydrophobic nano copper sulfide includes：1) at 40~100 DEG C, elemental sulfur is dissolved
In oleyl amine；2) mixed solution of chloroform and oleyl amine containing acetylacetone copper is added, is reacted 10~50 minutes at 40~100 DEG C；
3) nano-copper sulfide is obtained after cleaning, is scattered in standby in chloroform, hexamethylene equal solvent.
In one example, the preparation of hydrophobic nano copper sulfide includes：Using oleyl amine as solvent and reducing agent, at 70 DEG C
Under, add S sources (S simple substance), Cu sources (acetylacetone copper) are added after stirring and dissolving, carry out redox reaction, obtain surface
For the nano-copper sulfide nano dot (＜ 10nm) of oleyl amine parcel, the nano dot is hydrophobic.By obtained nano-copper sulfide point
It is dispersed in standby in chloroform.
Preparing the liposome of parcel copper sulfide can include：Phosphatide, cholesterol and hydrophobic nano copper sulfide are dissolved in
In hydrophobic solvent, the hydrophobic solvent is removed after well mixed, water or the aqueous solution is added, vibration, obtains wrapping up copper sulfide
Liposome aqueous solution.
In one example, by phosphatide (DPPC containing 20mg, 20mg DSPCs,
2mg DSPEs), 20mg surfactants (F68-68, Tween-80, F123 etc.), 2mg cholesterol
It is dissolved in 1mmol nano-copper sulfides in 5mL chloroforms, ultrasonic mixing is uniform；Then solvent is removed in 40 DEG C of rotary evaporations, to appearance
It is thin that device bottle wall forms one layer of green, uniform lipid.Then 5mL phosphate buffer solutions or deionized water, sonic oscillation are added
Come off to film, obtain wrapping up the liposome aqueous solution of copper sulfide.The ratio between mole of surfactant and phosphatide can be (1~3)：
(17~55).
Preparing while wrapping up fluorocarbons and the liposome of copper sulfide to include：In the fat of the parcel copper sulfide of gained
Fluorocarbons is added in the plastid aqueous solution, homogeneous stirring, obtains the liposome base nanometer diagnosis and treatment agent.
In one example, in the liposome aqueous solution of 5mL parcel copper sulfides, 1mL fluorocarbons-perfluor penta is added
Alkane, homogeneous stirring, low-speed centrifugal are layered liquid suspension, discard the larger microbubble of upper strata particle diameter, remove a layer light green color emulsion,
Cleaning 3-4 times, then by 0.22 μm of film, removes big aggregate.Finally it is resuspended and is wrapped up fluorine carbon and copper sulfide simultaneously
Liposome.
The liposome base nanometer diagnosis and treatment agent of the present invention has good disperse in physiological saline and phosphate buffer solution
Property, it is placed in 4 DEG C of environment, can stablizes and be kept for more than 3 months.
Embodiment is enumerated further below to describe the present invention in detail.It will similarly be understood that following examples are served only for this
Invention is further described, it is impossible to is interpreted as limiting the scope of the invention, those skilled in the art is according to this hair
Some nonessential modifications and adaptations that bright the above is made belong to protection scope of the present invention.Following examples are specific
Technological parameter etc. is also only an example in OK range, i.e. those skilled in the art can be done properly by this paper explanation
In the range of select, and do not really want to be defined in the concrete numerical value of hereafter example.
Embodiment
Main agents：DPPC (DPPC), DSPC (DSPC), distearyl phosphorus
Acyl monoethanolamine (DSPE-PEG2000-NH2), surfactant (F68-68), cholesterol, perflenapent and chloroform etc..
First, hydrophobic nano copper sulfide is prepared
64mg S simple substance is dissolved in 12mL oleyl amines, it is completely molten to S simple substance to be placed in magnetic agitation 30min in 70 DEG C of water-baths
Solution is in oleyl amine；
The mixed solution of the 20mL chloroforms for the acetylacetone copper containing 523.5mg being pre-mixed and 5mL oleyl amines is added again
Into above-mentioned solution, keep continuing to stir 30min at a temperature of this, solution colour is changed into blackish green from brown color；
Centrifuge, and use washes of absolute alcohol 2-3 times, most product is dispersed in 40mL chloroforms at last.
2nd, the liposome of parcel copper sulfide is prepared
By phosphatide (DPPC containing 20mg, 20mg DSPCs, 2mg distearyl phosphorus
Acyl monoethanolamine), 20mg surfactants (F68-68), 2mg cholesterol and 1mmol nano-copper sulfides be dissolved in 5mL chlorine
In imitative, ultrasonic mixing is uniform；
Then solvent is removed in 40 DEG C of rotary evaporation 1h, it is thin to form one layer of green, uniform lipid to container bottle wall；
5mL phosphate buffer solutions or deionized water are added, sonic oscillation to film comes off, and obtains wrapping up the fat of copper sulfide
The plastid aqueous solution.
3rd, the liposome for wrapping up fluorocarbons and copper sulfide simultaneously is prepared
In the liposome aqueous solution of 5mL parcel copper sulfides, 1mL fluorocarbons-perflenapent, homogeneous stirring are added；
Then low-speed centrifugal is layered liquid suspension, discards the larger microbubble of upper strata particle diameter, removes a layer light green color emulsion,
Cleaning 3-4 times；
Finally by 0.22 μm of film, big aggregate is removed, the liposome for being wrapped up fluorine carbon and copper sulfide simultaneously is resuspended.
Fig. 1 a are the scanning transmission electron microscope photo of liposome manufactured in the present embodiment while wrapping up fluorine carbon and copper sulfide, are schemed
In wrap up fluorine carbon and the liposomal dispersion of copper sulfide is good simultaneously, be single dispersing structure, particle diameter is about 50-120nm, copper sulfide
Entered with fluorine carbon by successfully parcel in liposome.
Fig. 1 b are the ultraviolet-visible absorption spectroscopy figure of liposome manufactured in the present embodiment while wrapping up fluorine carbon and copper sulfide,
Wrap up fluorine carbon and the liposome of copper sulfide has strong optical absorption characteristic near infrared light region simultaneously in figure, and maximum absorption band is
λ=1064nm.
Fig. 2 is the liposome (a of manufactured in the present embodiment parcel fluorine carbon1：Pre-irradiation, a2：After irradiation) and wrap up fluorine simultaneously
Liposome (the b of carbon and copper sulfide1：Pre-irradiation, b2：After irradiation) ultrasonic picture after near-infrared laser pre-irradiation.Described in figure
Only the liposome of parcel fluorine carbon bubble-free under laser irradiation produces, and strengthens ability without ultrasonic contrast.And fluorine carbon is wrapped up simultaneously
Bubble is generated under laser irradiation with the liposome of copper sulfide, has ultrasonic contrast to strengthen ability.
Wrapped up while Fig. 3 is various concentrations manufactured in the present embodiment the near-infrared heat of fluorine carbon and the liposome of copper sulfide into
As picture.The liposome for wrapping up fluorine carbon and copper sulfide described in figure simultaneously has enhancing near infrared light thermal imaging contrast ability, carries
High image sensitivity and speed.
Wrapped up while Fig. 4 is various concentrations manufactured in the present embodiment the external optoacoustic of fluorine carbon and the liposome of copper sulfide into
As signal graph.Fluorine carbon is wrapped up while figure cathetus is various concentrations and the liposome aqueous solution of copper sulfide swashs in 1064nm laser
The photoacoustic signal value given is with concentration curve, the liposome of parcel fluorine carbon and copper sulfide while illustration is various concentrations
The aqueous solution is embedded in the photoacoustic signal figure in agar gel.As can be seen from Figure 4, as concentration increases, photoacoustic signal value is linearly increasing,
The photoacoustic signal brightness increase of agar gel.
The liposome of fluorine carbon and copper sulfide is wrapped up while Fig. 5 is various concentrations manufactured in the present embodiment, in rated power
(power density is 1.41W cm to density laser-2, a) and (50ppm, b) is determined under concentration under the irradiation of different capacity density laser
Heating curve.The liposome aqueous solution of fluorine carbon and copper sulfide is wrapped up described in figure simultaneously as concentration and power density increase, on
The temperature increase risen.
In summary, liposome that is provided by the invention while wrapping up fluorine carbon and copper sulfide has good stability and life
Thing security, the shortcomings that overcoming organic and inorganic nano diagnosis and treatment agent each.Because copper sulfide has strong light absorbs and photo-thermal
Conversion capability, near-infrared heat/photoacoustic imaging contrast agent and photo-thermal therapy agent can be used as simultaneously.In addition, fluorocarbons is heated
Bubble can be produced when reaching phase transition temperature, ultrasonic contrast ability can be strengthened.Therefore provided by the present invention for multi-modal imaging
With a kind of liposome base nanometer diagnosis and treatment agent of photo-thermal therapy, its preparation method is simple, pollution-free, weight is reproducible, is imaged and controls
Excellent performance is treated, is expected to research of being used widely in clinic.
Claims (7)
1. a kind of liposome base nanometer diagnosis and treatment agent for multi-modal imaging and photo-thermal therapy, it is characterised in that include airborne
Body fat plastid, the hydrophobic nano copper sulfide being wrapped between the bilayer of the liposome and it is wrapped in the liposome
Organic liquid-gas phase transition medium fluorocarbons in kernel, the fluorocarbons are liquid fluorocarbon, including perflenapent and complete
At least one of fluorine hexane；The liposome includes phosphatide and cholesterol, and wherein the ratio between mole of phosphatide and cholesterol is
（11~15）：1；In the liposome base nanometer diagnosis and treatment agent, the mole of liposome, nano-copper sulfide and fluorocarbons it
Than for（60~150）：（1~2）：（6~12）.
2. liposome base nanometer diagnosis and treatment agent according to claim 1, it is characterised in that the liposome base nanometer diagnosis and treatment agent
Particle diameter be 50~120 nm.
3. liposome base nanometer diagnosis and treatment agent according to claim 1 or 2, it is characterised in that the hydrophobic nano vulcanization
The nm of particle diameter ＜ 10 of the nano-copper sulfide kernel of copper.
A kind of 4. preparation method of the liposome base nanometer diagnosis and treatment agent any one of claims 1 to 3, it is characterised in that
Comprise the following steps：
1) phosphatide, cholesterol and hydrophobic nano copper sulfide are dissolved in hydrophobic solvent, described dredge is removed after well mixed
Aqueous solvent, water or the aqueous solution are added, vibration, obtains the liposome aqueous solution of parcel copper sulfide；
2) fluorocarbons is added in the liposome aqueous solution of the parcel copper sulfide of gained, homogeneous stirring, obtains the lipid
Body base nanometer diagnosis and treatment agent.
5. preparation method according to claim 4, it is characterised in that the preparation method bag of the hydrophobic nano copper sulfide
Include：Organic solvent with reproducibility, elemental sulfur and Cu sources are mixed, redox reaction is carried out at 40~100 DEG C and is obtained
To the hydrophobic nano copper sulfide.
6. preparation method according to claim 5, it is characterised in that the Cu sources are acetylacetone copper, copper nitrate and vinegar
At least one of sour copper, the organic solvent with reproducibility be oleyl amine, ethylenediamine, aniline, in nitroaniline at least
The ratio between one kind, the elemental sulfur, the Cu sources and the mole of organic solvent with reproducibility is（1~4）：（1~
2）：（18~26）.
7. the preparation method according to any one of claim 4 to 6, it is characterised in that in step 1), by phosphatide,
When cholesterol and hydrophobic nano copper sulfide are dissolved in hydrophobic solvent, surfactant, the surfactant are additionally added
It is with the ratio between the mole of the phosphatide（1~3）：（17~55）, the surfactant be F68-68, Tween-80,
And/or F123.
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| CN106729774A (en) * | 2016-11-03 | 2017-05-31 | 重庆医科大学 | Load tanshinone inversion of phases nanometer acoustic contrast agent of enoxolone modification and preparation method thereof |
| CN108014349B (en) * | 2017-12-28 | 2021-04-16 | 重庆医科大学附属第二医院 | Preparation method and application of gene-loaded multifunctional contrast agent |
| CN109078000A (en) * | 2018-09-17 | 2018-12-25 | 河南中医药大学 | The preparation method and application of active targeting thermal sensitive liposome based on nano-copper sulfide |
| CN111643677B (en) * | 2020-05-26 | 2023-06-27 | 四川省肿瘤医院 | Nanometer liposome for encapsulating TLR4/MyD88 signal pathway antagonist and preparation method and application thereof |
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| Ultrasmall Cu2−xS Nanodots for Highly Efficient Photoacoustic Imaging-Guided Photothermal Therapy;Juan Mou et al.;《small》;20150116;第11卷(第19期);第2275-2283页 * |
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