CN105920625A - Preparation method of diagnosis and treatment preparation integrating ultrasound contrast and thermal therapy - Google Patents
Preparation method of diagnosis and treatment preparation integrating ultrasound contrast and thermal therapy Download PDFInfo
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- CN105920625A CN105920625A CN201610246252.1A CN201610246252A CN105920625A CN 105920625 A CN105920625 A CN 105920625A CN 201610246252 A CN201610246252 A CN 201610246252A CN 105920625 A CN105920625 A CN 105920625A
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- indocyanine green
- menthol
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- 238000003745 diagnosis Methods 0.000 title claims abstract description 31
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- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 claims abstract description 41
- 239000002105 nanoparticle Substances 0.000 claims abstract description 38
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- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
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- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical class FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
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- 229930003658 monoterpene Natural products 0.000 description 1
- -1 monoterpenoid compounds Chemical class 0.000 description 1
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- 208000004296 neuralgia Diseases 0.000 description 1
- 150000001282 organosilanes Chemical class 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229960004692 perflenapent Drugs 0.000 description 1
- 229960004624 perflexane Drugs 0.000 description 1
- ZJIJAJXFLBMLCK-UHFFFAOYSA-N perfluorohexane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F ZJIJAJXFLBMLCK-UHFFFAOYSA-N 0.000 description 1
- NJCBUSHGCBERSK-UHFFFAOYSA-N perfluoropentane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F NJCBUSHGCBERSK-UHFFFAOYSA-N 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
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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
- A61K49/221—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by the targeting agent or modifying agent linked to the acoustically-active agent
-
- 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
-
- 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
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
-
- 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
- A61K9/5115—Inorganic compounds
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physics & Mathematics (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Acoustics & Sound (AREA)
- Radiology & Medical Imaging (AREA)
- Biomedical Technology (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Inorganic Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a preparation method of a diagnosis and treatment preparation integrating ultrasound contrast and thermal therapy. The preparation method comprises the following steps: (1) dissolving 1-50 mg of organic-inorganic complex lipid and 0.1-10 mg of polyethylene glycol into 0.1-1 mL of absolute ethyl alcohol; (2) dissolving 1-25 mg of menthol into 1-20 mL of ultrapure water, carrying out water-bath heating till the temperature reaches 45 DEG C, mixing the obtained solution with 1-10 mL of an aqueous solution of indocyanine green; (3) rapidly injecting the ethanol solution of the organic-inorganic complex lipid and polyethylene glycol obtained in the step (1) into the mixed solution obtained in the step (2) under the water bath and ultrasonic wave conditions; and (4) carrying out probe ultrasound treatment, thus obtaining organic-inorganic complex lipid nano-particles, wherein the inner cavities of the organic-inorganic complex lipid nano-particles are loaded with the indocyanine green and menthol and the surfaces of the organic-inorganic complex lipid nano-particles are covered by inorganic silicate shells being in nanoscale thickness and having good biocompatibility. The complex lipid diagnosis and treatment preparation provided by the invention can realize the photothermal therapy on tumor tissues under the ultrasound visual observation, the stability is good, no obvious toxic and side effects are caused to the human body, in addition, the preparation method is simple, and the requirements on devices are low.
Description
Technical field
The present invention relates to field of biomedical materials, be specifically related to a kind of preparation method integrating ultrasonic contrast and the diagnosis and treatment preparation of thermotherapy.
Background technology
Cancer is that one has height heterogeneity and extremely strong adaptive disease, needs the progress of the feature according to patient and disease to select different types of diagnosis and therapeutic scheme.The nanometer diagnosis and treatment preparation of Clinics and Practices function integration is gradually risen by one class at therapeutic field of tumor.It is combined nanometer formulation during diagnosis and treatment and the diagnoses and treatment scheme of various personalization can be provided for patient, thus improve therapeutic effect.Therefore, research and development novel multifunctional nano diagnosis and treatment preparation has great importance, and ultra sonic imaging is the most wide variety of current diagnostic method.
Acoustic contrast agent is the diagnostic preparation that a class can be obviously enhanced ultrasound detection signal, and its main component is microbubble.Acoustic contrast agent can strengthen backscatter signals, thus is greatly improved ultrasonic diagnosis effect.At present, domestic acoustic contrast agent Shi Sheng Novi (SonoVue) used clinically, it is the microvesicle formed by phospholipid parcel SF6 gas, and particle diameter is 2～8 m.Although the micron order acoustic contrast agent with SonoVue as representative, obtain successfully application to varying degrees, but yet suffer from many problems: be on the one hand that particle diameter is big, therefore it is limited only to blood pool development, is difficult to realize the Clinics and Practices of disease outer to its blood vessel；On the other hand it is that sound Novi is lipid due to coated fertilizer, and lipid in nature is not sufficiently stable, and the persistent period falls short of in vivo, and the radiography persistent period is short, so the molecular imaging that microbubble contrast agent to be utilized realizes tumor there is also certain difficulty.Therefore, find miniaturization, acoustic contrast that penetration power is strong becomes as the important research direction in ultrasonic image field, also become clinical diagnosis and disease treatment in the urgent need to.Nanoscale ultrasound contrast agents, than commercial microbubble contrast agent about little ten times, has the potentiality of diagnosis outside blood vessel.Its particle diameter is little, can pass through blood vessel endothelium system, it is achieved develop outside blood vessel.Although nano level acoustic contrast agent can realize developing outside blood vessel, but is simply possible to use in the early diagnosis of cancer.
At present, studying more liquid fluorocarbon class ultrasonic contrast, such as perflexane, perflenapent, perfluorinated butane etc., liquid core classes contrast agent is mainly logical is that the mode of overbunching realizes ultrasonic development and strengthens, but this mode can not reach preferable ultrasonic development effect.Therefore, researcher develops a kind of Solid core class contrast agent menthol.Menthol is that a kind of energy produces the natural ring monoterpenoid compounds that typical case is mint flavored, with free and the state existence of ester, also referred to as Mentholum.Have antipruritic, pain relieving, anticorrosion, stimulate, anaesthetize, the pharmacy application such as refrigerant, antiinflammatory and antibacterial, can be used for treating headache, neuralgia, pruritus and respiratory inflammation, atrophic rhinitis, celostomia etc..It is commonly used for the additive of medicated cigarette, toothpaste, perfume, beverage and confection.The strong volatility of menthol is extremely strong, can produce menthol gas microbubbles in its natural state, plays the effect strengthening ultrasonic contrast.By experimental results demonstrate, the acoustic contrast agent with menthol as core is good with the performance of its slow release, and bag load rate is high, the feature of ultrasonic effective and ultrasonic persistent period length and be expected to become clinical ultrasound contrast agent of future generation.After selection fusing point is relatively low, and the most a large amount of solid state class acoustic contrast agents producing gaseous microbubble that volatilize are by being injected intravenously body in the liquid state, tumor tissues ultrasonic development can be realized.
In recent years, photo-thermal therapy (Photothermal
Therapy) as a kind of method that oncotherapy is emerging, because having the advantages such as location treatment, Micro trauma, the study hotspot in this field it has been increasingly becoming.Photo-thermal therapy depends on photothermal deformation agent can be converted to heat energy by near infrared light (NIR), utilizes normal structure and the tumor cell difference to temperature tolerance, reaches to make apoptosis of tumor cells, does not the most damage the therapeutic purposes of normal structure.Photo-thermal therapy has become the another new therapy after operation, radiotherapy, chemotherapy and immunotherapy, is a kind of new effective means for the treatment of tumor.At present, common photothermal deformation agent includes the materials such as gold nanorods, nanometer gold shell, indocyanine green, polypyrrole, Graphene, CNT, wherein indocyanine green be unique a kind of by U.S. food Drug Administration (FDA) ratify for physianthropy imaging and the reagent of diagnosis, the advantages such as the photothermal deformation usefulness of its brilliance and good safety, are applied to biomedical diagnostic and treatment field by people are widely studied.But, free indocyanine green is assembled the most rapidly in polar solvent, less stable, and it is easily quickly removed in blood plasma, and circulation time is short in vivo, and these defects greatly limit the application of indocyanine green.
Summary of the invention
Present invention aims to above-mentioned existing problems and deficiency, it is provided that a kind of bag carries indocyanine green and menthol, and the preparation method integrating ultrasonic contrast and the organo-mineral complexing lipid diagnosis and treatment preparation of thermotherapy of good stability.
The technical scheme is that and be achieved in that:
The preparation method integrating ultrasonic contrast and the diagnosis and treatment preparation of thermotherapy of the present invention, is characterized in comprising the following steps:
1) 1-50mg organo-mineral complexing lipid and 0.1-10mg Polyethylene Glycol are dissolved in 0.1-1mL dehydrated alcohol；
2) 1-25mg menthol is dissolved in 1-20mL ultra-pure water, heating in water bath to 45 DEG C, then with the aqueous solution of 1-10mL indocyanine green；
3) ethanol solution of the organo-mineral complexing lipid obtained in step 1) and Polyethylene Glycol is rapidly injected step 2 under conditions of water bath sonicator) in the mixed liquor that obtains；
4), after Probe Ultrasonic Searching, obtain inner chamber bag and be loaded with indocyanine green and menthol and surface is coated with the organo-mineral complexing lipidic nanoparticles of inorganic silicate shell of nanometer grade thickness and good biocompatibility.
Wherein, described step 1) in the structure of an organic inorganic compounding lipid both can be:
；
Can also be:
。
The novel lipid molecule that an organic inorganic compounding lipid is made up of molecule two hydrophobic carbon chain of connection and a hydrophilic organosilane molecules, this molecule can form lipoid plastid by sol-gel and self assembling process in water, thus realize bag in the inner chamber of lipoid plastid and be loaded with menthol droplet and indocyanine green solution, the inorganic silicate shell of the good biocompatibility of nanometer grade thickness it is coated with on its surface.
Ultrasonic time in described step 4) is 0.5-5min, and ultrasonic power is 30W, and work 3s stops 3s.
The present invention compared with prior art, has the effect that
(1) the complex lipid diagnosis and treatment preparation of the present invention can not only reach tumor locus and angiography, and while radiography, tumor by local can be heated, reach thermotherapy and kill the effect of tumor cell and tissue, thus realize under ultrasonic visualization is observed, tumor tissues being carried out the purpose of photo-thermal therapy；
(2) contrasting effects of the complex lipid diagnosis and treatment preparation of the present invention is the longest, owing to nano grain surface is coated with the inorganic silicate shell of nanometer grade thickness, so compared with traditional lipid ultrasonic contrast agent, siloxane network significantly increases the stability of complex lipid, owing to menthol has solid-liquid-vapour three phase in version, therefore gas microbubbles can continuously be produced in the way of gentle and unconventional fierce phase in version, thus extend complex lipid diagnosis and treatment preparation blood circulation time in vivo, provide the more time for diagnosis；
(3) the complex lipid diagnosis and treatment preparation of the present invention has excellent biocompatibility and degradability, and raw materials used indocyanine green, menthol etc. are to human body all without obvious toxic-side effects, and preparation method is simple, and equipment requirements is relatively low.
The present invention is further illustrated below in conjunction with the accompanying drawings.
Accompanying drawing explanation
Fig. 1 is the structural representation of diagnosis and treatment preparation of the present invention.
Fig. 2 is the dynamic light scattering grain size distribution of diagnosis and treatment preparation of the present invention.
Fig. 3 is the transmission electron micrograph of diagnosis and treatment preparation of the present invention.
Fig. 4 is the stability result detection figure in diagnosis and treatment preparation 24h of the present invention.
Fig. 5 is the shading value schematic diagram that diagnosis and treatment preparation of the present invention is measured in UV, visible light spectrophotometer with free indocyanine green.
Fig. 6 is the photothermal conversion experimental result schematic diagram of diagnosis and treatment preparation of the present invention.
Fig. 7 is the diagnosis and treatment preparation of the present invention external supersonic imaging picture after 808nm laser irradiates 5min.
Fig. 8 is the external continual ultrasonic imaging picture of diagnosis and treatment preparation of the present invention.
Detailed description of the invention
Embodiment 1:
Weigh 1mg organo-mineral complexing lipid and 0.1mg Polyethylene Glycol (DSPE-PEG2000) injects in 0.1mL dehydrated alcohol and disperses.Take 1mg menthol powder and join in the serum bottle filling 1mL ultra-pure water, heating in water bath to 45 DEG C, then add the aqueous solution that 1mL concentration is 1mg/mL indocyanine green.Under the conditions of water bath sonicator, the ethanol solution of organo-mineral complexing lipid obtained above and Polyethylene Glycol is rapidly injected in the mixed liquor of indocyanine green, Herba Menthae alcohol and water, obtains pre-emulsion.The Probe Ultrasonic Searching 0.5min(of pre-emulsion ultrasonic cell disintegration instrument is arranged ultrasonic power is 30w, and work 3s, stops 3s) after, obtain bag and carry indocyanine green and the silicone grease matter nanoemulsions of menthol.Finally dialysis removes free indocyanine green, obtains inner chamber bag and is loaded with indocyanine green and menthol and surface is coated with the organo-mineral complexing lipidic nanoparticles of inorganic silicate shell of nanometer grade thickness and good biocompatibility.The structure of this complex lipid nano-particle is as shown in Figure 1.
Embodiment 2:
Weigh 50mg organo-mineral complexing lipid and 10mg Polyethylene Glycol (DSPE-PEG2000) injects in 1mL dehydrated alcohol and disperses.Take 25mg menthol powder and join in the serum bottle filling 20mL ultra-pure water, heating in water bath to 45 DEG C, then add the aqueous solution that 10mL concentration is 1mg/mL indocyanine green.Under the conditions of water bath sonicator, the ethanol solution of organo-mineral complexing lipid obtained above and Polyethylene Glycol is rapidly injected in the mixed liquor of indocyanine green, Herba Menthae alcohol and water, obtains pre-emulsion.The Probe Ultrasonic Searching 5min(of pre-emulsion ultrasonic cell disintegration instrument is arranged ultrasonic power is 30w, and work 3s, stops 3s) after, obtain bag and carry indocyanine green and the silicone grease matter nanoemulsions of menthol.Finally dialysis removes free indocyanine green, obtains inner chamber bag and is loaded with indocyanine green and menthol and surface is coated with the organo-mineral complexing lipidic nanoparticles of inorganic silicate shell of nanometer grade thickness and good biocompatibility.The structure of this complex lipid nano-particle is as shown in Figure 1.
Embodiment 3:
Weigh 25mg organo-mineral complexing lipid and 5mg Polyethylene Glycol (DSPE-PEG2000) injects in 5mL dehydrated alcohol and disperses.Take 12mg menthol powder and join in the serum bottle filling 10mL ultra-pure water, heating in water bath to 45 DEG C, then add the aqueous solution that 5mL concentration is 1mg/mL indocyanine green.Under the conditions of water bath sonicator, the ethanol solution of organo-mineral complexing lipid obtained above and Polyethylene Glycol is rapidly injected in the mixed liquor of indocyanine green, Herba Menthae alcohol and water, obtains pre-emulsion.The Probe Ultrasonic Searching 2min(of pre-emulsion ultrasonic cell disintegration instrument is arranged ultrasonic power is 30w, and work 3s, stops 3s) after, obtain bag and carry indocyanine green and the silicone grease matter nanoemulsions of menthol.Finally dialysis removes free indocyanine green, obtains inner chamber bag and is loaded with indocyanine green and menthol and surface is coated with the organo-mineral complexing lipidic nanoparticles of inorganic silicate shell of nanometer grade thickness and good biocompatibility.The structure of this complex lipid nano-particle is as shown in Figure 1.
Embodiment 4:
Weigh 5mg organo-mineral complexing lipid and 0.5mg Polyethylene Glycol (DSPE-PEG2000) injects in 0.5mL dehydrated alcohol and disperses.Take 25mg menthol powder and join in the serum bottle filling 4mL ultra-pure water, heating in water bath to 45 DEG C, then add the aqueous solution that 1mL concentration is 1mg/mL indocyanine green.Under the conditions of water bath sonicator, the ethanol solution of organo-mineral complexing lipid obtained above and Polyethylene Glycol is rapidly injected in the mixed liquor of indocyanine green, Herba Menthae alcohol and water, obtains pre-emulsion.The Probe Ultrasonic Searching 0.5min(of pre-emulsion ultrasonic cell disintegration instrument is arranged ultrasonic power is 30w, and work 3s, stops 3s) after, obtain bag and carry indocyanine green and the silicone grease matter nanoemulsions of menthol.Finally dialysis removes free indocyanine green, obtains inner chamber bag and is loaded with indocyanine green and menthol and surface is coated with the organo-mineral complexing lipidic nanoparticles of inorganic silicate shell of nanometer grade thickness and good biocompatibility.The structure of this complex lipid nano-particle is as shown in Figure 1.
The particle diameter using Malvern (Malvern) laser particle analyzer and zeta potential instrument to measure the complex lipid nano-particle obtained in above-described embodiment is 197.4 ± 6.9nm, current potential is 12.5 ± 1.8mV, and obtains dynamic light scattering histogram of particle size distribution as shown in Figure 2.As seen from Figure 2, the nanometer particle size distribution of the complex lipid nano-particle that melted alcohol injection prepares is narrower, and at about 200nm, transmission electron microscope photo is as shown in Figure 3.The nano-particle of this small particle can penetrate tumor vessel wall and arrive inside tumor tissues, is expected to realize ultrasonic contrast imaging at tumor locus.
The vitro stability of organo-mineral complexing lipidic nanoparticles is tested:
The organo-mineral complexing lipidic nanoparticles prepared in above-described embodiment is dispersed in respectively the phosphate buffer of PH=7.4 and containing in the phosphate buffer of 10% hyclone, it is placed in 24h on the shaking table of 37 DEG C, measuring its change of size every 1h laser particle analyzer, result is as shown in Figure 4.As can be seen from the figure this nano-particle is under conditions of simulation human internal environment, and particle diameter does not has significant change, and having good stability of nano-particle is described, is expected to reach in vivo to circulate for a long time.
The UV, visible light spectrophotometric value of organo-mineral complexing lipidic nanoparticles is measured:
The organo-mineral complexing lipidic nanoparticles prepared in above-described embodiment is formulated as 4 μ g/mL according to the concentration of indocyanine green, and measures its OD value.As comparison, free indocyanine green is also configured to identical concentration and measures its OD value.As it is shown in figure 5, material concentration only 22 μ g/mL(indocyanine green concentration is 4 μ g/mL) time, this complex lipid nano-particle is to have obvious absworption peak near 808nm at wavelength.The OD value of the indocyanine green that corresponding comparable sodium unentrapped enters nano-particle is roughly equal.It can be seen that this complex lipid nano-particle is to have obvious absorbance value under 808nm laser irradiates at wavelength, it is expected to the light of absorption is converted into heat.
The photothermal conversion efficiency of organo-mineral complexing lipidic nanoparticles is measured:
The organo-mineral complexing lipidic nanoparticles of preparation in above-described embodiment is used to carry out photothermal conversion experiment, as shown in Figure 6, the indocyanine green solution that concentration is different is set, take above-mentioned solution 2mL respectively to be placed in quartz colorimetric utensil, wrapping up in lucifuge paper bag outside cuvette, taking an area on lucifuge paper is 1cm2Loophole, use wavelength is 808nm, power be 2w laser device irradiate, irradiation distance is 5cm, and irradiated area is 1cm2, irradiation time is 15min.As shown in Figure 6, each circulation is 30min, and front 15min uses laser to irradiate, and laser device is closed by rear 15min, records a temperature value every 30s, obtains curve as shown in Figure 6.It can be seen that this nano-particle still has higher photothermal conversion efficiency when relatively low concentration, as concentration only 50 μ g/mL, nanoparticles solution temperature can reach more than 65 DEG C, can realize thermotherapy and kill the effect of tumor tissues.
To the external supersonic imaging experiment of organo-mineral complexing lipidic nanoparticles under different frequency:
Taking the organo-mineral complexing lipidic nanoparticles 1mL prepared in above-described embodiment and join in the dropper filling 3mL de aerated water, same use wavelength is 808nm, and power is that the laser of 2w carries out irradiation, and exposure time is 5min, irradiation distance 5cm.Irradiation is placed in the tank that temperature is 37 DEG C, with Doppler Sonography diagnostic apparatus high frequency probe, and mechanical index (MI=0.4),
Depth=3.0cm.Scanning preserve picture under frequency is f=3.5Hz, 6.5Hz and 8.0Hz respectively, using the normal saline of equivalent as comparison, compares the difference of complex lipid nano-particle ultrasonic development under different frequency, and result is as shown in Figure 7.There it can be seen that this complex lipid nano-particle the most all has obvious contrasting effects, under high frequency probe, contrasting effects is more preferably.The menthol that this explanation complex lipid nano-particle after laser irradiation is wrapped up is become liquid by solid, then liquid volatilizees again and becomes substantial amounts of gas microbubbles, make this nano-particle achieve the transformation of " solid-liquid-gas " three-phase, and then realize more preferable radiography function.The acoustic contrast agent of this three-phase transformation type had both solved the oversize of ultrasound microbubble contrast agent, the shortcoming that can only carry out blood pool Trace imaging, had accomplished again the imaging results of microcapsular ultrasound contrast agent.
The external supersonic of organo-mineral complexing lipidic nanoparticles is persistently imaged test:
Persistently image experiment according to the method operating body outer ultrasonic of the external supersonic imaging experiment of organo-mineral complexing lipidic nanoparticles under different frequency, and record the ultrasonoscopy image of different time under f=8.0Hz, as shown in Figure 8.It can be seen that this complex lipid nano-particle has the lasting development effect up to 25min, this explanation contrast agent with an organic inorganic compounding lipid as sheathing material, ultrasonic sound field has superior stability and higher resistance to acoustic pressure.
The present invention is photothermal conversion character based on indocyanine green, and under the irradiation that wavelength is 808nm infrared light, the indocyanine green temperature of complex lipid intracoelomic cavity raises, and can kill tumor cell and tissue.But, this difficult problem very fast of its afunction is made owing to there is the strong volatility of menthol.Therefore, the present invention has synthesized organic-inorganic compound lipid and wraps load, storage and change based on temperature and carry out slow release and put menthol.The menthol of organic-inorganic compound lipid internal package is heated and can carry out solid-liquid-gas three phase circulation transformation, produces gas microbubbles and can be used for ultrasonic contrast, thus reaches the effect of ultrasonic contrast and photo-thermal therapy.
The present invention the most controlled this diagnoses and treatment preparation is expected to, as sensitive temperature response multifunctional carrier, to be realized the photo-thermal therapy under ultra sonic imaging is monitored by intravenous injection, have extremely vast potential for future development in ultrasonic clinical practice.
The present invention is described by embodiment, but do not limit the invention, with reference to description of the invention, other changes of the disclosed embodiments, as the professional person for this area is readily apparent that, such change should belong within the scope of the claims in the present invention restriction.
Claims (4)
1. the preparation method integrating ultrasonic contrast and the diagnosis and treatment preparation of thermotherapy, it is characterised in that comprise the following steps:
1) 1-50mg organo-mineral complexing lipid and 0.1-10mg Polyethylene Glycol are dissolved in 0.1-1mL dehydrated alcohol；
2) 1-25mg menthol is dissolved in 1-20mL ultra-pure water, heating in water bath to 45 DEG C, then with the aqueous solution of 1-10mL indocyanine green；
3) ethanol solution of the organo-mineral complexing lipid obtained in step 1) and Polyethylene Glycol is rapidly injected step 2 under conditions of water bath sonicator) in the mixed liquor that obtains；
4), after Probe Ultrasonic Searching, obtain inner chamber bag and be loaded with indocyanine green and menthol and surface is coated with the organo-mineral complexing lipidic nanoparticles of inorganic silicate shell of nanometer grade thickness and good biocompatibility.
The preparation method of the diagnosis and treatment preparation integrating ultrasonic contrast and thermotherapy the most according to claim 1, it is characterised in that: described step 1) in the structure of an organic inorganic compounding lipid be:
。
The preparation method of the diagnosis and treatment preparation integrating ultrasonic contrast and thermotherapy the most according to claim 1, it is characterised in that: described step 1) in the structure of an organic inorganic compounding lipid be:
。
The preparation method integrating ultrasonic contrast and the diagnosis and treatment preparation of thermotherapy the most according to claim 1, it is characterised in that: the ultrasonic time in described step 4) is 0.5-5min, and ultrasonic power is 30W, and work 3s stops 3s.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107496918A (en) * | 2017-08-02 | 2017-12-22 | 中山大学附属第医院 | A kind of composite Nano diagnosis and treatment preparation and preparation method thereof |
| CN109054013A (en) * | 2018-08-22 | 2018-12-21 | 东北大学 | A kind of modified indocyanine green and preparation method thereof |
| CN109602907A (en) * | 2019-01-18 | 2019-04-12 | 北京大学 | A kind of silica nodule nanoparticle pharmaceutical carrier and its diagnoses and treatment preparation and preparation method |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103480008A (en) * | 2013-09-11 | 2014-01-01 | 中山大学 | Thermal enhancement type organic-inorganic compound lipid nanometer liquid state fluorocarbon ultrasonic contrast agent and preparation method thereof |
| CN103690486A (en) * | 2013-12-27 | 2014-04-02 | 深圳先进技术研究院 | Indocyanine green nano-targeted liposome and preparation method and application thereof |
| CN104474559A (en) * | 2014-12-01 | 2015-04-01 | 中国科学院上海硅酸盐研究所 | Hollow mesoporous prussian blue nano photo-thermal diagnosis and treatment agent with ultrasound contrast function and preparation method of hollow mesoporous prussian blue nano photo-thermal diagnosis and treatment agent |
| CN104826140A (en) * | 2015-04-08 | 2015-08-12 | 中山大学 | Drug-loaded silicone grease ultrasonic contrast agent and its preparation method and use |
-
2016
- 2016-04-19 CN CN201610246252.1A patent/CN105920625B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103480008A (en) * | 2013-09-11 | 2014-01-01 | 中山大学 | Thermal enhancement type organic-inorganic compound lipid nanometer liquid state fluorocarbon ultrasonic contrast agent and preparation method thereof |
| CN103690486A (en) * | 2013-12-27 | 2014-04-02 | 深圳先进技术研究院 | Indocyanine green nano-targeted liposome and preparation method and application thereof |
| CN104474559A (en) * | 2014-12-01 | 2015-04-01 | 中国科学院上海硅酸盐研究所 | Hollow mesoporous prussian blue nano photo-thermal diagnosis and treatment agent with ultrasound contrast function and preparation method of hollow mesoporous prussian blue nano photo-thermal diagnosis and treatment agent |
| CN104826140A (en) * | 2015-04-08 | 2015-08-12 | 中山大学 | Drug-loaded silicone grease ultrasonic contrast agent and its preparation method and use |
Non-Patent Citations (1)
| Title |
|---|
| 张鉴等: "《中药制剂技术与设备》", 30 September 2009, 山东友谊出版社 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107496918A (en) * | 2017-08-02 | 2017-12-22 | 中山大学附属第医院 | A kind of composite Nano diagnosis and treatment preparation and preparation method thereof |
| CN107496918B (en) * | 2017-08-02 | 2020-09-04 | 中山大学附属第一医院 | Composite nano diagnosis and treatment preparation and preparation method thereof |
| CN109054013A (en) * | 2018-08-22 | 2018-12-21 | 东北大学 | A kind of modified indocyanine green and preparation method thereof |
| CN109602907A (en) * | 2019-01-18 | 2019-04-12 | 北京大学 | A kind of silica nodule nanoparticle pharmaceutical carrier and its diagnoses and treatment preparation and preparation method |
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