CN107982535A - A kind of targeting microwave controlled release medicament-carrying nano-microsphere and its preparation method and application - Google Patents
A kind of targeting microwave controlled release medicament-carrying nano-microsphere and its preparation method and application Download PDFInfo
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Abstract
The present invention discloses a kind of targeting microwave controlled release medicament-carrying nano-microsphere and its preparation method and application, the medicament-carrying nano-microsphere framework material is mixture of phospholipids, skeleton surface modification fucose, kernel loads ionic liquid and chemotherapeutics, by mixture of phospholipids is formed a film, is coated ionic liquid and chemotherapeutics, surface modification and etc. be prepared.The present invention carries out fucose molecular modification to microwave sensitizing type liposome nano granule first, realize targeted delivery while to liver cancer in situ and metastatic hepatic carcinoma, under the conditions of local microwave irradiation, excellent tumor inhibition effect is achieved, there is wide potential applicability in clinical practice.
Description
Technical field
The present invention relates to medicament-carrying nano-microsphere preparation field, and in particular to a kind of targeting microwave controlled release medicament-carrying nano-microsphere
And its preparation method and application.
Background technology
Liver cancer is one of malignant tumour common in world wide, and China is even more liver cancer big country, and serious threat people's
Health and Living quality.According to the clinical liver cancer treatment guide of world authority, to early liver cancer (diameter is less than 3cm), can use
The treatment means such as surgery radical excision, local minimally invasive thermal ablation techniques and liver transfer operation achieve the purpose that radical cure.However, due to liver
Cancer onset is invisible, to middle and advanced stage when most of patients is found, can only often take systemic treatment and symptomatic treatment, Huan Zhezhi
Therapeutic effect is poor, prognosis is undesirable.Therefore, the treatment of liver cancer, is still one in clinic especially to therapy for advanced hepatocellular carcinoma patient
Hang-up.
In recent years, the fast development of nano biological medical technology brings revolutionary character for the inherent defect of traditional anti-tumor preparation
Breakthrough.Such as：(1) by the way that antitumor drug is encapsulated into nano carrier, drug solubility can be improved, extend blood and follow
The ring time, improves curative effect of medication；(2) the enhancing infiltration using tumor-microvessel wall and delay (Enhanced permeability
And retention effect, EPR) effect, realize specific selectivity of the medicine to tumour cell, increase target area medicine is dense
Degree, reduces adverse reaction；(3) the multidrug resistance problem of clinical research generally existing is overcome；(4) realize that the medicine of different mechanisms is total to
Carry, play effect of synergy etc..However, deepening continuously with research, also finds that existing nano-medicament carrier exists not
Foot, including：Targeting Performance is relatively low, permeance property is poor, drug release site non-selectivity etc..Further, by nanometer
Delivery vector carries out surface modification, it is possessed active targeting ability, is specifically combined with tumor cell surface acceptor, can be shown
Increase target area drug concentration is write, reduces drug loss, is expected to realize high concentration enrichment and precisely of the Nano medication in therapy area
Controlled release.
The content of the invention
Goal of the invention：The technical problems to be solved by the invention are in view of the deficiencies of the prior art, there is provided one kind has micro-
The medicament-carrying nano-microsphere of ripple sensitizing property and targeting ability, the microballoon is with good stability and biocompatibility, nontoxic pair
Effect, is used directly in animal body, in terms of the chemotherapy of early liver cancer and therapy for advanced hepatocellular carcinoma and local microwave heat therapeutic, has
Good clinical value.
In order to solve the above-mentioned technical problem, it is described the invention discloses a kind of targeting microwave controlled release medicament-carrying nano-microsphere
Medicament-carrying nano-microsphere framework material is mixture of phospholipids, skeleton surface modification fucose, kernel loading ionic liquid and change
Treat medicine.
Phosphatide is a kind of good biocompatibility, can will not produce poison by the organic molecule material of the complete catabolism of human body
Side effect, is widely used in the fields such as bio-pharmaceuticals, medical engineering material, and it is skeleton material that the application, which selects mixture of phospholipids,
Material, by simple sound and vibration emulsification method, makes it have the performance of targeting, chemotherapy and microwave enhanced sensitivity.Fucose, selects P
Selecting element has high affinity, can substantially suppress the tumour cell of P selectins mediation and the blood for sticking and activating of endothelial cell
The combination of platelet and tumour cell, participates in suppressing the dynamic cascading reaction process of this high degree of controlled of tumorigenesis, can make
For the surface modification molecule of Nano medication delivery vector, while targeted delivery chemotherapeutics is to liver lesion in situ and DISTANT METASTASES IN
Lesion, improves target area Nano medication concentration.After Nano medication targeting is delivered to therapy area, it can traditionally pass through near-infrared
The outside stimulus such as light, ultrasound destroy carrier, release medicine.But since near infrared light penetrability is weak, ultrasound but easily by gas,
Bone disturbs and seriously limits its application in vivo.Comparatively speaking, microwave has thermal conversion efficiency height, tissue penetration
Depth is deep, the advantages that being not easy to be disturbed by bone and gas.When ionic liquid is covered by the confined space of nanoparticle,
Motion collision is further exacerbated by under microwave action, and frictional heat increases, and then nano particle is become efficient heat generating body one by one
And play the effect of increase microwave pyrogenicity efficiency.
Wherein, the mixture of phospholipids is selected from dipalmitoylphosphatidylcholine, polyethylene glycol-distearoylphosphatidyl ethanol
Three kinds in amine, glycerophosphatide and cholesterol or four kinds, dipalmitoylphosphatidylcholine, polyethylene glycol-distearoylphosphatidyl
The mass ratio of monoethanolamine, glycerophosphatide and cholesterol is 4~5:2:0~2:1~2；The ionic liquid is selected from chlorination 1- ethyls
One or more in 3- methylimidazoles acetate, chlorination 1- butyl 3- methylimidazoles, 1- butyl -3- methylimidazole L lactates；
One or more of the chemotherapeutics in adriamycin, 5 FU 5 fluorouracil, capecitabine and cis-platinum.
A diameter of 85~the 115nm of medicament-carrying nano-microsphere, polydispersity index be 0.17~0.25, surface charge for-
12.4~-18.6mV.
The present invention also provides the preparation method of the targeting microwave controlled release medicament-carrying nano-microsphere, include the following steps：
Step 1：Mixture of phospholipids is dissolved in chloroform, obtains solution A, resulting solution A vacuum under water bath condition
Rotary evaporation is to forming uniform lipid membrane；
Step 2：Ionic liquid and chemotherapeutics are dissolved in deionized water, obtain solution B；
Step 3：By lipid membrane aquation obtained by step 1 in step 2 resulting solution B, vibration shakes up transparent to being formed
Suspension C；
Step 4：By suspension C obtained by step 3, sound and vibration emulsifies under condition of ice bath, obtains emulsion D；
Step 5：Fucose is added in emulsion D obtained by step 4, after vibration shakes up, sound and vibration, which emulsifies, to be emulsified
Liquid E；
Step 6：By emulsion E centrifugations obtained by step 5, take precipitation to be dissolved in sterile phosphate buffer to obtain the final product.
In step 1, the mixture of phospholipids is dissolved in chloroform with total 1~2.5mg/mL of mass-volume concentration；
The water bath condition is 25~40 DEG C, 8~12h of rotary evaporation time.
In step 2, the ionic liquid is dissolved in deionized water by 0.5~1.0mg/mL of concentration, the chemotherapeutic
Thing is dissolved in deionized water by 0.5~2mg/mL of concentration.
In step 3, the mass volume ratio that the lipid membrane is mixed with solution B is 3~8mg/mL.
In step 4 and step 5, power used in sound and vibration emulsification is 30~60W, sound and vibration 10s, stops 10s；Step 4
Sound and vibration emulsification total time be 1~3min, the sound and vibration emulsification of step 5 is always 30~50s.
In step 5, the mass ratio of the fucose and mixture of phospholipids is 1~2:10, ensure that fucose exists
It is excessive in reaction.
In step 6, the centrifugal condition is 20000~30000g, and the time is no less than 30min.
The present invention also provides above-mentioned targeting microwave controlled release medicament-carrying nano-microsphere to prepare chemotherapy of hepatocellular carcinoma medicine and local micro-
Application in ripple thermotherapy medicine.
Above-mentioned targeting microwave controlled release medicament-carrying nano-microsphere is in enhancing tumour cell to the application in microwave action sensitiveness
Also in protection scope of the present invention.
Beneficial effect：
1st, the application medicament-carrying nano-microsphere skeleton surface is modified using fucose, and kernel loads ionic liquid, can be real
Now to the dual-targeting function of liver cancer in situ and DISTANT METASTASES IN stove, and the characteristic with microwave enhanced sensitivity.
2nd, the application medicament-carrying nano-microsphere preparation method is simple, and required raw material is easy to get, and is not required to special installation, prepared by this method
Targeting microwave controlled release medicament-carrying nano-microsphere size uniformity, pattern rule, granularity is controllable and stability is high, can efficient loading
Ionic liquid and chemotherapeutics；Simultaneously as the nanoparticle has good biocompatibility, animal body is used directly for
Interior experiment.
Brief description of the drawings
The present invention is done with reference to the accompanying drawings and detailed description and is further illustrated, of the invention is above-mentioned
And/or otherwise advantage will become apparent.
Fig. 1 is the structure diagram for the targeting microwave controlled release medicament-carrying nano-microsphere that embodiment 2 is prepared.
Fig. 2 is the targeting microwave controlled release medicament-carrying nano-microsphere transmission electron microscope figure that embodiment 2 is prepared.
Fig. 3 is the targeting microwave controlled release medicament-carrying nano-microsphere grain size distribution that embodiment 2 is prepared.
Fig. 4 is the targeting microwave controlled release medicament-carrying nano-microsphere stability observing that embodiment 2 is prepared.
Fig. 5 is the targeting microwave controlled release medicament-carrying nano-microsphere drug release patterns in vitro that embodiment 2 is prepared.
Fig. 6 is transmitted electron before and after the targeting microwave controlled release medicament-carrying nano-microsphere insoluble drug release that embodiment 2 is prepared
Microscope figure compares.
Fig. 7 is the external microwave heating figure of targeting microwave controlled release medicament-carrying nano-microsphere that embodiment 2 is prepared.
Fig. 8 is microwave heating figure in targeting microwave controlled release medicament-carrying nano-microsphere body that embodiment 2 is prepared.
Embodiment
Embodiment 1
10mg dipalmitoylphosphatidylcholine, polyethylene glycol Distearoyl Phosphatidylethanolamine, glycerophosphatide and courage are consolidated
Alcohol presses certain mass ratio (5:2:1.5:1.5) it is dissolved in 5mL chloroforms and forms solution A, then by resulting solution A in 35 DEG C of water
Rotary evaporation in vacuo 12h under the conditions of bath, to forming uniform lipid membrane；By 1- butyl -3- methylimidazole L lactates (with concentration
0.5mg/ml) it is dissolved in adriamycin (with concentration 1mg/ml) in deionized water, obtains solution B；By lipid membrane with quality volume
Than 5mg/mL aquation in solution B, vibration is shaken up to transperent suspension liquid C is formed, and further sound and vibration emulsifies under condition of ice bath
2min, obtains emulsion D, the sound and vibration power of selection is 50W, and sound and vibration 10s, stop 10s, and interruption carries out；It will be added again in emulsion D
1mg fucose, after vibration shakes up, selects above-mentioned sound and vibration parameter sound and vibration emulsification 40s, obtains emulsion E；By emulsion E at a high speed
Centrifuge 3 times (30000g, 30min), abandon supernatant, take precipitation to be scattered in sterile phosphate buffer, obtain targeting microwave
Controlled release medicament-carrying nano-microsphere, its a diameter of 90~110nm, polydispersity index are 0.17~0.21, surface charge for -12.5~-
14.2mV。
Microwave heats up and therapeutic test：
5mg medicament-carrying nano-microspheres are scattered in 1mL deionized waters, use 1.8W/cm2Microwave irradiation 5min, use is infrared
Thermal imaging system monitors temperature rise effect, and it is 10.2 DEG C higher than deionized water control group to measure its microwave temperature rise effect.In BALB/c nude mices
HepG2 original positions Hepatic neoplasm model and distant place Lung metastases model are established in vivo, Hepatic neoplasm model in situ is through median abdominal incision pair
Right lobe of liver implantation tumour tissue block (1mm × 1mm × 1mm) is established；Liver cancer distant place Lung metastases model is thin through tail vein injection HepG2
Born of the same parents' suspension (1 × 106/ only) establish.After being injected intravenously targeting microwave controlled release medicament-carrying nano-microsphere 5mg/kg, 24h, ultrasound or CT
Image-guided lower local microwave irradiation affected area, 450MHz, power 1.2W/cm2, exposure time 3min, passes through infrared heat
Imager monitors affected area temperature change in real time, and tumour position temperature can reach 50 DEG C in 180s, which can kill
Dead tumour cell simultaneously can rapidly and efficiently discharge chemotherapeutics, strengthen local chemotherapy and thermotherapy.
Embodiment 2
10mg dipalmitoylphosphatidylcholine, polyethylene glycol Distearoyl Phosphatidylethanolamine, glycerophosphatide and courage are consolidated
Alcohol presses certain mass ratio (4:2:2:2) it is dissolved in 10mL chloroforms and forms solution A, then by resulting solution A in 40 DEG C of water-baths
Under the conditions of rotary evaporation in vacuo 12h, to forming uniform lipid membrane；By 1- butyl -3- methylimidazole L lactates (with concentration
0.5mg/ml) it is dissolved in adriamycin (with concentration 2mg/ml) in deionized water, obtains solution B；By lipid membrane with quality volume
Than 5mg/mL aquation in solution B, vibration is shaken up to transperent suspension liquid C is formed, and further sound and vibration emulsifies under condition of ice bath
2min, obtains emulsion D, the sound and vibration power of selection is 50W, and sound and vibration 10s, stop 10s, and interruption carries out；It will be added again in emulsion D
1mg fucose, after vibration shakes up, selects above-mentioned sound and vibration parameter sound and vibration emulsification 40s, obtains emulsion E；By emulsion E at a high speed
Centrifuge 3 times (20000g, 30min), abandon supernatant, take precipitation to be scattered in sterile phosphate buffer, obtain targeting microwave
Controlled release medicament-carrying nano-microsphere, its a diameter of 90~115nm, polydispersity index are 0.20~0.25, surface charge for -12.5~-
15.4mV.Fig. 1 is the structure diagram for the targeting microwave controlled release medicament-carrying nano-microsphere that the embodiment is prepared, wherein：1 table
Show fucose, 2 represent polyethylene glycol Distearoyl Phosphatidylethanolamine, and 3 represent dipalmitoylphosphatidylcholine, and 4 represent
Glycerophosphatide and cholesterol, 5 represent chemotherapeutics, and 6 represent ionic liquid.Fig. 2 is that the transmitted electron of the medicament-carrying nano-microsphere is shown
Micro mirror figure, shows form rule, in ball-type.Fig. 3 is the medicament-carrying nano-microsphere grain size distribution, and display particle diameter distribution is homogeneous.
Microwave heats up and therapeutic test：
5mg medicament-carrying nano-microspheres are scattered in 1ml deionized waters, use 1.8W/cm2Microwave irradiation 5min, use is infrared
Thermal imaging system monitors temperature rise effect, and it is 11.4 DEG C higher than deionized water control group to measure its microwave temperature rise effect.In BALB/c nude mices
HepG2 original positions Hepatic neoplasm model and distant place Lung metastases model are established in vivo, are injected intravenously targeting microwave controlled release medicament-carried nano
After microballoon 24h, ultrasound or the lower local microwave irradiation affected area (with embodiment 1) of CT images guiding are real by infrared thermography
When monitor affected area temperature change, tumour position temperature can reach 50 DEG C in 160s, and it is thin which can kill tumour
Born of the same parents simultaneously can rapidly and efficiently discharge chemotherapeutics, strengthen local chemotherapy and thermotherapy.Fig. 4 is the medicament-carrying nano-microsphere dimensionally stable
Property result figure, shows nanoparticle energy with good stability in 37 DEG C of deionized waters.Fig. 5 is the medicament-carrying nano-microsphere
Drug release patterns in vitro figure, under weakly acidic condition (pH 5.5), passes through discontinuously external microwave radiation (arrow institute in figure three times
Show), there is more prominent insoluble drug release ability compared to no microwave radiation group.Before and after Fig. 6 is medicament-carrying nano-microsphere insoluble drug release
Transmission electron microscope figure compares.It can be seen that nanoparticle form is complete before insoluble drug release, nanoparticle form disappears after insoluble drug release
Lose, be shown as irregular, unbodied lipid fragment.The external microwave heating figure of Fig. 7 medicament-carrying nano-microspheres, Fig. 8 medicament-carried nanos are micro-
Microwave heating figure in sphere.In vitro, the visible nanoparticle group of experiment in vivo has more compared to control group after microwave irradiation
Good heating performance.
Embodiment 3
10mg dipalmitoylphosphatidylcholine, polyethylene glycol Distearoyl Phosphatidylethanolamine and cholesterol are pressed into certain matter
Amount is than (5:2:3) be dissolved in 5mL chloroforms and form solution A, then by resulting solution A under 35 DEG C of water bath conditions vacuum rotating
8h is evaporated, to forming uniform lipid membrane；By 1- butyl -3- methylimidazole L lactates (with concentration 0.5mg/ml) and adriamycin
(with concentration 0.5mg/ml) is dissolved in deionized water, obtains solution B；By lipid membrane with mass volume ratio 8mg/mL aquations in molten
In liquid B, vibration is shaken up to transperent suspension liquid C is formed, and further sound and vibration emulsifies 3min under condition of ice bath, obtains emulsion D, is selected
Sound and vibration power be 30W, sound and vibration 10s, stop 10s, and interruption carries out；1mg fucose will be added in emulsion D again, vibration is shaken
After even, above-mentioned sound and vibration parameter sound and vibration emulsification 50s is selected, obtains emulsion E；By 3 (30000g of emulsion E high speed centrifugations；
30min), abandon supernatant, take precipitation to be scattered in sterile phosphate buffer, it is micro- to obtain targeting microwave controlled release medicament-carried nano
Ball, its a diameter of 85~110nm, polydispersity index are 0.18~0.22, and surface charge is -12.8~-16.6mV.
Microwave heats up and therapeutic test：
5mg medicament-carrying nano-microspheres are scattered in 1ml deionized waters, use 1.8W/cm2Microwave irradiation 5min, use is infrared
Thermal imaging system monitors temperature rise effect, and it is 9.8 DEG C higher than deionized water control group to measure its microwave temperature rise effect.In BALB/c nude mouses
HepG2 original positions Hepatic neoplasm model and distant place Lung metastases model are inside established, intravenous injection targeting microwave controlled release medicament-carried nano is micro-
After ball 24h, ultrasound or the lower local microwave irradiation affected area (with embodiment 1) of CT images guiding are real-time by infrared thermography
Affected area temperature change is monitored, tumour position temperature can reach 50 DEG C in 240s, which can kill tumour cell
And chemotherapeutics can be rapidly and efficiently discharged, strengthen local chemotherapy and thermotherapy.
Embodiment 4
10mg dipalmitoylphosphatidylcholine, polyethylene glycol Distearoyl Phosphatidylethanolamine, glycerophosphatide and courage are consolidated
Alcohol presses certain mass ratio (5:2:1.5:1.5) it is dissolved in 4ml chloroforms and forms solution A, then by resulting solution A in 35 DEG C of water
Rotary evaporation in vacuo 8h under the conditions of bath, to forming uniform lipid membrane；By chlorination 1- ethyl 3- methylimidazoles (with concentration 0.5mg/
Ml) it is dissolved in adriamycin (with concentration 1mg/ml) in deionized water, obtains solution B；By lipid membrane with mass volume ratio 8mg/
ML aquations are in solution B, and vibration is shaken up to transperent suspension liquid C is formed, and further sound and vibration emulsifies 1min under condition of ice bath, obtains newborn
Change liquid D, the sound and vibration power of selection is 60W, and sound and vibration 10s, stop 10s, and interruption carries out；1mg rocks algae will be added in emulsion D according to poly- again
Sugar, after vibration shakes up, selects above-mentioned sound and vibration parameter sound and vibration emulsification 30s, obtains emulsion E；By emulsion E high speed centrifugations 3 times
(20000g, 30min), abandons supernatant, takes precipitation to be scattered in sterile phosphate buffer, obtains targeting microwave controlled release and carries medicine
Nanoparticle, its a diameter of 95~115nm, polydispersity index are 0.20~0.25, and surface charge is -13.5~-18.6mV.
Microwave heats up and therapeutic test：
5mg medicament-carrying nano-microspheres are scattered in 1ml deionized waters, use 1.8W/cm2Microwave irradiation 5min, use is infrared
Thermal imaging system monitors temperature rise effect, and it is 10.7 DEG C higher than deionized water control group to measure its microwave temperature rise effect.In BALB/c nude mices
HepG2 original positions Hepatic neoplasm model and distant place Lung metastases model are established in vivo, are injected intravenously targeting microwave controlled release medicament-carried nano
After microballoon 24h, ultrasound or the lower local microwave irradiation affected area (with embodiment 1) of CT images guiding are real by infrared thermography
When monitor affected area temperature change, tumour position temperature can reach 50 DEG C in 180s, and it is thin which can kill tumour
Born of the same parents simultaneously can rapidly and efficiently discharge chemotherapeutics, strengthen local chemotherapy and thermotherapy.
Embodiment 5
10mg dipalmitoylphosphatidylcholine, polyethylene glycol Distearoyl Phosphatidylethanolamine, glycerophosphatide and courage are consolidated
Alcohol presses certain mass ratio (5:2:1:2) it is dissolved in 4ml chloroforms and forms solution A, then by resulting solution A in 25 DEG C of water-bath bars
Rotary evaporation in vacuo 10h under part, to forming uniform lipid membrane；By 1- butyl -3- methylimidazole L lactates (with concentration
0.5mg/ml) it is dissolved in capecitabine (with concentration 2mg/ml) in deionized water, obtains solution B；By lipid membrane with mass body
Product is than 3mg/mL aquation in solution B, and vibration is shaken up to transperent suspension liquid C is formed, and further sound and vibration emulsifies under condition of ice bath
2min, obtains emulsion D, the sound and vibration power of selection is 50W, and sound and vibration 10s, stop 10s, and interruption carries out；It will be added again in emulsion D
1mg fucose, after vibration shakes up, selects above-mentioned sound and vibration parameter sound and vibration emulsification 40s, obtains emulsion E；By emulsion E at a high speed
Centrifuge 3 times (20000g, 30min), abandon supernatant, take precipitation to be scattered in sterile phosphate buffer, obtain targeting microwave
Controlled release medicament-carrying nano-microsphere, its a diameter of 88~110nm, polydispersity index are 0.17~0.22, surface charge for -14.5~-
18.6mV。
Microwave heats up and therapeutic test：
5mg medicament-carrying nano-microspheres are scattered in 1ml deionized waters, use 1.8W/cm2Microwave irradiation 5min, use is infrared
Thermal imaging system monitors temperature rise effect, and it is 11.6 DEG C higher than deionized water control group to measure its microwave temperature rise effect.In BALB/c nude mices
HepG2 original positions Hepatic neoplasm model and distant place Lung metastases model are established in vivo, are injected intravenously targeting microwave controlled release medicament-carried nano
After microballoon 24h, ultrasound or the lower local microwave irradiation affected area (with embodiment 1) of CT images guiding are real by infrared thermography
When monitor affected area temperature change, tumour position temperature can reach 50 DEG C in 200s, and it is thin which can kill tumour
Born of the same parents simultaneously can rapidly and efficiently discharge chemotherapeutics, strengthen local chemotherapy and thermotherapy.
Embodiment 6
10mg dipalmitoylphosphatidylcholine, polyethylene glycol Distearoyl Phosphatidylethanolamine, glycerophosphatide and courage are consolidated
Alcohol presses certain mass ratio (4:2:2:2) it is dissolved in 4ml chloroforms and forms solution A, then by resulting solution A in 25 DEG C of water-bath bars
Rotary evaporation in vacuo 12h under part, to forming uniform lipid membrane；By chlorination 1- butyl 3- methylimidazoles (with concentration 0.5mg/ml)
It is dissolved in 5 FU 5 fluorouracil (with concentration 0.5mg/ml) in deionized water, obtains solution B；By lipid membrane with mass volume ratio
8mg/mL aquations are in solution B, and vibration is shaken up to transperent suspension liquid C is formed, and further sound and vibration emulsifies 2min under condition of ice bath,
Emulsion D is obtained, the sound and vibration power of selection is 50W, and sound and vibration 10s, stop 10s, and interruption carries out；2mg rock algaes will be added in emulsion D again
According to glycan, after vibration shakes up, above-mentioned sound and vibration parameter sound and vibration emulsification 40s is selected, obtains emulsion E；By emulsion E high speed centrifugations 3 times
(30000g, 30min), abandons supernatant, takes precipitation to be scattered in sterile phosphate buffer, obtains targeting microwave controlled release load medicine and receives
Meter Wei Qiu, its a diameter of 93~113nm, polydispersity index are 0.21~0.25, and surface charge is -12.4~-15.2mV.
Microwave heats up and therapeutic test：
5mg medicament-carrying nano-microspheres are scattered in 1ml deionized waters, use 1.8W/cm2Microwave irradiation 5min, use is infrared
Thermal imaging system monitors temperature rise effect, and it is 10.2 DEG C higher than deionized water control group to measure its microwave temperature rise effect.In BALB/c nude mices
HepG2 original positions Hepatic neoplasm model and distant place Lung metastases model are established in vivo, are injected intravenously targeting microwave controlled release medicament-carried nano
After microballoon 24h, ultrasound or the lower local microwave irradiation affected area (with embodiment 1) of CT images guiding are real by infrared thermography
When monitor affected area temperature change, tumour position temperature can reach 50 DEG C in 240s, and it is thin which can kill tumour
Born of the same parents simultaneously can rapidly and efficiently discharge chemotherapeutics, strengthen local chemotherapy and thermotherapy.
The present invention provides a kind of targeting microwave controlled release medicament-carrying nano-microsphere and its preparation method and application thinking and
Method, implements that method and the approach of the technical solution are very much, and the above is only the preferred embodiment of the present invention, should
Point out, for those skilled in the art, without departing from the principle of the present invention, if can also make
Dry improvements and modifications, these improvements and modifications also should be regarded as protection scope of the present invention.Each composition being not known in the present embodiment
The available prior art in part is realized.
Claims (10)
1. a kind of targeting microwave controlled release medicament-carrying nano-microsphere, it is characterised in that the medicament-carrying nano-microsphere framework material is phosphorus
Lipoprotein mixture, skeleton surface modification fucose, kernel load ionic liquid and chemotherapeutics.
2. targeting microwave controlled release medicament-carrying nano-microsphere according to claim 1, it is characterised in that the mixture of phospholipids
Three kinds in dipalmitoylphosphatidylcholine, polyethylene glycol-distearoyl phosphatidyl ethanolamine, glycerophosphatide and cholesterol
Or four kinds, dipalmitoylphosphatidylcholine, polyethylene glycol-distearoyl phosphatidyl ethanolamine, the matter of glycerophosphatide and cholesterol
Amount is than being 4~5:2:0~2:1~2；The ionic liquid is selected from chlorination 1- ethyl 3- methylimidazoles acetate, chlorination 1- butyl
One or more in 3- methylimidazoles, 1- butyl -3- methylimidazole L lactates；The chemotherapeutics is selected from adriamycin, 5- fluorine
One or more in uracil, capecitabine and cis-platinum.
3. targeting microwave controlled release medicament-carrying nano-microsphere according to claim 1, it is characterised in that the medicament-carried nano is micro-
Bulb diameter is 85~115nm, and polydispersity index is 0.17~0.25, and surface charge is -12.4~-18.6mV.
4. the preparation method of targeting microwave controlled release medicament-carrying nano-microsphere described in claim 1, it is characterised in that including following step
Suddenly：
Step 1：Mixture of phospholipids is dissolved in chloroform, obtains solution A, resulting solution A vacuum rotatings under water bath condition
It is evaporated to form uniform lipid membrane；
Step 2：Ionic liquid and chemotherapeutics are dissolved in deionized water, obtain solution B；
Step 3：By lipid membrane aquation obtained by step 1 in step 2 resulting solution B, vibration is shaken up to formation transperent suspension
Liquid C；
Step 4：By suspension C obtained by step 3, sound and vibration emulsifies under condition of ice bath, obtains emulsion D；
Step 5：Fucose is added in emulsion D obtained by step 4, after vibration shakes up, sound and vibration emulsifies to obtain emulsion E；
Step 6：By emulsion E centrifugations obtained by step 5, take precipitation to be dissolved in sterile phosphate buffer to obtain the final product.
5. the preparation method of targeting microwave controlled release medicament-carrying nano-microsphere according to claim 4, it is characterised in that step 1
In, the mixture of phospholipids is dissolved in chloroform with total 1~2.5mg/mL of mass-volume concentration；The water bath condition is
25~40 DEG C, 8~12h of rotary evaporation time.
6. the preparation method of targeting microwave controlled release medicament-carrying nano-microsphere according to claim 4, it is characterised in that step 2
In, the ionic liquid is dissolved in deionized water by 0.5~1.0mg/mL of concentration, and the chemotherapeutics is using concentration as 0.5
~2mg/mL is dissolved in deionized water.
7. the preparation method of targeting microwave controlled release medicament-carrying nano-microsphere according to claim 4, it is characterised in that step 3
In, the mass volume ratio that the lipid membrane is mixed with solution B is 3~8mg/mL.
8. the preparation method of targeting microwave controlled release medicament-carrying nano-microsphere according to claim 4, it is characterised in that step 5
In, the mass ratio of the fucose and mixture of phospholipids is 1~2:10.
9. application of the targeting microwave controlled release medicament-carrying nano-microsphere in chemotherapy of hepatocellular carcinoma medicine is prepared described in claim 1.
10. application of the targeting microwave controlled release medicament-carrying nano-microsphere described in claim 1 in local microwave heat therapeutic medicine is prepared.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111420056A (en) * | 2020-05-08 | 2020-07-17 | 四川大学华西医院 | Nanoparticle for releasing P L GA shell through microwave touch, preparation method and application thereof |
| CN113713119A (en) * | 2021-08-23 | 2021-11-30 | 成都六方生物技术有限公司 | Medicine for treating solid malignant tumor and preparation method thereof |
| WO2023006003A1 (en) * | 2021-07-27 | 2023-02-02 | Mien-Chie Hung | Pharmaceutical composition comprising polysaccharide |
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2017
- 2017-12-05 CN CN201711267705.XA patent/CN107982535B/en active Active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111420056A (en) * | 2020-05-08 | 2020-07-17 | 四川大学华西医院 | Nanoparticle for releasing P L GA shell through microwave touch, preparation method and application thereof |
| WO2023006003A1 (en) * | 2021-07-27 | 2023-02-02 | Mien-Chie Hung | Pharmaceutical composition comprising polysaccharide |
| CN113713119A (en) * | 2021-08-23 | 2021-11-30 | 成都六方生物技术有限公司 | Medicine for treating solid malignant tumor and preparation method thereof |
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