CN103520726B - Preparation method of invisible thermosensitive liposome as well as application of drug delivery system of invisible thermosensitive liposome in tumor treatment drugs - Google Patents
Preparation method of invisible thermosensitive liposome as well as application of drug delivery system of invisible thermosensitive liposome in tumor treatment drugs Download PDFInfo
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Abstract
The invention relates to a preparation method of a drug delivery system of an invisible thermosensitive liposome as well as an application of the drug delivery system of the invisible thermosensitive liposome in tumor treatment drugs, and can be used for effectively solving the problems that an existing tumor treatment drug is large in side effect, poor in treatment effect, and the like. The drug delivery system of the invisible thermosensitive liposome is composed of a thermosensitive liposome-loaded targeted heat sensitizing agent and chemotherapy drugs in a weight ratio of 1:3, wherein the invisible thermosensitive liposome is obtained through synthesis of carboxylic nanotubes, synthesis of folate-targeted carbon nano tube-lysine, preparation of the invisible thermosensitive liposome or synthesis of carboxylic nanotubes, synthesis of carbon nano tubes loaded with chemotherapy drugs, and preparation of the thermosensitive liposome. The preparation method disclosed by the invention is good in physical and chemical stability, simple and practicable in preparation condition, rich in material resources, low in cost, small in side effect and capable of effectively restraining multiplication of tumor cells, so that the effect of tumor-targeted treatment is achieved, and therefore, the preparation method is an innovation of a drug carrier in tumor-targeted treatment.
Description
Technical field
The present invention relates to drug world, particularly a kind of preparation of stealthy thermal sensitive liposome and the application of drug delivery system in anti-tumor medicine thereof.
Background technology
Stealthy thermal sensitive liposome is the drug delivery carrier of a kind of physical chemistry and active targeting.At normal body temperature, hydrophilic medicament is difficult to diffuse out through liposome membrane, and when liposome passes through by the target organ heated with blood circulation, the high temperature of local can impel medicine discharge at target site and form higher drug level; The study hotspot that stealthy thermal sensitive liposome has good medicine carrying, targeting and biocompatibility and becomes in biomedicine field, has reported that thermal sensitive liposome local heating methods has immersion method, microwave method, radio frequency method etc. at present.
Single wall or multi-walled carbon nano-tubes, Graphene, nanometer gold has huge specific surface area (~ 2600m
2/ g), the characteristic such as higher near-infrared Thermogenesis, unique cross-film ability and large delocalized pi-bond, be widely used in biomedicine field.CNT effectively can carry the bioactive substances such as protein, antibody, polypeptide, medicine and nucleic acid and enter cell, thus becomes the carrier of people's concern.The near infrared light of CNT to 700 ~ 1100nm scope has high-selenium corn characteristic, and the near infrared light of biosystem to this scope has height permeability simultaneously, and the photothermal deformation characteristic of CNT therefore can be utilized to carry out laserthermia to tumor.CNT is drug delivery carrier, is also the main body playing thermotherapy effect simultaneously, can be used as chemotherapeutics sensitizer and targeting heat sensitizer.But CNT is water insoluble and organic solvent, and easily assembles bunchy in the solution, be difficult to dispersion, have a strong impact on its application.
DPPC (dipalmitoyl phosphatidyl choline), C
40h
80nO
8p, molecular weight 734.04, phase transition temperature 41-42 DEG C, can be used as main material prepared by thermal sensitive liposome, thermal sensitive liposome just can be caused to discharge rapidly interior drug containing, realize targeted therapy when temperature reaches its phase transition temperature; DSPE-PEG2000(DSPE-PEG 2000) there is good hydrophilic and pliability, can prolong drug carrier circulation time in vivo.
At present, form drug delivery system by stealthy thermal sensitive liposome load targeting heat sensitizer (as CNT) and chemotherapeutics, the application particularly in anti-tumor medicine there is not yet report.
Summary of the invention
For above-mentioned situation, overcome the defect of prior art, the object of the present invention is just to provide a kind of stealthy preparation method of thermosensitive liposome drug movement system and the application in anti-tumor medicine thereof, effectively can solve the problems such as existing anti-tumor medicine side effect is large, therapeutic effect is not good.
The technical scheme that the present invention solves is, be made up of stealthy thermal sensitive liposome load targeting heat sensitizer and chemotherapeutics, wherein, the mass ratio of targeting heat sensitizer and chemotherapeutics is 1:3, and described targeting heat sensitizer is the one of SWCN and derivant, multi-walled carbon nano-tubes and derivant thereof, Graphene and derivant, nanometer gold and derivant thereof, nanometer silver and derivant thereof, organic polymer; Described chemotherapeutics be doxorubicin hydrochloride, Farmorubine Hydrochloride, daunorubicin, mitoxantrone hydrochloride, Docetaxel, paclitaxel, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, vinorelbine, lomustine, carmustine, Xi Tabin, methotrexate, hydroxy camptothecin, the few adopted antinucleus thuja acid of small nut acids and siRNA one or more compositions.
The preparation method of described stealthy thermal sensitive liposome, is realized by following steps:
(1) synthesis of carboxylic carbon nano-tube: get 95 ~ 110mg CNT, put into 250mL flask, add the nitration mixture of 120mL, the hydrogenperoxide steam generator of 11 ~ 13mL mass concentration 30%, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μm of microporous filter membrane and buchner funnel sucking filtration, be neutral with ultrapure water to pH, put into baking oven 80 DEG C of freeze-day with constant temperature, obtain carboxylated CNT (CNTs-COOH); The mixed acid that described nitration mixture forms with volume ratio 3 ︰ 1 for concentrated sulphuric acid and concentrated nitric acid;
(2) synthesis of the CNT-lysine of folate-targeted: get carboxylated CNT 45 ~ 55mg, add the lysine solution of 25mL0.1 ~ 0.3M, add folic acid 9 ~ 11mg again, 45 ~ 55mg1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCHCl), 9 ~ 11mg N-hydroxy-succinamide (NHS), be placed in flask, after ultrasonic disperse 2h, under ice bath, stirring 24h with 100r/min makes it fully react, dialyse after reaction terminates 48h in bag filter, remove unreacted EDCHCl, NHS, folic acid and lysine, vacuum drying 24h at 60 DEG C, obtain the CNT-lysine (FA-Lys/CNTs) of folate-targeted,
(3) preparation of stealthy thermal sensitive liposome: take 45 ~ 55mg dipalmitoyl phosphatidyl choline (DPPC), 1 ~ 3mg DSPE-PEG 2000(DSPE-PEG2000) and the cholesterol of 18 ~ 22mg, be placed in 100mL eggplant type flask, add ether to make to dissolve completely, add 5mL PBS solution again, ultrasonic emulsification 40min, form stable O/W type Emulsion, ether is removed under 45 DEG C of decompressions rotate, visit super (200W, 2min), after the 48h that dialyses in bag filter, stealthy thermal sensitive liposome is obtained; Described PBS solution is the solution that the CNT-lysine of 10mg folate-targeted and 6mg doxorubicin hydrochloride are dissolved in 5mL PBS (pH7.4) and are formed.
Also can be realized by following steps:
(1) synthesis of carboxylic carbon nano-tube: get 95 ~ 110mg CNT, put into 250mL flask, add 120mL nitration mixture, 11 ~ 13mL mass concentration 30% hydrogenperoxide steam generator, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μm of microporous filter membrane and buchner funnel sucking filtration, be neutral with ultrapure water to pH, put into baking oven 80 DEG C of freeze-day with constant temperature, obtain carboxylic carbon nano-tube (CNTs-COOH); The mixed acid that described nitration mixture forms with volume ratio 3 ︰ 1 for concentrated sulphuric acid and concentrated nitric acid;
(2) synthesis of the CNT-lysine of load chemotherapeutics: take carboxylic carbon nano-tube 45 ~ 55mg, add 25mL0.1 ~ 0.3M lysine solution, 45 ~ 55mg1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCHCl) and 9 ~ 11mg N-hydroxy-succinamide (NHS), be placed in flask, after ultrasonic disperse 2h, under ice bath, 24h is stirred with 100r/min, it is made fully to react, dialyse after reaction terminates 48h in bag filter, remove unreacted EDCHCl, NHS and lysine, vacuum drying 24h at 60 DEG C, obtain CNT-lysine (Lys/CNTs), take 9 ~ 11mg CNT-lysine again, add 10mL ultra-pure water, ultrasonic to entirely molten, then add 18 ~ 22mg chemotherapeutics, ultrasonic 4h, dialyse 24h in bag filter, the medicine that removing is free, obtains the CNT-lysine of carrying medicament,
(3) preparation of stealthy thermal sensitive liposome: the dipalmitoyl phosphatidyl choline (DPPC) getting 45 ~ 55mg, the DSPE-PEG 2000(DSPE-PEG2000 of 1 ~ 3mg) and the cholesterol of 18 ~ 22mg, be placed in 100mL eggplant type flask, add ether to make to dissolve completely, add 5mL PBS solution again, ultrasonic emulsification 40min, form stable O/W type Emulsion, ether is removed under 45 DEG C of decompressions rotate, visit super (200W, 2min), dialyse 48h in bag filter, obtains stealthy thermal sensitive liposome; Described PBS solution is the solution that the CNT-lysine of 10mg load chemotherapeutics and 6mg doxorubicin hydrochloride are dissolved in 5mL PBS (pH7.4) and are formed.
Described stealthy thermosensitive liposome drug movement system, may be used for intravenous injection, intramuscular injection, intratumor injection and subcutaneous injection, transdermal administration, et al. Ke.
Stealthy thermal sensitive liposome load targeting heat sensitizer (as CNT) of the present invention and chemotherapeutics, targeting heat sensitizer can load slightly solubility chemotherapeutics, there is high light hot-cast socket characteristic and produce active oxygen ability, also there is the feature of tumor-targeting, laser irradiation is carried out at tumor locus, utilize heat sensitizer heat production under laser irradiates to cause the heat sensitivity of thermo-sensitive material to make drug delivery system locate release medicine, thus reach the effect of neoplasm targeted therapy; Body physical and chemical stability of the present invention is good, preparation condition simple possible, abundant raw material source, and cost is low, and side effect is little, can the propagation of effective inhibition tumor cell, is the innovation on neoplasm targeted therapy Chinese medicine carrier.
Detailed description of the invention
Below in conjunction with embodiment, the specific embodiment of the present invention is described in further detail.
Embodiment 1
Preparation method of the present invention, in concrete enforcement, can be realized by following steps:
(1) synthesis of carboxylic carbon nano-tube: take 100mg CNT, put into 250mL round-bottomed flask, add the nitration mixture of 120mL, the hydrogenperoxide steam generator of 12mL mass concentration 30%, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μm of microporous filter membrane and buchner funnel sucking filtration, be neutral with ultrapure water to pH, put into baking oven 80 DEG C of freeze-day with constant temperature, obtain carboxylated CNT (CNTs-COOH); The mixed acid that described nitration mixture forms with volume ratio 3 ︰ 1 for concentrated sulphuric acid and concentrated nitric acid;
(2) synthesis of the CNT-lysine of folate-targeted: take carboxylated CNT 50mg, add the lysine solution of 25mL0.2M, add folic acid 10mg again, 50mg1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCHCl), 10mg N-hydroxy-succinamide (NHS), be placed in flask, after ultrasonic disperse 2h, under ice bath, stirring 24h with 100r/min makes it fully react, dialyse after reaction terminates 48h in bag filter, remove unreacted EDCHCl, NHS, folic acid and lysine, vacuum drying 24h at 60 DEG C, obtain the CNT-lysine (FA-Lys/CNTs) of folate-targeted,
(3) preparation of stealthy thermal sensitive liposome: take 50mg dipalmitoyl phosphatidyl choline (DPPC), 2mg DSPE-PEG 2000(DSPE-PEG2000) and the cholesterol of 20mg, be placed in 100mL eggplant type flask, add ether to make to dissolve completely, add 5mL PBS solution again, ultrasonic emulsification 40min, form stable O/W type Emulsion, ether is removed under 45 DEG C of decompressions rotate, visit super (200W, 2min), after the 48h that dialyses in bag filter, stealthy thermal sensitive liposome is obtained; Described PBS solution is the solution that the CNT-lysine of 10mg folate-targeted and 6mg doxorubicin hydrochloride are dissolved in 5mLPBS (pH7.4) and are formed.
Embodiment 2
Preparation method of the present invention, in concrete enforcement, also can be realized by following steps:
(1) synthesis of carboxylic carbon nano-tube: take 105mg CNT, put into 250mL round-bottomed flask, add the nitration mixture of 120mL, the hydrogenperoxide steam generator of 13mL mass concentration 30%, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μm of microporous filter membrane and buchner funnel sucking filtration, be neutral with ultrapure water to pH, put into baking oven 80 DEG C of freeze-day with constant temperature, obtain carboxylated CNT (CNTs-COOH);
(2) synthesis of the CNT-lysine of folate-targeted: take carboxylated CNT 53mg, add the lysine solution of 25mL0.2M, add folic acid 11mg again, 53mg1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCHCl), 11mg N-hydroxy-succinamide (NHS), be placed in flask, after ultrasonic disperse 2h, under ice bath, stirring 24h with 100r/min makes it fully react, dialyse after reaction terminates 48h in bag filter, remove unreacted EDCHCl, NHS, folic acid and lysine, vacuum drying 24h at 60 DEG C, obtain the CNT-lysine (FA-Lys/CNTs) of folate-targeted,
(3) preparation of stealthy thermal sensitive liposome: take 53mg dipalmitoyl phosphatidyl choline (DPPC), 3mg DSPE-PEG 2000(DSPE-PEG2000) and the cholesterol of 22mg, be placed in 100mL eggplant type flask, add ether to make to dissolve completely, add 5mL PBS solution again, ultrasonic emulsification 40min, form stable O/W type Emulsion, ether is removed under 45 DEG C of decompressions rotate, visit super (200W, 2min), after the 48h that dialyses in bag filter, stealthy thermal sensitive liposome is obtained; Described PBS solution is the solution that the CNT-lysine of 10mg folate-targeted and 6mg doxorubicin hydrochloride are dissolved in 5mLPBS (pH7.4) and are formed.
Embodiment 3
Preparation method of the present invention, in concrete enforcement, can be realized by following steps:
(1) synthesis of carboxylic carbon nano-tube: take 100mg CNT, put into 250mL round-bottomed flask, add 120mL nitration mixture, the hydrogenperoxide steam generator of 12mL mass concentration 30%, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μm of microporous filter membrane and buchner funnel sucking filtration, be neutral with ultrapure water to pH, put into baking oven 80 DEG C of freeze-day with constant temperature, obtain carboxylic carbon nano-tube (CNTs-COOH);
(2) synthesis of the CNT-lysine of load doxorubicin hydrochloride: take carboxylic carbon nano-tube 50mg, add 25mL0.2M lysine solution, 50mg1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCHCl) and 10mg N-hydroxy-succinamide (NHS), be placed in flask, after ultrasonic disperse 2h, under ice bath, 24h is stirred with 100r/min, it is made fully to react, dialyse after reaction terminates 48h in bag filter, remove unreacted EDCHCl, NHS and lysine, vacuum drying 24h at 60 DEG C, obtain CNT-lysine (Lys/CNTs), take 10mg CNT-lysine again, add 10mL ultra-pure water, ultrasonic to entirely molten, add 20mg doxorubicin hydrochloride again, ultrasonic 4h, dialyse 24h in bag filter, the medicine that removing is free, obtains the CNT-lysine (Lys/CNTs-DOX) of load doxorubicin hydrochloride,
(3) preparation of stealthy thermal sensitive liposome: the dipalmitoyl phosphatidyl choline (DPPC) taking 50mg, the DSPE-PEG 2000(DSPE-PEG2000 of 2mg) and the cholesterol of 20mg, be placed in 100mL eggplant type flask, add ether to make to dissolve completely, add 5mL PBS solution again, ultrasonic emulsification 40min, form stable O/W type Emulsion, ether is removed under 45 DEG C of decompressions rotate, visit super (200W, 2min), dialyse 48h in bag filter, obtains stealthy thermal sensitive liposome; Described PBS solution is the solution that the CNT-lysine of 10mg load doxorubicin hydrochloride and 6mg doxorubicin hydrochloride are dissolved in 5mL PBS (pH7.4) and are formed.
Embodiment 4
Preparation method of the present invention, in concrete enforcement, also can be realized by following steps:
(1) synthesis of carboxylic carbon nano-tube: take 105mg CNT, put into 250mL round-bottomed flask, add 120mL nitration mixture, the hydrogenperoxide steam generator of 13mL mass concentration 30%, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μm of microporous filter membrane and buchner funnel sucking filtration, be neutral with ultrapure water to pH, put into baking oven 80 DEG C of freeze-day with constant temperature, obtain carboxylic carbon nano-tube (CNTs-COOH);
(2) synthesis of the CNT-lysine of load Docetaxel: take carboxylic carbon nano-tube 53mg, add 25mL0.15M lysine solution, 53mg1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCHCl) and 11mg N-hydroxy-succinamide (NHS), be placed in flask, after ultrasonic disperse 2h, under ice bath, 24h is stirred with 100r/min, it is made fully to react, dialyse after reaction terminates 48h in bag filter, remove unreacted EDCHCl, NHS and lysine, vacuum drying 24h at 60 DEG C, obtain CNT-lysine (Lys/CNTs), take 10mg CNT-lysine again, add 10mL ultra-pure water, ultrasonic to entirely molten, add 22mg Docetaxel again, ultrasonic 4h, dialyse 24h in bag filter, the medicine that removing is free, obtains the CNT-lysine (Lys/CNTs-DOC) of load Docetaxel,
(3) preparation of stealthy thermal sensitive liposome: the DPPC taking 53mg, the cholesterol of DSPE-PEG2000 and 22mg of 2mg, is placed in 100mL eggplant type flask, adds ether and makes to dissolve completely, add 5mL PBS solution again, ultrasonic emulsification 40min, forms stable O/W type Emulsion, under 45 DEG C of decompressions rotate, remove ether, visit super (200W, 2min), dialyse 48h in bag filter, obtains stealthy thermal sensitive liposome; Described PBS solution is the solution that the CNT-lysine of 10mg load Docetaxel and 6mg doxorubicin hydrochloride are dissolved in 5mL PBS (pH7.4) and are formed.
Preparation method and the application of drug delivery system in anti-tumor medicine thereof of stealthy thermal sensitive liposome of the present invention are divided in vitro and in vivo two parts:
(1) in body: stealthy thermosensitive liposome drug movement system of the present invention is joined in cancerous cell and cultivates, shine by the wide wavelength light source of 780 ~ 1100nm wavelength or 808nm laser light after administration 3h, light application time 1 ~ 5min, continues to cultivate 24h, measures the survival rate of cancerous cell.
Above-mentioned cancerous cell is: organ surface or the inner various solid tumors occurred, pulmonary carcinoma, nasopharyngeal carcinoma, esophageal carcinoma, gastric cancer, hepatocarcinoma, colorectal cancer, breast carcinoma, ovarian cancer, bladder cancer, leukemia, cancer of pancreas, cervical cancer, laryngeal carcinoma, thyroid carcinoma, carcinoma of tongue, cerebroma (intracranial tumor), intestinal tumor, carcinoma of gallbladder, cancer of biliary duct, renal carcinoma, carcinoma of prostate, carcinoma of penis, tumor of testis, carcinoma of endometrium, choriocarcinoma, For Primary Vaginal Carcinoma, Vulvar, Hodgkin, non-Hodgkin lymphoma, skin carcinoma, the one in malignant melanoma.
(2) external: by stealthy thermosensitive liposome drug movement system of the present invention intravenous injection in tumor-bearing mice body, shine by the wide wavelength light source of 780 ~ 1100nm wavelength or 808nm laser light after administration 3h, light application time is 1 ~ 5min, measures the gross tumor volume size of tumor-bearing mice.
Above-mentioned tumor-bearing mice is: organ surface or the inner various solid tumors occurred, pulmonary carcinoma, nasopharyngeal carcinoma, esophageal carcinoma, gastric cancer, hepatocarcinoma, colorectal cancer, breast carcinoma, ovarian cancer, bladder cancer, leukemia, cancer of pancreas, cervical cancer, laryngeal carcinoma, thyroid carcinoma, carcinoma of tongue, cerebroma (intracranial tumor), intestinal tumor, carcinoma of gallbladder, cancer of biliary duct, renal carcinoma, carcinoma of prostate, carcinoma of penis, tumor of testis, carcinoma of endometrium, choriocarcinoma, For Primary Vaginal Carcinoma, Vulvar, Hodgkin, non-Hodgkin lymphoma, skin carcinoma, the one in malignant melanoma.
The stealthy thermal sensitive liposome of the present invention's novel targeted temperature-sensitive sensitizer mediation can be made into multi-medicament dosage form as heat sensitizer, as injection, aseptic powder needle for injection, dispersant, patch, gel, implant etc.Preparation of the present invention can add various formulation additives, as normal saline, glucose, buffer solution and antiseptic etc.Administering mode can be intravenous injection, intramuscular injection, intratumor injection and subcutaneous injection, transdermal administration, et al. Ke mode etc.
Correlation test data is as follows:
One, illumination is used to penetrate the stealthy thermosensitive liposome drug movement system of the present invention to the mensuration of tumor cell growth activity.
Drug delivery system anti-tumor activity experiment is in vitro penetrated: by MCF-7 breast cancer cell (being provided by Shanghai cell bank) as cancerous cell to be investigated by illumination.MCF-7 cell culture is being contained hyclone (FBS) 10%, and in the RPMI1640 culture medium of mycillin mixed liquor 1%, incubator condition is 37 DEG C, 5%CO
2, within every 2 ~ 3 days, go down to posterity once.Collect logarithmic (log) phase cell, adjustment concentration of cell suspension, the 96 every holes of orifice plate add 200 μ l, and bed board makes cell to be measured adjust density to 6 × 10
3individual/hole, (the aseptic PBS of edge hole fills).Be placed in 5%CO
2, hatch 24h for 37 DEG C, be paved with (96 hole flat underside) at the bottom of hole to cell monolayer, add the stealthy thermal sensitive liposome in the embodiment 1 of Concentraton gradient (12.5,25,50,100 μ g/ml), arranging multiple hole is 4 ~ 6.Light group is placed on 2min in 808nm near infrared light 2W, and in maintenance During Illumination, temperature is at 37 DEG C, and illumination terminates rear aluminium foil parcel cell plates and is placed in CO
2hatch 24h in incubator, for for light group, then direct aluminium foil parcel cell plates are placed in CO
2hatch 24h in incubator, stop cultivating, sucking-off pastille culture medium, every hole 150 μ l PBS wash 2 times, add the 10%TCA200 μ l of pre-cooling, place 1h for 4 DEG C.Outwell fixative, every hole deionized water washes 5 times, dries, air drying.Every hole adds the SRB solution of 100 μ l, leaves standstill and places 10min, do not wash 5 times, air drying with protein bound SRB 1% acetic acid.In conjunction with SRB 150 μ l10mmol/L non-buffered Tris alkali dissolutions.The OD value in every hole is measured at 808nm place.The computing formula of survival rate: survival rate=experimental group OD value/matched group OD value, wherein experimental group and matched group are the value after deducting blank group.
Experiment proves, irradiates 2min when using up, drug delivery system of the present invention add the propagation directly affecting MCF-7 cell.Two, when illumination is penetrated, the determination of activity of the present invention's stealthy thermosensitive liposome drug movement system anti-tumor in vivo.
Get mouse S180 ascites sarcoma cell, with injection normal saline with after 3:1 dilution proportion, every mice, in lumbar injection 0.3ml, after mice feeds 7 days, extracts mouse S180 ascites sarcoma cell, becomes concentration for 2 × 10 after counting with injection normal saline dilution
6the cell suspension of individual/ml, subcutaneous vaccination and mice right fore top.After mouse inoculation tumor 7d, get wherein 36 gross tumor volume>=100mm
3kunming mice, is divided into 6 groups at random, often organizes 6.Specifically be grouped as follows: (1) matched group (normal saline group); (2) normal saline laser group; (3) drug solution group; (4) drug solution laser group; (5) preparation group; (6) preparation laser group.6 groups of modes all adopting intravenously administrable, the light source that wherein light group uses is 808nm near-infrared light source, and power is 2W, and after administration 3h, laser irradiates tumor locus, and the once irradiating time is 2min.Every 2d is administered once, the formulation soln 200 μ l of per injection normal saline or drug solution or 1mg/ml, altogether administration 7 times.In whole experimentation, every day observes mice animation, and every 2d claims its body weight and uses the major diameter (A) of vernier caliper measurement murine sarcoma and minor axis (B), by formula gross tumor volume
calculate gross tumor volume.
Experiment proves, administration stealthy thermal sensitive liposome of the present invention, obviously can suppress the increase of mouse tumor volume under light illumination.
Three, the mensuration of stealthy thermosensitive liposome drug movement system drug loading of the present invention.
Get the stealthy thermal sensitive liposome drug-supplying system of doxorubicin hydrochloride of the present invention, by adding the doxorubicin hydrochloride encapsulated in 40 times of methanol extraction drug-supplying systems, it is 1.85mg/mL that ultraviolet spectrophotometer measures drug loading, shows that the stealthy thermal sensitive liposome of doxorubicin hydrochloride of the present invention can as the carrier of antitumor drug.
Four, the stealthy particle size of thermal sensitive liposome drug-supplying system of doxorubicin hydrochloride of the present invention and the determination of surface band electricity.
The stealthy particle size of thermal sensitive liposome drug-supplying system of doxorubicin hydrochloride in the present invention and the determination of surface band electricity, Nano-ZS90 type laser particle size analyzer is used to measure, refractive index is set to 1.590, absorptance is set to 0.010, temperature is set to 25 DEG C, measurement pattern is set to automatically, using Z average statistical value as measurement result.Each horizontal condensation body all prepares 3 parts, measures once, gets the meansigma methods of three measured values as measurement result for every part.Dielectric constant is set to 79, and coefficient of viscosity is set to 0.8872, and temperature is set to 25 DEG C, and measurement pattern is set to automatically.Each horizontal condensation body all prepares 3 parts, measures once, gets the meansigma methods of three measured values as measurement result for every part.The result recorded is particle diameter is 100 ~ 200nm, and current potential is-40mV.
The anti tumor activity in vitro of the stealthy thermal sensitive liposome drug-supplying system of the doxorubicin hydrochloride five, in the present invention.
The anti tumor activity in vitro of the stealthy thermal sensitive liposome drug-supplying system of the doxorubicin hydrochloride in the present invention, by MCF-7 breast cancer cell (being provided by Shanghai cell bank) as cancerous cell to be investigated.MCF-7 cell culture is being contained hyclone (FBS) 10%, and in the RPMI1640 culture medium of mycillin mixed liquor 1%, incubator condition is 37 DEG C, 5%CO
2, within every 2 ~ 3 days, go down to posterity once.Collect logarithmic (log) phase cell, adjustment concentration of cell suspension, the 96 every holes of orifice plate add 200 μ l, and bed board makes cell to be measured adjust density to 6 × 10
3individual/hole, (the aseptic PBS of edge hole fills).Be placed in 5%CO
2hatch 24h for 37 DEG C, (96 hole flat underside) at the bottom of hole is paved with to cell monolayer, add the stealthy thermal sensitive liposome of doxorubicin hydrochloride in the embodiment 1 of Concentraton gradient (0,0.5,1,2,4,6,8 μ g/ml), the stealthy thermal sensitive liposome of doxorubicin hydrochloride do not added in embodiment 1 is matched group, and arranging multiple hole is 4 ~ 6.Light group is placed on 2min in 808nm near infrared light 2W, and in maintenance During Illumination, temperature is at 37 DEG C, and illumination terminates rear aluminium foil parcel cell plates and is placed in CO
2hatch 24h in incubator, for not light group, then direct aluminium foil parcel cell plates are placed in CO2 incubator and hatch 24h, and stop cultivating, sucking-off pastille culture medium, every hole 150 μ l PBS wash 2 times, add the 10%TCA200 μ l of pre-cooling, 4 DEG C of placement 1h.Outwell fixative, every hole deionized water washes 5 times, dries, air drying.Every hole adds the SRB solution of 100 μ l, leaves standstill and places 10min, do not wash 5 times, air drying with protein bound SRB 1% acetic acid.In conjunction with SRB 150 μ l10mmol/L non-buffered Tris alkali dissolutions.The OD value in every hole is measured at 515nm place.The computing formula of suppression ratio: suppression ratio=1-experimental group OD value/matched group OD value, wherein experimental group and matched group are the value after deducting blank group.
Experiment proves, the stealthy thermal sensitive liposome of doxorubicin hydrochloride of the present invention drug loading can enter inside tumor cells as during pharmaceutical carrier, plays the curative effect of antitumor drug better, and in conjunction with after illumination, can the propagation of more obvious inhibition tumor cell.The anti-tumor in vivo of the stealthy thermal sensitive liposome drug-supplying system of the doxorubicin hydrochloride six, in the present invention is active.
The anti-tumor in vivo of the stealthy thermal sensitive liposome drug-supplying system of the doxorubicin hydrochloride in the present invention is active, get mouse S180 ascites sarcoma cell, with injection normal saline with after 3:1 dilution proportion, every mice is in lumbar injection 0.3ml, after mice feeds 7 days, extract mouse S180 ascites sarcoma cell, after counting, become concentration for 2 × 10 with injection normal saline dilution
6the cell suspension of individual/ml, subcutaneous vaccination and mice right fore top.After mouse inoculation tumor 7d, get wherein 24 gross tumor volume>=100mm
3kunming mice, is divided into 4 groups at random, often organizes 6.Specifically be grouped as follows: (1) matched group (normal saline group); (2) doxorubicin hydrochloride inj group; (3) stealthy thermal sensitive liposome group; (4) stealthy thermal sensitive liposome laser group.The doxorubicin hydrochloride dosage of the stealthy thermal sensitive liposome group of doxorubicin hydrochloride inj group, doxorubicin hydrochloride and the stealthy thermal sensitive liposome light group of doxorubicin hydrochloride is equal, is 10.125mg/kg.4 groups of modes all adopting intravenously administrable, the light source that wherein light group uses is 808nm near-infrared light source, and power is 2W, and after administration 3h, laser irradiates tumor locus, and the once irradiating time is 2min.Every 2d is administered once, altogether administration 7 times.In whole experimentation, every day observes mice animation, and every 2d claims its body weight and uses the major diameter (A) of vernier caliper measurement murine sarcoma and minor axis (B), by formula gross tumor volume
calculate gross tumor volume.
After the stealthy thermal sensitive liposome of doxorubicin hydrochloride of the present invention is given in administration, the increase of mouse tumor volume is significantly suppressed than doxorubicin hydrochloride inj, and when irradiating in conjunction with laser, the increase of mouse tumor volume obtains more significantly suppressing.
Meanwhile, additionally use other light sources and antitumor drug has done similar experiment, all achieve identical and similar result, the present invention divides into groups science, and method is reliable and stable.
Advantageous Effects:
(1) the stealthy thermal sensitive liposome of the present invention can not destroy the characteristic of CNT itself, and its water dispersible is strong, very low to the toxicity of organism, and well, quality is good, preparation condition simple possible, and abundant raw material source, cost is low for physics and chemical stability.
(2) the stealthy thermal sensitive liposome of the present invention can as a kind of good heat sensitizer of tumor temperature-sensitive treatment, and no matter experiment is external or in body if showing, in conjunction with all can the obviously generation of inhibition tumor cell and tissue and development when illumination; And when unglazed photograph, the present invention is to normal cell and organize toxic and side effects very little, optionally killing tumor cells tissue and cell can be come according to means such as the focusing of light.
(3) the stealthy thermal sensitive liposome of the present invention can as a kind of carrier of good antitumor drug, and have toxicity minimum, water solublity is stronger, good biocompatibility, specific surface area is large, chemical inertness, there is slow-releasing and targeting, and better antitumous effect can be played in conjunction with laser irradiation.
Claims (7)
1. a preparation method for stealthy thermal sensitive liposome, is characterized in that, is realized by following steps:
(1) synthesis of carboxylic carbon nano-tube: get 95 ~ 110mg CNT, put into 250mL flask, add the nitration mixture of 120mL, 11 ~ 13mL mass concentration is the hydrogenperoxide steam generator of 30%, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μm of microporous filter membrane and buchner funnel sucking filtration, be neutral with ultrapure water to pH, put into baking oven 80 DEG C of freeze-day with constant temperature, obtain carboxylated CNT; The mixed acid that described nitration mixture forms with volume ratio 3 ︰ 1 for concentrated sulphuric acid and concentrated nitric acid;
(2) synthesis of the CNT-lysine of folate-targeted: get carboxylated CNT 45 ~ 55mg, add the lysine solution of 25mL 0.1 ~ 0.3M, add 9 ~ 11mg folic acid again, 45 ~ 55mg 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 9 ~ 11mg N-hydroxy-succinamide, be placed in flask, after ultrasonic disperse 2h, under ice bath, stirring 24h with 100r/min makes it fully react, dialyse after reaction terminates 48h in bag filter, remove unreacted 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, N-hydroxy-succinamide, folic acid and lysine, vacuum drying 24h at 60 DEG C, obtain the CNT-lysine of folate-targeted,
(3) preparation of stealthy thermal sensitive liposome: take 45 ~ 55mg dipalmitoyl phosphatidyl choline, the cholesterol of 1 ~ 3mg DSPE-PEG 2000 and 18 ~ 22mg, be placed in 100mL eggplant type flask, add ether and make to dissolve completely, then add 5mL PBS solution, ultrasonic emulsification 40min, form stable O/W type Emulsion, under 45 DEG C of decompressions rotate, remove ether, 200W visits super 2min, dialyse in bag filter after 48h, obtain stealthy thermal sensitive liposome; Described PBS solution is the solution that the CNT-lysine of 10mg folate-targeted and 6mg doxorubicin hydrochloride are dissolved in 5mL PBS, pH7.4 and are formed.
2. the preparation method of stealthy thermal sensitive liposome according to claim 1, is characterized in that, realized by following steps:
(1) synthesis of carboxylic carbon nano-tube: get 100mg CNT, put into 250mL flask, add the nitration mixture of 120mL, 12mL mass concentration is the hydrogenperoxide steam generator of 30%, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μm of microporous filter membrane and buchner funnel sucking filtration, be neutral with ultrapure water to pH, put into baking oven 80 DEG C of freeze-day with constant temperature, obtain carboxylated CNT;
(2) synthesis of the CNT-lysine of folate-targeted: get carboxylated CNT 50mg, add the lysine solution of 25mL 0.2M, add 10mg folic acid again, 50mg 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 10mg N-hydroxy-succinamide, be placed in flask, after ultrasonic disperse 2h, under ice bath, stirring 24h with 100r/min makes it fully react, dialyse after reaction terminates 48h in bag filter, remove unreacted 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, N-hydroxy-succinamide, folic acid and lysine, vacuum drying 24h at 60 DEG C, obtain the CNT-lysine of folate-targeted,
(3) preparation of stealthy thermal sensitive liposome: get 50mg dipalmitoyl phosphatidyl choline; the cholesterol of 2mg DSPE-PEG 2000 and 20mg; be placed in 100mL eggplant type flask, add ether and make to dissolve completely, then add 5mL PBS solution; ultrasonic emulsification 40min; form stable O/W type Emulsion, under 45 DEG C of decompressions rotate, remove ether, 200W visits super 2min; dialyse in bag filter after 48h, obtain stealthy thermal sensitive liposome.
3. the preparation method of stealthy thermal sensitive liposome according to claim 1, is characterized in that, realized by following steps:
(1) synthesis of carboxylic carbon nano-tube: get 105mg CNT, put into 250mL flask, add the nitration mixture of 120mL, 13mL mass concentration is the hydrogenperoxide steam generator of 30%, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μm of microporous filter membrane and buchner funnel sucking filtration, be neutral with ultrapure water to pH, put into baking oven 80 DEG C of freeze-day with constant temperature, obtain carboxylated CNT;
(2) synthesis of the CNT-lysine of folate-targeted: take carboxylated CNT 53mg, add the lysine solution of 25mL 0.2M, add 11mg folic acid again, 53mg 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 11mg N-hydroxy-succinamide, be placed in flask, after ultrasonic disperse 2h, under ice bath, stirring 24h with 100r/min makes it fully react, dialyse after reaction terminates 48h in bag filter, remove unreacted 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, N-hydroxy-succinamide, folic acid and lysine, vacuum drying 24h at 60 DEG C, obtain the CNT-lysine of folate-targeted,
(3) preparation of stealthy thermal sensitive liposome: take 53mg dipalmitoyl phosphatidyl choline; the cholesterol of 3mg DSPE-PEG 2000 and 22mg; be placed in 100mL eggplant type flask, add ether and make to dissolve completely, then add 5mL PBS solution; ultrasonic emulsification 40min; form stable O/W type Emulsion, under 45 DEG C of decompressions rotate, remove ether, 200W visits super 2min; dialyse in bag filter after 48h, obtain stealthy thermal sensitive liposome.
4. a preparation method for stealthy thermal sensitive liposome, is characterized in that, is realized by following steps:
(1) synthesis of carboxylic carbon nano-tube: get 95 ~ 110mg CNT, put into 250mL flask, add 120mL nitration mixture, 11 ~ 13mL mass concentration is the hydrogenperoxide steam generator of 30%, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μm of microporous filter membrane and buchner funnel sucking filtration, be neutral with ultrapure water to pH, put into baking oven 80 DEG C of freeze-day with constant temperature, obtain carboxylic carbon nano-tube; The mixed acid that described nitration mixture forms with volume ratio 3 ︰ 1 for concentrated sulphuric acid and concentrated nitric acid;
(2) synthesis of the CNT-lysine of load chemotherapeutics: take carboxylic carbon nano-tube 45 ~ 55mg, add 25mL 0.1 ~ 0.3M lysine solution, 45 ~ 55mg 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 9 ~ 11mg N-hydroxy-succinamide, be placed in flask, after ultrasonic disperse 2h, under ice bath, 24h is stirred with 100r/min, it is made fully to react, dialyse after reaction terminates 48h in bag filter, remove unreacted 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, N-hydroxy-succinamide and lysine, vacuum drying 24h at 60 DEG C, obtain CNT-lysine, take 9 ~ 11mg CNT-lysine again, add 10mL ultra-pure water, ultrasonic to entirely molten, then add 18 ~ 22mg chemotherapeutics, ultrasonic 4h, dialyse 24h in bag filter, the medicine that removing is free, obtains the CNT-lysine of carrying medicament,
(3) preparation of stealthy thermal sensitive liposome: get 45 ~ 55mg dipalmitoyl phosphatidyl choline, 1 ~ 3mg DSPE-PEG 2000 and 18 ~ 22mg cholesterol, be placed in 100mL eggplant type flask, add ether and make to dissolve completely, then add 5mL PBS solution, ultrasonic emulsification 40min, form stable O/W type Emulsion, under 45 DEG C of decompressions rotate, remove ether, 200W visits super 2min, dialyse 48h in bag filter, obtains stealthy thermal sensitive liposome; Described PBS solution is the solution that the CNT-lysine of 10mg load chemotherapeutics and 6mg doxorubicin hydrochloride are dissolved in 5mL PBS, pH7.4 and are formed.
5. the preparation method of stealthy thermal sensitive liposome according to claim 4, is characterized in that, realized by following steps:
(1) synthesis of carboxylic carbon nano-tube: get 100mg CNT, put into 250mL flask, add 120mL nitration mixture, 12mL mass concentration is the hydrogenperoxide steam generator of 30%, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μm of microporous filter membrane and buchner funnel sucking filtration, be neutral with ultrapure water to pH, put into baking oven 80 DEG C of freeze-day with constant temperature, obtain carboxylic carbon nano-tube;
(2) synthesis of the CNT-lysine of load doxorubicin hydrochloride: get carboxylic carbon nano-tube 50mg, add 25mL 0.2M lysine solution, 50mg 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 10mg N-hydroxy-succinamide, be placed in flask, after ultrasonic disperse 2h, under ice bath, 24h is stirred with 100r/min, it is made fully to react, dialyse after reaction terminates 48h in bag filter, remove unreacted 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, N-hydroxy-succinamide and lysine, vacuum drying 24h at 60 DEG C, obtain CNT-lysine, get 10mg CNT-lysine again, add 10mL ultra-pure water, ultrasonic to entirely molten, then add 20mg doxorubicin hydrochloride, ultrasonic 4h, dialyse 24h in bag filter, the medicine that removing is free, obtains the CNT-lysine of load doxorubicin hydrochloride,
(3) preparation of stealthy thermal sensitive liposome: take 50mg dipalmitoyl phosphatidyl choline, 2mg DSPE-PEG 2000 and 20mg cholesterol, be placed in 100mL eggplant type flask, add ether and make to dissolve completely, then add 5mL PBS solution, ultrasonic emulsification 40min, form stable O/W type Emulsion, under 45 DEG C of decompressions rotate, remove ether, 200W visits super 2min, dialyse 48h in bag filter, obtains stealthy thermal sensitive liposome; Described PBS solution is the solution that the CNT-lysine of 10mg load doxorubicin hydrochloride and 6mg doxorubicin hydrochloride are dissolved in 5mL PBS, pH7.4 and are formed.
6. the preparation method of stealthy thermal sensitive liposome according to claim 4, is characterized in that, realized by following steps:
(1) synthesis of carboxylic carbon nano-tube: get 105mg CNT, put into 250mL round-bottomed flask, add 120mL nitration mixture, 13mL mass concentration is the hydrogenperoxide steam generator of 30%, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μm of microporous filter membrane and buchner funnel sucking filtration, be neutral with ultrapure water to pH, put into baking oven 80 DEG C of freeze-day with constant temperature, obtain carboxylic carbon nano-tube;
(2) synthesis of the CNT-lysine of load Docetaxel: take carboxylic carbon nano-tube 53mg, add 25mL 0.15M lysine solution, 53mg 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and 11mg N-hydroxy-succinamide, be placed in flask, after ultrasonic disperse 2h, under ice bath, 24h is stirred with 100r/min, it is made fully to react, dialyse after reaction terminates 48h in bag filter, remove unreacted 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, N-hydroxy-succinamide and lysine, vacuum drying 24h at 60 DEG C, obtain CNT-lysine, take 10mg CNT-lysine again, add 10mL ultra-pure water, ultrasonic to entirely molten, then add 22mg Docetaxel, ultrasonic 4h, dialyse 24h in bag filter, the medicine that removing is free, obtains the CNT-lysine of load Docetaxel,
(3) preparation of stealthy thermal sensitive liposome: take 53mg dipalmitoyl phosphatidyl choline, 3mg DSPE-PEG 2000 and 22mg cholesterol, be placed in 100mL eggplant type flask, add ether and make to dissolve completely, then add 5mL PBS solution, ultrasonic emulsification 40min, form stable O/W type Emulsion, under 45 DEG C of decompressions rotate, remove ether, 200W visits super 2min, dialyse 48h in bag filter, obtains stealthy thermal sensitive liposome; Described PBS solution is the solution that the CNT-lysine of 10mg load Docetaxel and 6mg doxorubicin hydrochloride are dissolved in 5mL PBS, pH7.4 and are formed.
7. the stealthy thermal sensitive liposome that described in any one of claim 1 or claim 2-6 prepared by method is as the application of drug delivery system in preparation tumor.
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| CN114699371B (en) * | 2022-04-12 | 2023-04-28 | 河南中医药大学 | Transferrin-mediated single-wall carbon nano Guan Tao sevoflurane U liposome complex and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103007281A (en) * | 2012-12-26 | 2013-04-03 | 郑州大学 | Preparation method of multi-mechanism treatment tumor photo-thermal controlled-release long-circulation medicament transit system and application thereof |
| CN103284951A (en) * | 2013-04-27 | 2013-09-11 | 浙江大学 | Photosensitive liposome with encapsulated water-soluble medicament |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103007281A (en) * | 2012-12-26 | 2013-04-03 | 郑州大学 | Preparation method of multi-mechanism treatment tumor photo-thermal controlled-release long-circulation medicament transit system and application thereof |
| CN103284951A (en) * | 2013-04-27 | 2013-09-11 | 浙江大学 | Photosensitive liposome with encapsulated water-soluble medicament |
Non-Patent Citations (2)
| Title |
|---|
| Photoinduced drug release from thermosensitive AuNPs-liposome using a AuNPs-switch;Xueqin An et al.;《Chem. Commun.》;20100827;第46卷;7202-7204 * |
| 纳米开关控制释放药物脂质体的制备和功能;安学勤等;《第一届全国生物物理化学会议暨生物物理化学发展战略研讨会论文摘要集》;20101231;62 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107233314A (en) * | 2017-05-08 | 2017-10-10 | 荆楚理工学院 | It is a kind of that there are double target areas to pass composite phospholipid thermal sensitive liposome of drug effect fruit and its preparation method and application simultaneously |
| CN107233314B (en) * | 2017-05-08 | 2020-09-18 | 荆楚理工学院 | Composite phospholipid thermosensitive liposome with double-target-region simultaneous drug delivery effect and preparation method and application thereof |
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