CN103520726A - 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 drug delivery system thereof the application in anti-tumor medicine.
Background technology
Stealthy thermal sensitive liposome is the drug delivery carrier of a kind of physical chemistry and active targeting.Under normal body temperature, hydrophilic medicament be difficult to see through liposome membrane and diffuses out, and when liposome is with blood circulation during through heated target organ, and the high temperature of part can impel medicine discharge and form higher drug level at target site; Stealthy thermal sensitive liposome has good medicine carrying, targeting and biocompatibility and forms as the study hotspot in biomedicine field, has reported that at present thermal sensitive liposome local heat method has immersion method, microwave method, radio frequency method etc.
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 can effectively carry the bioactive substances such as protein, antibody, polypeptide, medicine and nucleic acid and enter cell, thereby becomes the carrier that people pay close attention to.CNT has high absorption characteristic to the near infrared light of 700～1100nm scope, and biosystem has height permeability to the near infrared light of this scope simultaneously, therefore can utilize the photo-thermal transfer characteristic of CNT to carry out laserthermia to tumor.CNT is drug delivery carrier, is also the main body of performance thermotherapy effect simultaneously, can be used as chemotherapeutics sensitizer and targeting heat sensitizer.But CNT is water insoluble and organic solvent, and in solution, easily assemble bunchy, be difficult to disperse, have a strong impact on its application.
DPPC (dipalmitoyl phosphatidyl choline), C
40h
80nO
8p, molecular weight 734.04, phase transition temperature 41-42 ℃, can be used as main material prepared by thermal sensitive liposome, just can cause that thermal sensitive liposome discharges and includes medicine rapidly, realizes 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, by stealthy thermal sensitive liposome load targeting heat sensitizer (as CNT) and chemotherapeutics, form drug delivery system, the particularly application in anti-tumor medicine and there is not yet report.
Summary of the invention
For above-mentioned situation, overcome the defect of prior art, the present invention's object is just to provide a kind of preparation method of stealthy thermal sensitive liposome drug delivery system and the application in anti-tumor medicine thereof, can effectively 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, by stealthy thermal sensitive liposome load targeting heat sensitizer and chemotherapeutics, formed, wherein, the mass ratio of targeting heat sensitizer and chemotherapeutics is 1:3, and described targeting heat sensitizer is a kind of of SWCN and derivant, multi-walled carbon nano-tubes and derivant thereof, Graphene and derivant thereof, 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, one or more compositions of Xi Tabin, methotrexate, hydroxy camptothecin, the few adopted antinucleus thuja acid of small nut acids and siRNA.
The preparation method of described stealthy thermal sensitive liposome, is realized by following steps:
(1) carboxylic carbon nano-tube is synthetic: get 95～110mg CNT, put into 250mL flask, the nitration mixture that adds 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 μ m microporous filter membrane and buchner funnel sucking filtration, it is neutral with ultra-pure water, rinsing to pH, puts into 80 ℃ of freeze-day with constant temperature of baking oven, obtains carboxylated CNT (CNTs-COOH); Described nitration mixture is the mixed acid that concentrated sulphuric acid and concentrated nitric acid are formed with volume ratio 3 ︰ 1;
(2) CNT-lysine of folate-targeted is synthetic: get carboxylated CNT 45～55mg, the lysine solution that adds 25mL0.1～0.3M, add again folic acid 9～11mg, 45～55mg1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCHCl), 9～11mg N-hydroxy-succinamide (NHS), be placed in flask, after ultrasonic dispersion 2h, under ice bath, with 100r/min, stirring 24h fully reacts it, 48h dialyses after reaction finishes in bag filter, remove unreacted EDCHCl, NHS, folic acid and lysine, vacuum drying 24h at 60 ℃, 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 again 5mL PBS solution, ultrasonic emulsification 40min, form stable O/W type Emulsion, under 45 ℃ of decompression rotations, remove ether, visit super (200W, 2min), in bag filter, dialyse after 48h, obtain stealthy thermal sensitive liposome; Described PBS solution is that CNT-lysine and the 6mg doxorubicin hydrochloride of 10mg folate-targeted is dissolved in the solution that 5mL PBS (pH7.4) forms.
Also can be realized by following steps:
(1) carboxylic carbon nano-tube is synthetic: 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 μ m microporous filter membrane and buchner funnel sucking filtration, it is neutral with ultra-pure water, rinsing to pH, puts into 80 ℃ of freeze-day with constant temperature of baking oven, obtains carboxylic carbon nano-tube (CNTs-COOH); Described nitration mixture is the mixed acid that concentrated sulphuric acid and concentrated nitric acid are formed with volume ratio 3 ︰ 1;
(2) CNT-lysine of load chemotherapeutics is synthetic: 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 dispersion 2h, under ice bath, with 100r/min, stir 24h, it is fully reacted, 48h dialyses after reaction finishes in bag filter, remove unreacted EDCHCl, NHS and lysine, vacuum drying 24h at 60 ℃, obtain CNT-lysine (Lys/CNTs), take again 9～11mg CNT-lysine, add 10mL ultra-pure water, ultrasonic to entirely molten, then add 18～22mg chemotherapeutics, and ultrasonic 4h, the 24h that dialyses in bag filter, removes free medicine, obtains the CNT-lysine of carrying medicament,
(3) preparation of stealthy thermal sensitive liposome: the dipalmitoyl phosphatidyl choline (DPPC) of 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 again 5mL PBS solution, ultrasonic emulsification 40min, form stable O/W type Emulsion, under 45 ℃ of decompression rotations, remove ether, visit super (200W, 2min), the 48h that dialyses in bag filter, obtains stealthy thermal sensitive liposome; Described PBS solution is that CNT-lysine and the 6mg doxorubicin hydrochloride of 10mg load chemotherapeutics is dissolved in the solution that 5mL PBS (pH7.4) forms.
Described stealthy thermal sensitive liposome drug delivery system, can be implanted into for intravenous injection, intramuscular injection, intratumor injection and subcutaneous injection, transdermal administration, body.
Stealthy thermal sensitive liposome load targeting heat sensitizer of the present invention (as CNT) and chemotherapeutics, targeting heat sensitizer can load slightly solubility chemotherapeutics, there is the hot transfer characteristic of high light and produce active oxygen ability, the feature also with tumor-targeting, at tumor locus, carry out laser irradiation, utilize heat sensitizer heat production under laser irradiation to cause the heat sensitivity of thermo-sensitive material to make drug delivery system location discharge medicine, thereby reach the effect of neoplasm targeted therapy; Body physical and chemical stability of the present invention is good, preparation condition simple possible, and raw material sources are abundant, and cost is low, and side effect is little, and effectively the propagation of inhibition tumor cell, is the innovation on neoplasm targeted therapy Chinese medicine carrier.
The specific embodiment
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) carboxylic carbon nano-tube is synthetic: take 100mg CNT, put into 250mL round-bottomed flask, the nitration mixture that adds 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 μ m microporous filter membrane and buchner funnel sucking filtration, it is neutral with ultra-pure water, rinsing to pH, puts into 80 ℃ of freeze-day with constant temperature of baking oven, obtains carboxylated CNT (CNTs-COOH); Described nitration mixture is the mixed acid that concentrated sulphuric acid and concentrated nitric acid are formed with volume ratio 3 ︰ 1;
(2) CNT-lysine of folate-targeted is synthetic: take carboxylated CNT 50mg, the lysine solution that adds 25mL0.2M, add again folic acid 10mg, 50mg1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCHCl), 10mg N-hydroxy-succinamide (NHS), be placed in flask, after ultrasonic dispersion 2h, under ice bath, with 100r/min, stirring 24h fully reacts it, 48h dialyses after reaction finishes in bag filter, remove unreacted EDCHCl, NHS, folic acid and lysine, vacuum drying 24h at 60 ℃, 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 again 5mL PBS solution, ultrasonic emulsification 40min, form stable O/W type Emulsion, under 45 ℃ of decompression rotations, remove ether, visit super (200W, 2min), in bag filter, dialyse after 48h, obtain stealthy thermal sensitive liposome; Described PBS solution is that CNT-lysine and the 6mg doxorubicin hydrochloride of 10mg folate-targeted is dissolved in the solution that 5mLPBS (pH7.4) forms.
Embodiment 2
Preparation method of the present invention, in concrete enforcement, also can be realized by following steps:
(1) carboxylic carbon nano-tube is synthetic: take 105mg CNT, put into 250mL round-bottomed flask, the nitration mixture that adds 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 μ m microporous filter membrane and buchner funnel sucking filtration, it is neutral with ultra-pure water, rinsing to pH, puts into 80 ℃ of freeze-day with constant temperature of baking oven, obtains carboxylated CNT (CNTs-COOH);
(2) CNT-lysine of folate-targeted is synthetic: take carboxylated CNT 53mg, the lysine solution that adds 25mL0.2M, add again folic acid 11mg, 53mg1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCHCl), 11mg N-hydroxy-succinamide (NHS), be placed in flask, after ultrasonic dispersion 2h, under ice bath, with 100r/min, stirring 24h fully reacts it, 48h dialyses after reaction finishes in bag filter, remove unreacted EDCHCl, NHS, folic acid and lysine, vacuum drying 24h at 60 ℃, 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 again 5mL PBS solution, ultrasonic emulsification 40min, form stable O/W type Emulsion, under 45 ℃ of decompression rotations, remove ether, visit super (200W, 2min), in bag filter, dialyse after 48h, obtain stealthy thermal sensitive liposome; Described PBS solution is that CNT-lysine and the 6mg doxorubicin hydrochloride of 10mg folate-targeted is dissolved in the solution that 5mLPBS (pH7.4) forms.
Embodiment 3
Preparation method of the present invention, in concrete enforcement, can be realized by following steps:
(1) carboxylic carbon nano-tube is synthetic: 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 μ m microporous filter membrane and buchner funnel sucking filtration, it is neutral with ultra-pure water, rinsing to pH, puts into 80 ℃ of freeze-day with constant temperature of baking oven, obtains carboxylic carbon nano-tube (CNTs-COOH);
(2) CNT-lysine of load doxorubicin hydrochloride is synthetic: 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 dispersion 2h, under ice bath, with 100r/min, stir 24h, it is fully reacted, 48h dialyses after reaction finishes in bag filter, remove unreacted EDCHCl, NHS and lysine, vacuum drying 24h at 60 ℃, obtain CNT-lysine (Lys/CNTs), take again 10mg CNT-lysine, add 10mL ultra-pure water, ultrasonic to entirely molten, add again 20mg doxorubicin hydrochloride, ultrasonic 4h, 24h dialyses in bag filter, remove free medicine, obtain the CNT-lysine (Lys/CNTs-DOX) of load doxorubicin hydrochloride,
(3) preparation of stealthy thermal sensitive liposome: the dipalmitoyl phosphatidyl choline (DPPC) that takes 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 again 5mL PBS solution, ultrasonic emulsification 40min, form stable O/W type Emulsion, under 45 ℃ of decompression rotations, remove ether, visit super (200W, 2min), the 48h that dialyses in bag filter, obtains stealthy thermal sensitive liposome; Described PBS solution is that CNT-lysine and the 6mg doxorubicin hydrochloride of 10mg load doxorubicin hydrochloride is dissolved in the solution that 5mL PBS (pH7.4) forms.
Embodiment 4
Preparation method of the present invention, in concrete enforcement, also can be realized by following steps:
(1) carboxylic carbon nano-tube is synthetic: 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 μ m microporous filter membrane and buchner funnel sucking filtration, it is neutral with ultra-pure water, rinsing to pH, puts into 80 ℃ of freeze-day with constant temperature of baking oven, obtains carboxylic carbon nano-tube (CNTs-COOH);
(2) CNT-lysine of load Docetaxel is synthetic: 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 dispersion 2h, under ice bath, with 100r/min, stir 24h, it is fully reacted, 48h dialyses after reaction finishes in bag filter, remove unreacted EDCHCl, NHS and lysine, vacuum drying 24h at 60 ℃, obtain CNT-lysine (Lys/CNTs), take again 10mg CNT-lysine, add 10mL ultra-pure water, ultrasonic to entirely molten, add again 22mg Docetaxel, ultrasonic 4h, 24h dialyses in bag filter, remove free medicine, obtain the CNT-lysine (Lys/CNTs-DOC) of load Docetaxel,
(3) preparation of stealthy thermal sensitive liposome: the DPPC that takes 53mg, the DSPE-PEG2000 of 2mg and the cholesterol of 22mg, be placed in 100mL eggplant type flask, adds ether to make to dissolve completely, add again 5mL PBS solution, ultrasonic emulsification 40min, forms stable O/W type Emulsion, under 45 ℃ of decompression rotations, removes ether, visit super (200W, 2min), the 48h that dialyses in bag filter, obtains stealthy thermal sensitive liposome; Described PBS solution is that CNT-lysine and the 6mg doxorubicin hydrochloride of 10mg load Docetaxel is dissolved in the solution that 5mL PBS (pH7.4) forms.
The application in anti-tumor medicine of the preparation method of stealthy thermal sensitive liposome of the present invention and drug delivery system thereof is divided in vitro and in vivo two parts:
(1) in body: stealthy thermal sensitive liposome drug delivery system of the present invention is joined in cancerous cell and cultivated, wide wavelength light source or 808nm laser light with 780～1100nm wavelength after administration 3h are shone, 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 that occur, 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, a kind of in malignant melanoma.
(2) external: stealthy thermal sensitive liposome drug delivery system of the present invention intravenous injection is arrived in tumor-bearing mice body, wide wavelength light source or 808nm laser light with 780～1100nm wavelength after administration 3h are shone, 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 that occur, 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, a kind of in malignant melanoma.
The stealthy thermal sensitive liposome of the novel targeted temperature-sensitive sensitizer mediation of the present invention 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, body is implanted into mode etc.
Correlation test data is as follows:
One, use the mensuration of the stealthy thermal sensitive liposome drug delivery system of rayed the present invention to tumor cell growth activity.
By rayed drug delivery system in vitro anti-tumor activity test: 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 to hyclone (FBS) 10%, and in the RPMI1640 culture medium of mycillin mixed liquor 1%, incubator condition is 37 ℃, 5%CO
2, within every 2～3 days, go down to posterity once.Collect logarithmic (log) phase cell, adjust 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, (edge hole is filled with aseptic PBS).Be placed in 5%CO
2, hatch 24h for 37 ℃, at the bottom of being paved with hole to cell monolayer (96 hole flat underside), add the stealthy thermal sensitive liposome in the embodiment 1 of Concentraton gradient (12.5,25,50,100 μ g/ml), it is 4～6 that multiple hole is set.Light group is placed on 2min in 808nm near infrared light 2W, keeps in During Illumination temperature at 37 ℃, and illumination finishes with aluminium foil parcel cell plates, to be placed in CO afterwards
2in incubator, hatch 24h, for for light group, directly with aluminium foil parcel cell plates, be placed in CO
2in incubator, hatch 24h, stop cultivating, sucking-off pastille culture medium, every hole is washed 2 times with 150 μ l PBS, adds the 10%TCA200 μ l of pre-cooling, places 1h for 4 ℃.Outwell fixative, every hole is washed 5 times with deionized water, dries air drying.Every hole adds the SRB solution of 100 μ l, and standing placement 10min does not wash 5 times air drying with 1% acetic acid with protein bound SRB.In conjunction with the non-buffering of 150 μ l10mmol/L Tris alkali dissolution for SRB.At 808nm place, measure the OD value in every hole.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 deduction blank group.
Experiment showed, when using rayed 2min, the propagation that adds the direct MCF-7 of impact cell of drug delivery system of the present invention.Two, during rayed, the determination of activity of the stealthy thermal sensitive liposome drug delivery system of the present invention anti-tumor in vivo.
Get mouse S180 ascites sarcoma cell, after using injection normal saline with 3:1 dilution proportion, every mice is in lumbar injection 0.3ml, and mice was fed after 7 days, extracted mouse S180 ascites sarcoma cell, and the injection normal saline dilution of take after counting becomes concentration as 2 * 10
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, 6 every group.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 that all adopt intravenously administrable, the light source that wherein light group is used is 808nm near-infrared light source, power is 2W, laser irradiation tumor locus after administration 3h, 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, and administration is 7 times altogether.In whole experimentation, observe mice animation every day, and every 2d claims its body weight and uses the major diameter (A) and minor axis (B) of vernier caliper measurement murine sarcoma, presses formula gross tumor volume
calculate gross tumor volume.
Experiment showed, administration stealthy thermal sensitive liposome of the present invention under rayed, can obviously suppress the increase of mouse tumor volume.
Three, the mensuration of stealthy thermal sensitive liposome drug delivery 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 of sealing in 40 times of methanol extraction drug-supplying systems, it is 1.85mg/mL that ultraviolet spectrophotometer is measured drug loading, shows that the stealthy thermal sensitive liposome of doxorubicin hydrochloride of the present invention can be used as the carrier of antitumor drug.
Four, the particle size of the stealthy thermal sensitive liposome drug-supplying system of doxorubicin hydrochloride of the present invention and surface band electric weight determines.
The particle size of the stealthy thermal sensitive liposome drug-supplying system of doxorubicin hydrochloride in the present invention and determining of surface band electric weight, use Nano-ZS90 type laser particle size analyzer to measure, refractive index is set to 1.590, absorptance is set to 0.010, temperature setting is set to 25 ℃, measurement pattern is set to automatically, usings Z average statistics value as measurement result.Each horizontal condensation body is all prepared 3 parts, and every part of measurement once, is got the meansigma methods of three measured values as measurement result.Dielectric constant is set to 79, and coefficient of viscosity is set to 0.8872, and temperature setting is set to 25 ℃, and measurement pattern is set to automatically.Each horizontal condensation body is all prepared 3 parts, and every part of measurement once, is got the meansigma methods of three measured values as measurement result.The result recording is that particle diameter is 100～200nm, and current potential is-40mV.
Five, the anti tumor activity in vitro of the stealthy thermal sensitive liposome drug-supplying system of the doxorubicin hydrochloride in the present invention.
The anti tumor activity in vitro of the stealthy thermal sensitive liposome drug-supplying system of doxorubicin hydrochloride in the present invention, is used as cancerous cell to be investigated by MCF-7 breast cancer cell (being provided by Shanghai cell bank).MCF-7 cell culture is being contained to hyclone (FBS) 10%, and in the RPMI1640 culture medium of mycillin mixed liquor 1%, incubator condition is 37 ℃, 5%CO
2, within every 2～3 days, go down to posterity once.Collect logarithmic (log) phase cell, adjust 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, (edge hole is filled with aseptic PBS).Be placed in 5%CO
2hatch 24h for 37 ℃, at the bottom of being paved with hole to cell monolayer (96 hole flat underside), 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), not adding the stealthy thermal sensitive liposome of doxorubicin hydrochloride in embodiment 1 is matched group, and it is 4～6 that multiple hole is set.Light group is placed on 2min in 808nm near infrared light 2W, keeps in During Illumination temperature at 37 ℃, and illumination finishes with aluminium foil parcel cell plates, to be placed in CO afterwards
2in incubator, hatch 24h, for light group not, directly with aluminium foil parcel cell plates, be placed in CO2 incubator and hatch 24h, stop cultivating, sucking-off pastille culture medium, every hole is washed 2 times with 150 μ l PBS, adds the 10%TCA200 μ l of pre-cooling, 4 ℃ of placement 1h.Outwell fixative, every hole is washed 5 times with deionized water, dries air drying.Every hole adds the SRB solution of 100 μ l, and standing placement 10min does not wash 5 times air drying with 1% acetic acid with protein bound SRB.In conjunction with the non-buffering of 150 μ l10mmol/L Tris alkali dissolution for SRB.At 515nm place, measure the OD value in every hole.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 deduction blank group.
While experiment showed, the stealthy thermal sensitive liposome of doxorubicin hydrochloride of the present invention as pharmaceutical carrier, can drug loading enter tumor cell inside, bring into play better the curative effect of antitumor drug, and in conjunction with after illumination, propagation that can more obvious inhibition tumor cell.Six, the anti-tumor in vivo of the stealthy thermal sensitive liposome drug-supplying system of the doxorubicin hydrochloride in the present invention is active.
The anti-tumor in vivo of the stealthy thermal sensitive liposome drug-supplying system of doxorubicin hydrochloride in the present invention is active, get mouse S180 ascites sarcoma cell, with injection normal saline with 3:1 dilution proportion after, every mice is in lumbar injection 0.3ml, mice was fed after 7 days, extract mouse S180 ascites sarcoma cell, the injection normal saline dilution of take after counting becomes concentration as 2 * 10
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, 6 every group.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 doxorubicin hydrochloride inj group, the stealthy thermal sensitive liposome group of doxorubicin hydrochloride and the stealthy thermal sensitive liposome light group of doxorubicin hydrochloride equates, is 10.125mg/kg.4 groups of modes that all adopt intravenously administrable, the light source that wherein light group is used is 808nm near-infrared light source, power is 2W, laser irradiation tumor locus after administration 3h, the once irradiating time is 2min.Every 2d is administered once, and administration is 7 times altogether.In whole experimentation, observe mice animation every day, and every 2d claims its body weight and uses the major diameter (A) and minor axis (B) of vernier caliper measurement murine sarcoma, presses formula gross tumor volume
calculate gross tumor volume.
When administration, give after the stealthy thermal sensitive liposome of doxorubicin hydrochloride of the present invention, the increase of mouse tumor volume is significantly suppressed than doxorubicin hydrochloride inj, and during in conjunction with laser irradiation, the increase of mouse tumor volume obtains more significantly suppressing.
Meanwhile, also adopt other light sources and antitumor drug to do similar experiment, all obtained identical and similar result, the present invention's science of dividing into groups, method is reliable and stable.
Useful technique effect:
(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 physics and chemical stability are good, and quality is good, preparation condition simple possible, and raw material sources are abundant, and cost is low.
(2) the stealthy thermal sensitive liposome of the present invention can be used as a kind of good heat sensitizer of tumor temperature-sensitive treatment, experiment shows no matter be external or body in, in conjunction with all obviously generation of inhibition tumor cell and tissue and development in the situation of illumination; And the in the situation that of unglazed photograph, the present invention is to normal cell and organize toxic and side effects very little, can come optionally killing tumor cells tissue and cell according to the means such as focusing of light.
(3) the stealthy thermal sensitive liposome of the present invention can be used as a kind of carrier of good antitumor drug, has toxicity minimum, and water solublity is stronger, good biocompatibility, specific surface area is large, chemical inertness, there is slow-releasing and targeting, and can bring into play better antitumous effect in conjunction with laser irradiation.
Claims (9)
1. the drug delivery system of a stealthy thermal sensitive liposome, it is characterized in that, by stealthy thermal sensitive liposome load targeting heat sensitizer and chemotherapeutics, formed, wherein, the mass ratio of targeting heat sensitizer and chemotherapeutics is 1:3, and described targeting heat sensitizer is a kind of of SWCN and derivant, multi-walled carbon nano-tubes and derivant thereof, Graphene and derivant thereof, 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, one or more compositions of Xi Tabin, methotrexate, hydroxy camptothecin, the few adopted antinucleus thuja acid of small nut acids and siRNA.
2. the drug delivery system of stealthy thermal sensitive liposome according to claim 1, is characterized in that, the particle diameter of this system is 100 ~ 200nm.
3. the application of the drug delivery system of a kind of stealthy thermal sensitive liposome claimed in claim 1 in anti-tumor medicine.
4. the preparation method of stealthy thermal sensitive liposome claimed in claim 1, is characterized in that, by following steps, is realized:
(1) carboxylic carbon nano-tube is synthetic: get 95～110mg CNT, put into 250mL flask, the nitration mixture that adds 120mL, 11～13mL mass concentration is 30% hydrogenperoxide steam generator, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μ m microporous filter membrane and buchner funnel sucking filtration, it is neutral with ultra-pure water, rinsing to pH, puts into 80 ℃ of freeze-day with constant temperature of baking oven, obtains carboxylated CNT; Described nitration mixture is the mixed acid that concentrated sulphuric acid and concentrated nitric acid are formed with volume ratio 3 ︰ 1;
(2) CNT-lysine of folate-targeted is synthetic: get carboxylated CNT 45～55mg, the lysine solution that adds 25mL 0.1～0.3M, add again 9～11mg folic acid, 45～55mg 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 9～11mg N-hydroxy-succinamide, be placed in flask, after ultrasonic dispersion 2h, under ice bath, with 100r/min, stirring 24h fully reacts it, 48h dialyses after reaction finishes 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 ℃, 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 to make to dissolve completely, then add 5mL PBS solution, ultrasonic emulsification 40min, form stable O/W type Emulsion, under 45 ℃ of decompression rotations, remove ether, 200W visits super 2min, in bag filter, dialyse after 48h, obtain stealthy thermal sensitive liposome; Described PBS solution is that CNT-lysine and the 6mg doxorubicin hydrochloride of 10mg folate-targeted is dissolved in the solution that 5mL PBS, pH7.4 form.
5. the preparation method of stealthy thermal sensitive liposome according to claim 4, is characterized in that, by following steps, is realized:
(1) carboxylic carbon nano-tube is synthetic: get 100mg CNT, put into 250mL flask, the nitration mixture that adds 120mL, 12mL mass concentration is 30% hydrogenperoxide steam generator, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μ m microporous filter membrane and buchner funnel sucking filtration, it is neutral with ultra-pure water, rinsing to pH, puts into 80 ℃ of freeze-day with constant temperature of baking oven, obtains carboxylated CNT;
(2) CNT-lysine of folate-targeted is synthetic: get carboxylated CNT 50mg, the lysine solution that adds 25mL 0.2M, add again 10mg folic acid, 50mg 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 10mg N-hydroxy-succinamide, be placed in flask, after ultrasonic dispersion 2h, under ice bath, with 100r/min, stirring 24h fully reacts it, 48h dialyses after reaction finishes 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 ℃, 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 to make to dissolve completely, then add 5mL PBS solution; ultrasonic emulsification 40min; form stable O/W type Emulsion, under 45 ℃ of decompression rotations, remove ether, 200W visits super 2min; in bag filter, dialyse after 48h, obtain stealthy thermal sensitive liposome.
6. the preparation method of stealthy thermal sensitive liposome according to claim 4, is characterized in that, by following steps, is realized:
(1) carboxylic carbon nano-tube is synthetic: get 105mg CNT, put into 250mL flask, the nitration mixture that adds 120mL, 13mL mass concentration is 30% hydrogenperoxide steam generator, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μ m microporous filter membrane and buchner funnel sucking filtration, it is neutral with ultra-pure water, rinsing to pH, puts into 80 ℃ of freeze-day with constant temperature of baking oven, obtains carboxylated CNT;
(2) CNT-lysine of folate-targeted is synthetic: take carboxylated CNT 53mg, the lysine solution that adds 25mL0.2M, add again 11mg folic acid, 53mg 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 11mg N-hydroxy-succinamide, be placed in flask, after ultrasonic dispersion 2h, under ice bath, with 100r/min, stirring 24h fully reacts it, 48h dialyses after reaction finishes 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 ℃, 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 to make to dissolve completely, then add 5mL PBS solution; ultrasonic emulsification 40min; form stable O/W type Emulsion, under 45 ℃ of decompression rotations, remove ether, 200W visits super 2min; in bag filter, dialyse after 48h, obtain stealthy thermal sensitive liposome.
7. the preparation method of stealthy thermal sensitive liposome claimed in claim 1, is characterized in that, by following steps, is realized:
(1) carboxylic carbon nano-tube is synthetic: get 95～110mg CNT, put into 250mL flask, add 120mL nitration mixture, 11～13mL mass concentration is 30% hydrogenperoxide steam generator, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μ m microporous filter membrane and buchner funnel sucking filtration, it is neutral with ultra-pure water, rinsing to pH, puts into 80 ℃ of freeze-day with constant temperature of baking oven, obtains carboxylic carbon nano-tube; Described nitration mixture is the mixed acid that concentrated sulphuric acid and concentrated nitric acid are formed with volume ratio 3 ︰ 1;
(2) CNT-lysine of load chemotherapeutics is synthetic: 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 dispersion 2h, under ice bath, with 100r/min, stir 24h, it is fully reacted, 48h dialyses after reaction finishes in bag filter, remove unreacted 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, N-hydroxy-succinamide and lysine, vacuum drying 24h at 60 ℃, obtain CNT-lysine, take again 9～11mg CNT-lysine, add 10mL ultra-pure water, ultrasonic to entirely molten, then add 18～22mg chemotherapeutics, and ultrasonic 4h, the 24h that dialyses in bag filter, removes free medicine, 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 to make to dissolve completely, then add 5mL PBS solution, ultrasonic emulsification 40min, form stable O/W type Emulsion, under 45 ℃ of decompression rotations, remove ether, 200W visits super 2min, the 48h that dialyses in bag filter, obtains stealthy thermal sensitive liposome; Described PBS solution is that CNT-lysine and the 6mg doxorubicin hydrochloride of 10mg load chemotherapeutics is dissolved in the solution that 5mL PBS, pH7.4 form.
8. the preparation method of stealthy thermal sensitive liposome according to claim 7, is characterized in that, by following steps, is realized:
(1) carboxylic carbon nano-tube is synthetic: get 100mg CNT, put into 250mL flask, add 120mL nitration mixture, 12mL mass concentration is 30% hydrogenperoxide steam generator, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μ m microporous filter membrane and buchner funnel sucking filtration, it is neutral with ultra-pure water, rinsing to pH, puts into 80 ℃ of freeze-day with constant temperature of baking oven, obtains carboxylic carbon nano-tube;
(2) CNT-lysine of load doxorubicin hydrochloride is synthetic: 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 dispersion 2h, under ice bath, with 100r/min, stir 24h, it is fully reacted, 48h dialyses after reaction finishes in bag filter, remove unreacted 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, N-hydroxy-succinamide and lysine, vacuum drying 24h at 60 ℃, obtain CNT-lysine, get again 10mg CNT-lysine, add 10mL ultra-pure water, ultrasonic to entirely molten, then add 20mg doxorubicin hydrochloride, and ultrasonic 4h, the 24h that dialyses in bag filter, removes free medicine, 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 to make to dissolve completely, then add 5mL PBS solution, ultrasonic emulsification 40min, form stable O/W type Emulsion, under 45 ℃ of decompression rotations, remove ether, 200W visits super 2min, the 48h that dialyses in bag filter, obtains stealthy thermal sensitive liposome; Described PBS solution is that CNT-lysine and the 6mg doxorubicin hydrochloride of 10mg load doxorubicin hydrochloride is dissolved in the solution that 5mL PBS, pH7.4 form.
9. the preparation method of stealthy thermal sensitive liposome according to claim 7, is characterized in that, by following steps, is realized:
(1) carboxylic carbon nano-tube is synthetic: get 105mg CNT, put into 250mL round-bottomed flask, add 120mL nitration mixture, 13mL mass concentration is 30% hydrogenperoxide steam generator, after the ultrasonic 1h of ultrasonic cleaner, adds the dilution of 1L ultra-pure water, with 0.22 μ m microporous filter membrane and buchner funnel sucking filtration, it is neutral with ultra-pure water, rinsing to pH, puts into 80 ℃ of freeze-day with constant temperature of baking oven, obtains carboxylic carbon nano-tube;
(2) CNT-lysine of load Docetaxel is synthetic: 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 dispersion 2h, under ice bath, with 100r/min, stir 24h, it is fully reacted, 48h dialyses after reaction finishes in bag filter, remove unreacted 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, N-hydroxy-succinamide and lysine, vacuum drying 24h at 60 ℃, obtain CNT-lysine, take again 10mg CNT-lysine, add 10mL ultra-pure water, ultrasonic to entirely molten, then add 22mg Docetaxel, and ultrasonic 4h, the 24h that dialyses in bag filter, removes free medicine, 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 to make to dissolve completely, then add 5mL PBS solution, ultrasonic emulsification 40min, form stable O/W type Emulsion, under 45 ℃ of decompression rotations, remove ether, 200W visits super 2min, the 48h that dialyses in bag filter, obtains stealthy thermal sensitive liposome; Described PBS solution is that CNT-lysine and the 6mg doxorubicin hydrochloride of 10mg load Docetaxel is dissolved in the solution that 5mL PBS, pH7.4 form.
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