CN103159959A - M-PLGA-TPGS star type amphiphilic copolymer and preparation method and application - Google Patents
M-PLGA-TPGS star type amphiphilic copolymer and preparation method and application Download PDFInfo
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- CN103159959A CN103159959A CN2013100732170A CN201310073217A CN103159959A CN 103159959 A CN103159959 A CN 103159959A CN 2013100732170 A CN2013100732170 A CN 2013100732170A CN 201310073217 A CN201310073217 A CN 201310073217A CN 103159959 A CN103159959 A CN 103159959A
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- China
- Prior art keywords
- plga
- tpgs
- reaction
- multipolymer
- preparation
- Prior art date
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Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- 229920001577 copolymer Polymers 0.000 title abstract description 17
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims abstract description 47
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 claims abstract description 24
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- 239000000178 monomer Substances 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
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- 239000003814 drug Substances 0.000 claims description 21
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 19
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims description 15
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Abstract
The invention discloses an M-PLGA-TPGS star type amphiphilic copolymer and a preparation method and an application. A structural formula of the M-PLGA-TPGS star type amphiphilic copolymer is shown as a formula I. The preparation method comprises the following steps: 1) preparation of M-PLGA; 2) carboxylation of TPGS; and 3) preparation of M-PLGA-TPGS star type amphiphilic copolymer. The M-PLGA-TPGS star type amphiphilic copolymer has good biocompatibility and biodegradability. The M-PLGA-TPGS star type amphiphilic copolymer can be used in the medicinal preparation and biomaterial and tissue engineering fields, and especially for the antineoplastic treatment medicinal preparation or anti-cardiovascular medicinal preparation fields (formula I).
Description
Technical field
The present invention relates to star-like amphipathic multipolymer of a kind of M-PLGA-TPGS and preparation method thereof and application.
Background technology
Biodegradable polymer material as pharmaceutical excipient, is base mateiral and the important component part of pharmaceutical preparation, because it has good biocompatibility and degradability, is widely used in the drug administration system carriers such as target slow-release, controlled release.
Vitamin E TPGS (TPGS) is the abbreviation of polyethylene glycol 1000 vitamin E succinic acid ester (D-α-tocopherol polyethylene glycol1000succinate), it is the soluble derivative of vitamin-E, carboxyl and cetomacrogol 1000 (PEG1000) esterification by VE-succinate (TOS) form, relative molecular weight is about 1513, molecular structure is as follows, loaded " American Pharmacopeia ".
TPGS has been widely used in pharmaceutical preparation, foods and cosmetics research, TPGS is flaxen waxy solid, be close to tasteless, it is a kind of amphiphile, amphiphilic molecule, a hydrophilic polar head and a hydrophobic aliphatic carbon chain afterbody molecule are arranged, can be water-soluble, also can be dissolved in most of polar organic solvents.
Poly (glycolide-lactide) multipolymer (PLGA) is the main carriers material of getting permission in the world the slow controlled release medicament of clinical application at present, obtained by rac-Lactide and glycollide (will the using seasoning matter of drugs approved by FDA) copolymerization according to a certain ratio, it has the advantage of bi-material concurrently, can well make up the deficiency of bi-material again simultaneously.PLGA has good biocompatibility, biodegradability and tensile strength, and is nontoxic at human body, without accumulation, has very tempting application prospect and high commercial value at biomedical sector.
N.F,USP MANNITOL (Mannitol) is a kind of hexan-hexol, and is pleasantly sweet because of when dissolving heat absorption, and there is comfort sense in the oral cavity, thus more be widely used in hangover medicine, mouthful in the manufacturing of the chewable tablet such as freshener, its granule type is specially made the vehicle of direct compression.Be soluble in hot water, be dissolved in pyridine and aniline, be insoluble to ether, have in vivo good biocompatibility.Its molecular structural formula is as follows:
Compare with existing single linear polymeric, star-like high molecular polymer has the improvement of the performances such as many physics, chemistry, biology: compare with the linear polymeric of same molecular amount, star-like polymer have less hydrodynamic volume, the viscosity in solution little, be difficult in blood blocked, medicine is had higher encapsulation rate and drug loading, drug releasing rate waits excellent properties soon.(et al.J.Polym.Sci.Pol.Chem.44 (2006) 2034 for Mohammad R N, et al.Polymer52 (2011) 2799 and Cai C).
Summary of the invention
The purpose of this invention is to provide star-like amphipathic multipolymer of a kind of M-PLGA-TPGS and preparation method thereof.
The star-like amphipathic multipolymer of M-PLGA-TPGS provided by the present invention, its structural formula is suc as formula shown in I:
(formula I)
Wherein: m=10-200 specifically can be 11-36; N=5-100 specifically can be 5-15.
Described in the formula I, TPGS represents the group shown in the formula II:
(formula II)
Wherein: p=23-140 specifically can be 23-46.
Prepare the method for the star-like amphipathic multipolymer of above-mentioned M-PLGA-TPGS, comprise the steps:
(1) preparation of M-PLGA: take lactide monomer, glycolide monomer and N.F,USP MANNITOL initiator as raw material, carry out polyreaction under the condition of anhydrous and oxygen-free and catalyzer existence, obtain the M-PLGA multipolymer;
(2) TPGS's is carboxylated: take the TPGS(polyethylene glycol 1000 vitamin E succinic acid ester), Succinic anhydried (SA) or maleic anhydride and catalyzer react as raw material, reaction precipitates with precipitation agent the reaction solution that obtains after finishing, filter, to precipitate drying, namely obtain carboxylated polyethylene glycol 1000 vitamin E succinic acid ester (CTPGS);
(3) preparation of M-PLGA-TPGS star-type polymer: M-PLGA, CTPGS and dehydrating condensation agent are reacted under the effect of catalyzer, reaction precipitates with precipitation agent the reaction solution that obtains after finishing, filter, to precipitate drying, namely obtain star-like amphipathic nature block polymer M-PLGA-TPGS.
Wherein, raw material described in step 1) feeds intake according to following molar percentage: lactide monomer 2%-93%, glycolide monomer 2%-94%, N.F,USP MANNITOL initiator 0.1%-20%; Preferred feed ratio is as follows: lactide monomer 70%-93%, glycolide monomer 5%-25%, N.F,USP MANNITOL initiator 0.8%-15%.
Catalyzer described in step 1) is selected from following at least a: stannous octoate, stannous iso caprylate, organic guanidine (as acetic acid tetramethyl-dibutyl guanidine), taurine, ethanol iron, n-propyl alcohol iron, metallic zinc, tributyltin chloride, ferric acetyl acetonade, zinc lactate, nano zine oxide, Virahol iron and propyl carbinol iron.The consumption of described catalyzer is the 0.01%-1% of described lactide monomer and glycolide monomer mole total amount.
In step 1), the temperature of reaction of described polyreaction is 140-180 ℃, and preferred 145-155 ℃, the reaction times is 6-24 hour, preferred 12-16 hour.The number-average molecular weight Mn of the M-PLGA multipolymer that obtains is 5000-40000.
Step 2) raw material described in feeds intake according to following molar percentage: TPGS5%-90%, Succinic anhydried (SA) or maleic anhydride 5%-90%, catalyzer 5%-80%; Preferred feed ratio is as follows: TPGS21%-30%, Succinic anhydried (SA) or maleic anhydride 26%-40%, catalyzer 30%-50%.
Step 2) catalyzer described in be selected from following a) and b) in any one or a) and b) according to mol ratio (0.1-2): 1 mixture that forms: a) pyridine, 2-picoline, 4-picoline or DMAP (DMAP); B) triethylamine, quadrol, triethylene diamine or tetrem alkene triamine.Step 2) described in, the reaction solvent of reaction can be dioxane, methylene dichloride, toluene, tetrahydrofuran (THF) or DMF (DMF) etc.Quantity of solvent is 2-20 times of reactant quality.
Step 2) described in, the temperature of reaction of reaction is 0-40 ℃, preferred 25-30 ℃, reacts and is 16-48 hour, preferred 24-30 hour.Described precipitation agent can be the mixture of ether, normal heptane, sherwood oil or their arbitrary proportion.Carry out drying under vacuum condition to being deposited in, dry temperature is 30-50 ℃, and the time is 12-48h
The mol ratio of CTPGS described in step 3) and M-PLGA can be 1-20:1, preferred 7-10:1.
In step 3), described dehydrating condensation agent can be N, and N-dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC), its add-on are 1-15 times of M-PLGA molar weight; Preferred 6-7 doubly.
Described catalyzer is pyridine, 2-picoline, 4-picoline or DMAP (DMAP), its add-on be the M-PLGA molar weight 0.01-10 doubly, preferred 0.2-1.5 is doubly.
The reaction solvent that reacts described in step 3) can be methylene dichloride (DCM), toluene, DMF (DMF), dioxane or tetrahydrofuran (THF), and its consumption is 2-20 times of reactant quality.
The temperature of reaction of reacting described in step 3) is 0-40 ℃, and preferred 25-30 ℃, the reaction times is 12-48 hour, preferred 24-30 hour.Described precipitation agent can be ether, normal heptane, sherwood oil, methyl alcohol, ethanol, the perhaps mixed solvent of these solvents.Carry out drying under vacuum condition to being deposited in, dry temperature is 30-50 ℃, and the time is 12-48h.
The number-average molecular weight of the star-like amphipathic nature block polymer M-PLGA-TPGS that step 3) obtains is 10000-70000.
A further object of the present invention is to provide the purposes of the star-like amphipathic nature block polymer of above-mentioned M-PLGA-TPGS.
The star-like amphipathic nature block polymer of this M-PLGA-TPGS can be used as on the one hand pharmaceutical excipient and uses in useful in preparing drug formulations (as drug-carrying nanometer particle, medicine carrying gel and medicine carrying microballoons etc.), also can be used as on the other hand the bioengineered tissue material and be applied to biomaterial and field of tissue engineering technology (artificial organs for example, sutures and intravascular stent etc.
M-PLGA-TPGS star copolymer of the present invention also is specially adapted to the pharmaceutical excipient of antitumor drug and cardiovascular disease resistant pharmaceutical preparation.
The method that the present invention prepares the M-PLGA-TPGS star copolymer is simple, pollution-free.The multipolymer that obtains has good biocompatibility, biodegradability, has higher using value and commercial value.
Description of drawings
Fig. 1 is the building-up reactions schema of star-like amphipathic nature block polymer M-PLGA-TPGS.
Fig. 2 is the star-type polymer M-PLGA of embodiment 2 preparation
13The CNMR spectrogram (
13CNMR).
Fig. 3 be multipolymer M-PLGA and the M-PLGA-TPGS of embodiment 2 preparation hydrogen nuclear magnetic resonance figure (
1HNMR).
Fig. 4 is the multipolymer M-PLGA of embodiment 2 preparations and the gel permeation chromatography figure (GPC) of M-PLGA-TPGS.
Fig. 5 is field emission scanning electron microscope collection of illustrative plates (FESEM) collection of illustrative plates of carrying docetaxel M-PLGA-TPGS nanoparticle.
Fig. 6 is particle diameter and the size distribution result that laser particle analyzer detects medicine carrying M-PLGA-TPGS nanoparticle.
Fig. 7 is the result that zeta potential instrument is measured medicine carrying M-PLGA-TPGS nanoparticle.
Fig. 8 is the result that differential scanning calorimeter characterizes Docetaxel crystal and carrying docetaxel PLGA and M-PLGA-TPGS nanoparticle.
Fig. 9 is the vitro drug release curve of carrying docetaxel PLGA and M-PLGA-TPGS nanoparticle.
Figure 10 is carrying docetaxel M-PLGA-TPGS nanoparticle and the cell viability experimental result of blank M-PLGA-TPGS nanoparticle (the identical nanoparticle suspension concentration with drug-carrying nanometer particle) to the MCF-7 cell.
Figure 11 is that the laser confocal scanning electron microscope observation is hatched the MCF-7 cell of 4 hours with year Coumarin-6 nanoparticle of M-PLGA-TPGS star copolymer material preparation under 37 ℃.Nucleus is dyed blueness with DAPI, and it is green carrying the Coumarin-6 nano particle, and respectively by EGFP passage and DAPI passage observation of cell picked-up situation: figure A is the situation of observing by the DAPI passage; Figure B is the situation of observing by the EGFP passage; Figure C is by the EGFP passage with by the result after the doubling of the image of DAPI passage observation.
Figure 12 is for carrying the Electronic Speculum figure of taxol M-PLGA-TPGS microballoon.
Embodiment
The present invention will be described below by specific embodiment, but the present invention is not limited thereto.
Experimental technique described in following embodiment if no special instructions, is ordinary method; Described reagent and material if no special instructions, all can obtain from commercial channels.
The preparation method of M-PLGA-TPGS star copolymer comprises the steps:
(1) by mole percentage composition get 93% lactide monomer, 5% glycolide monomer and 2% N.F,USP MANNITOL (M) is raw material, put into polymerizing pipe, add 0.5% zinc lactate of monomer molar amount, vacuumize inflated with nitrogen, triplicate, when vacuum tightness polymerizing pipe tube sealing during higher than 70pa, 145 ℃ of heating, reacted 16 hours, namely obtain number-average molecular weight and be 18309 multipolymer M-PLGA(m=36, n=8).
(2) by mole% the TPGS(Mn=1500 that gets 30%, i.e. p=23), 40% Succinic anhydried (SA), 30% catalyzer DMAP (DMAP) and triethylamine, wherein the molar ratio of DMAP and triethylamine is 1:1.Add the solvent dioxane that is equivalent to 10 times of quality of raw material, 25 ℃ of temperature of reaction, react and after 24 hours, product is precipitated out, precipitation agent is that ether and methyl alcohol volume ratio are the mixed solvent of 5:1, filter, 40 ℃ of vacuum-drying 24h will be deposited in, carboxylated polyethylene glycol 1000 vitamin E succinic acid ester (CTPGS) can be obtained.
(3) preparation of M-PLGA-TPGS star-type polymer.Reactant M-PLGA and CTPGS, the molar ratio of CTPGS are 10 times of M-PLGA; N, N-dicyclohexylcarbodiimide (DCC) is dehydrating condensation agent, add-on is 6 times of molar weight of M-PLGA; DMAP is catalyzer, and catalytic amount is 0.2 times of molar weight of M-PLGA.The methylene dichloride that is equivalent to 10 times of quality of raw material is reaction solvent.30 ℃ of temperature of reaction, after reaction 30h, product is precipitated out, precipitation agent is that sherwood oil and methyl alcohol volume ratio are the mixed solvent of 2:1, filter, to be deposited in 40 ℃ of vacuum-drying 24h, can obtain molecular weight is 27320(m=36, n=8, p=23) star-like amphipathic nature block polymer M-PLGA-TPGS.
The preparation method of M-PLGA-TPGS star copolymer comprises the steps:
(1) take 12.96g(0.09mol) lactide monomer, 3.48g(0.03mol) glycolide monomer and 0.182(0.001mol) N.F,USP MANNITOL (M) is raw material, put into polymerizing pipe, add 1-2 to drip stannous iso caprylate as catalyzer, vacuumize inflated with nitrogen, triplicate, with alcohol blast burner to the polymerizing pipe tube sealing, 148 ℃ of reacting by heating 12 hours, namely obtain number-average molecular weight and be 23650 multipolymer M-PLGA(m=45, n=15).
(2) be 6g(4mmol by quality) TPGS(Mn=1500, i.e. p=23), 0.50g(5.0mmol) Succinic anhydried, 0.61g(5.0mmol) DMAP (DMAP) and 0.485g(4.8mmol) triethylamine.80ml(82.7g) dioxane is as reaction solvent, 30 ℃ of temperature of reaction are reacted and after 24 hours, product are precipitated out, precipitation agent is ether, filter, will be deposited in 40 ℃ of vacuum-drying 24h, can obtain carboxylated polyethylene glycol 1000 vitamin E succinic acid ester (CTPGS).
(3) preparation of M-PLGA-TPGS star-type polymer.Reactant M-PLGA and CTPGS are respectively 3g(0.13mmol) and 1.5g(0.94mmol).Dehydrating condensation agent N, N-dicyclohexylcarbodiimide (DCC) 0.185g(0.90mmol), catalyzer DMAP (DMAP) 0.022g(0.18mmol).The methylene dichloride of 45ml is reaction solvent.30 ℃ of temperature of reaction, after reaction 24h, product is precipitated out, precipitation agent is that anhydrous diethyl ether and methyl alcohol volume ratio are the mixed solvent of 2:1, filter, to be deposited in 40 ℃ of vacuum-drying 24h, can obtain molecular weight is 33082(m=45, n=15, p=23) star-like amphipathic nature block polymer M-PLGA-TPGS.
Figure 1 shows that the building-up reactions schema of the star-like amphipathic nature block polymer of M-PLGA-TPGS.
Carbon-13 nmr spectra (
13CNMR), proton nmr spectra (
1HNMR) and the star-like amphipathic nature block polymer M-PLGA-TPGS of gel permeation chromatography (GPC) result proof synthesize successfully.Fig. 2 is the nuclear magnetic resonance of carbon spectrogram of star-type polymer M-PLGA, and Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of polymkeric substance M-PLGA and M-PLGA-TPGS.The absorption peak a(position that can clearly observe the methine carbon atom of rac-Lactide polymkeric substance from Fig. 2 is respectively δ=16.88ppm and 17.76ppm) and absorption peak b(δ=69.60ppm and the 69.78ppm of mesomethylene carbon atom), absorption peak c(δ=61.35ppm and the 61.48ppm of the mesomethylene carbon atom of glycollide); Also can see the absorption peak d(δ=168.98ppm of the carbonylic carbon atom of rac-Lactide, 169.06ppm and 169.22ppm) and absorption peak e(δ=166.12ppm and the 166.32ppm of the carbonylic carbon atom of glycollide).δ is about the solvent peak that is of 78ppm, forms structure with this multipolymer that has proved PLGA.Also can see the absorption peak g(δ of the mesomethylene carbon atom of N.F,USP MANNITOL=21.54ppm), proved six arms asteroids of polymkeric substance from figure.
Fig. 3 is multipolymer M-PLGA and M-PLGA-TPGS's
1The HNMR spectrogram, methyl (CH in the rac-Lactide in the PLGA segment
3) signal of hydrogen and methyne (CH) hydrogen appears at respectively the 1.62ppm(a peak) and the 5.21ppm(b peak) locate, being arranged in the 4.62-4.82ppm(c peak) fignal center of locating belongs to the methylene radical (CH of glycollide
2) proton.The absorption peak of methylene radical in the TPGS polyoxyethylene glycol (CH2) appears at the 3.65ppm(h peak) to locate, this is the characteristic peak of TPGS.The proton nmr spectra analytical results also illustrates that the M-PLGA-TPGS multipolymer synthesizes successfully.
Fig. 4 is the gel permeation chromatography figure (GPC) of polymkeric substance M-PLGA and M-PLGA-TPGS.As can be seen from the figure, polymkeric substance M-PLGA and M-PLGA-TPGS are unimodal, illustrate that these two polymkeric substance successfully synthesize and have a good monodispersity.This reaction product of unimodal explanation of polymkeric substance M-PLGA is not the physical mixed of glycolide monomer, lactide monomer and N.F,USP MANNITOL initiator; This reaction product of unimodal explanation of polymkeric substance M-PLGA-TPGS is not the physical mixed of M-PLGA and TPGS.Wherein, the appearance time of M-PLGA is 21.1min, and the M-PLGA-TPGS multipolymer appearance time be 18.6min.Can't detect the peak of TPGS in the GPC result of multipolymer M-PLGA-TPGS, and only occur one unimodal.The number-average molecular weight Mn that draws multipolymer M-PLGA by the GPC result is 23650, and multipolymer M-PLGA-TPGS number-average molecular weight Mn is 33082.Molecular weight by polymkeric substance M-PLGA and M-PLGA-TPGS also can draw TPGS and successfully be coupled to M-PLGA and form amphipathic nature block polymer.
Embodiment 3, preparation M-PLGA-TPGS star copolymer
The preparation method of M-PLGA-TPGS star copolymer comprises the steps:
(1) by mole percentage composition get 70% lactide monomer, 15% glycolide monomer and 15% N.F,USP MANNITOL (M) is raw material, put into polymerizing pipe, adding the feed molar amount is 0.2% catalyst acetic acid tetramethyl-dibutyl guanidine, vacuumize, inflated with nitrogen repeats 3 times, tube sealing under vacuum state, 155 ℃ of lower frit reactions 16 hours, namely obtaining number-average molecular weight Mn was 6328(m=11, n=5) multipolymer M-PLGA.
(2) by mole% the TPGS(Mn=2500 that gets 30%, i.e. p=46), 40% maleic anhydride, 30% catalyzer pyridine and triethylene tetramine, wherein the molar ratio of pyridine and triethylene tetramine is 1:1.Add the methylene chloride that is equivalent to 10 times of quality of raw material, 25 ℃ of temperature of reaction are reacted and after 30 hours, product are precipitated out, precipitation agent is the ice anhydrous diethyl ether, filter, will be deposited in 40 ℃ of vacuum-drying 24h, can obtain carboxylated polyethylene glycol 1000 vitamin E succinic acid ester (CTPGS).
(3) preparation of M-PLGA-TPGS star-type polymer.Reactant M-PLGA and CTPGS, the molar ratio of CTPGS are 8 times of M-PLGA.N, N-dicyclohexylcarbodiimide (DCC) is dehydrating condensation agent, add-on is 6 times of the molar weights of M-PLGA.DMAP is catalyzer, and catalytic amount is 0.5 times of the molar weight of M-PLGA.Adding the DMF (DMF) that is equivalent to 8 times of quality of raw material is reaction solvent.25 ℃ of temperature of reaction after reaction 24h are precipitated out product, and precipitation agent is sherwood oil, filter, will precipitate and 40 ℃ of vacuum-drying 24h, can obtain number-average molecular weight Mn is 21328(m=11, n=5, p=46) star-like amphipathic star block copolymer M-PLGA-TPGS.
The M-PLGA-TPGS nanoparticle of embodiment 4, preparation carrying docetaxel (Docetaxel)
Utilize ultrasonic emulsification/solvent evaporation method to prepare the M-PLGA-TPGS nanoparticle of carrying docetaxel (Docetaxel).The preparation method is as follows: accurately take M-PLGA-TPGS multipolymer and a certain amount of Docetaxel powder of 200mg embodiment 2 preparations, be dissolved in the 12ml methylene dichloride.Under agitation condition, the massfraction that this solution is joined 240ml is in the 0.03%TPGS aqueous solution.Disperse 120s with the 25w power ultrasonic under condition of ice bath, form emulsion oil-in-water, organic solvent is removed in the decompression volatilization.The centrifugal 15min of 20000rpm uses deionized water wash three times, to remove TPGS and free Docetaxel medicine.The gained precipitation is resuspended in the 10ml deionized water, and lyophilize gets carrying docetaxel M-PLGA-TPGS nanoparticle product.Utilize same method to prepare carrying docetaxel PLGA nanoparticle.
The scanning electron microscope of carrying docetaxel M-PLGA-TPGS nanoparticle the results are shown in Figure 5, and Nanoparticle Size is than homogeneous, and smooth in appearance is spherical in shape, and particle diameter is greatly about the 200nm left and right.As shown in Figure 6, the nanoparticle narrower particle size distribution, particle diameter has further confirmed the observations of scanning electron microscope greatly about the 200nm left and right.As shown in Figure 7, the Zeta potential of nanoparticle is in-20mV left and right, and the absolute value of surface charge is higher, and between particle, repulsive interaction is stronger, thereby stable at the disperse phase camber.As shown in table 1, using 0.03%TPGS to prepare drug loading as emulsifying agent is 10% polyene-containing taxol nanoparticle, and encapsulation rate is reached near 100%.As shown in Figure 8, the endotherm(ic)peak of Docetaxel crystal is at 173 ℃, and carrying docetaxel PLGA and M-PLGA-TPGS nanoparticle are showed no the endotherm(ic)peak of Docetaxel crystal, illustrate that Docetaxel is wrapped in nanoparticle, and its endotherm(ic)peak has disappeared.As shown in Figure 9, carrying docetaxel PLGA has similar release profiles with the M-PLGA-TPGS nanoparticle, is the two-phase release characteristic and follows initial " burst effect ".M-PLGA-TPGS nanoparticle release rate is faster, easily satisfies clinical requirement.As shown in figure 10, the blank M-PLGA-TPGS nanoparticle of medicine carrying does not have good biocompatibility, because it does not all have obvious toxicity to the MCF-7 cell under different nanoparticle suspension concentration; And carrying docetaxel M-PLGA-TPGS nanoparticle has obvious cytotoxicity.In addition, MTT experimental result explanation carrying docetaxel M-PLGA-TPGS nanoparticle has time and concentration dependent to the toxicity of MCF-7 cell.
Table 1. prepares in the polyene-containing taxol nanoparticle process with the M-PLGA-TPGS multipolymer, drug loading and emulsifying agent
Impact on particle diameter, Zeta potential and the encapsulation rate of nanoparticle
The M-PLGA-TPGS nanoparticle of Coumarin-6 is carried in embodiment 5, preparation
Utilize ultrasonic emulsification/solvent evaporation method preparation to carry the M-PLGA-TPGS nanoparticle of Coumarin-6.The preparation method is as follows: accurately take the M-PLGA-TPGS star copolymer of 100mg embodiment 2 preparations and the Coumarin-6 of 12mg, be dissolved in the 8ml methylene dichloride.Under agitation condition, this solution is joined in the 0.03%TPGS aqueous solution of 120ml.Disperse 120s with the 25w power ultrasonic under condition of ice bath, form emulsion oil-in-water, organic solvent is removed in the decompression volatilization.The centrifugal 15min of 20000rpm uses deionized water wash three times, to remove de-emulsifier TPGS and free Coumarin-6.The gained precipitation is resuspended in the 10ml deionized water, and lyophilize must be carried the M-PLGA-TPGS nanoparticle product of Coumarin-6.The nanoparticle particle diameter is about 220 nanometers.
Utilize DAPI that nucleus is dyeed, can be in cellular uptake experiment by nuclear location being determined year Coumarin-6 nanoparticle position in cell.Figure 11 observes the MCF-7 cell to the picked-up result of carrying the Coumarin-6 nano particle by the M-PLGA-TPGS preparation with laser confocal scanning electron microscope (CLSM).As can be seen from the figure, only after hatching 2h with cell, nanoparticle is just absorbed by cell.Merge from Figure 11 A and Figure 11 B Figure 11 C that obtains and can know to such an extent that see, greeny nanoparticle great majority are arranged in tenuigenin, tightly surround the nucleus that is blue.The CLSM experimental result shows that the M-PLGA-TPGS nanoparticle can be fully by cellular uptake, and then discharges anticarcinogen carry out slow release treatment in cell.
The M-PLGA-TPGS nanoparticle of cardiovascular disease resistant medicine genistein is carried in embodiment 6, preparation
Utilize ultrasonic emulsification/solvent evaporation method preparation to carry the M-PLGA-TPGS nanoparticle of anti-cardiovascular disease genistein.The preparation method is as follows: accurately take the M-PLGA-TPGS star copolymer of 100mg embodiment 2 preparations and the genistein of 10mg, be dissolved in the 8ml methylene dichloride.Under agitation condition, this solution is joined in the 0.03%TPGS aqueous solution of 120ml.Disperse 120s with the 25w power ultrasonic under condition of ice bath, form emulsion oil-in-water, organic solvent is removed in the decompression volatilization.The centrifugal 15min of 20000rpm uses deionized water wash three times, to remove de-emulsifier TPGS and free genistein.The gained precipitation is resuspended in the 10ml deionized water, and lyophilize must be carried the M-PLGA-TPGS nanoparticle product of genistein.The nanoparticle particle diameter is about 200 nanometers.
Taxol (Paclitaxel) M-PLGA-TPGS microballoon is carried in embodiment 7, preparation
Utilize the solvent evaporation method preparation to carry taxol (Paclitaxel) M-PLGA-TPGS microballoon.The preparation method is as follows: accurately take the M-PLGA-TPGS multipolymer of 150mg embodiment 2 preparations and the taxol powder of 50mg, be dissolved in the 16ml methylene dichloride.Under agitation condition, this solution is joined in 0.2% polyvinyl alcohol (PVA) aqueous solution of 500ml.Stirred two hours under the 800rpm rotating speed, form emulsion oil-in-water, under the 500rpm rotating speed, volatilization is spent the night.The centrifugal 15min of 2500rpm uses deionized water wash three times, to remove de-emulsifier PVA and free taxol drug.The gained precipitation is resuspended in the 10ml deionized water, and lyophilize must be carried taxol M-PLGA-TPGS microball preparation.As shown in figure 12, carry taxol M-PLGA-TPGS microsphere features smooth surface, particle diameter is 15 microns left and right.
Adopt the microballoon (preparation method is the same) that the PLGA bag carries taxol to do contrast, the drug loading that carries taxol M-PLGA-TPGS microballoon is about 25%, and encapsulation rate is more than 80%, and the drug loading of year taxol PLGA microballoon is about 12%, and encapsulation rate is in 58% left and right.
Claims (10)
1. the multipolymer shown in the formula I:
(formula I)
Wherein: m=10-200, n=5-100;
Described in the formula I, TPGS represents the group shown in the formula II:
(formula II)
Wherein: p=23-140.
2. the method for the multipolymer shown in preparation claim 1 Chinese style I, comprise the steps:
(1) take lactide monomer, glycolide monomer and N.F,USP MANNITOL initiator as raw material, carry out polyreaction under the condition of anhydrous and oxygen-free and catalyzer existence, obtain the M-PLGA multipolymer;
(2) react take polyethylene glycol 1000 vitamin E succinic acid ester, Succinic anhydried or maleic anhydride and catalyzer as raw material, reaction precipitates with precipitation agent the reaction solution that obtains after finishing, filter, to precipitate drying, obtain carboxylated polyethylene glycol 1000 vitamin E succinic acid ester CTPGS;
(3) described M-PLGA, CTPGS and dehydrating condensation agent are reacted under the effect of catalyzer, reaction precipitates with precipitation agent the reaction solution that obtains after finishing, and filters, and will precipitate drying, obtains the multipolymer shown in the formula I.
3. method according to claim 2, it is characterized in that: raw material described in step 1) feeds intake according to following molar percentage: lactide monomer 2%-93%, glycolide monomer 2%-94%, N.F,USP MANNITOL initiator 0.1%-20%;
Step 2) raw material described in feeds intake according to following molar percentage: TPGS5%-90%, Succinic anhydried (SA) or maleic anhydride 5%-90%, catalyzer 5%-80%;
The mol ratio of CTPGS described in step 3) and M-PLGA can be 1-20:1.
4. according to claim 2 or 3 described methods, it is characterized in that: catalyzer described in step 1) is selected from following at least a: stannous octoate, stannous iso caprylate, organic guanidine, taurine, ethanol iron, n-propyl alcohol iron, metallic zinc, tributyltin chloride, ferric acetyl acetonade, zinc lactate, nano zine oxide, Virahol iron and propyl carbinol iron; The consumption of described catalyzer is the 0.01%-1% of described lactide monomer and glycolide monomer mole total amount;
In step 1), the temperature of reaction of described polyreaction is 140-180 ℃, and the reaction times is 6-24 hour.
5. the described method of any one according to claim 2-4, it is characterized in that: described method also is included in step 2 after step 1)) front step of the M-PLGA multipolymer that obtains being carried out purifying, method is as follows: M-PLGA multipolymer crude product is dissolved in methylene dichloride or ethyl acetate, add methyl alcohol or sherwood oil to make M-PLGA multipolymer precipitation, filter, to be deposited in 30-50 ℃ of vacuum-drying, namely obtain the M-PLGA multipolymer of purifying.
6. the described method of any one according to claim 2-5, is characterized in that: step 2) described in catalyzer be selected from following a) and b) in any one or a) and b) according to mol ratio (0.1-2): 1 mixture that forms: a) pyridine, 2-picoline, 4-picoline or DMAP (DMAP); B) triethylamine, quadrol, triethylene diamine or tetrem alkene triamine;
Step 2) described in, the reaction solvent of reaction is selected from following at least a: dioxane, methylene dichloride, toluene, tetrahydrofuran (THF) or DMF, its consumption are 2-20 times of reactant total mass;
Step 2) described in, the temperature of reaction of reaction is 0-40 ℃, reacts to be 16-48 hour;
Step 2) precipitation agent described in is selected from following at least a: ether, normal heptane and sherwood oil; Step 2) in, described being deposited in carried out drying under vacuum condition, dry temperature is 30-50 ℃, and the time is 12-48h.
7. the described method of any one according to claim 2-6, it is characterized in that: in step 3), described dehydrating condensation agent is N, and N-dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, its add-on are 1-15 times of described M-PLGA molar weight;
In step 3), described catalyzer is pyridine, 2-picoline, 4-picoline or DMAP, and its add-on is 0.01-10 times of described M-PLGA molar weight;
The reaction solvent that reacts described in step 3) is selected from following at least a: methylene dichloride, toluene, DMF, dioxane and tetrahydrofuran (THF), its consumption are 2-20 times of reactant total mass.
The temperature of reaction of reacting described in step 3) is 0-40 ℃, and the reaction times is 12-48 hour,
Precipitation agent described in step 3) is selected from following at least a: ether, normal heptane, sherwood oil, methyl alcohol and ethanol; In step 3), described being deposited in carried out drying under vacuum condition, dry temperature is 30-50 ℃, and the time is 12-48h.
8. the application of the multipolymer shown in claim 1 Chinese style I in useful in preparing drug formulations.
9. application according to claim 8 is characterized in that: described pharmaceutical preparation is microparticle formulation, preferred drug-carrying nanometer particle, medicine carrying gel or medicine carrying microballoons; Described pharmaceutical preparation is anti-tumor medicinal preparation and/or cardiovascular disease resistant pharmaceutical preparation.
10. the multipolymer shown in claim 1 Chinese style I is as the application of tissue engineering material.
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| CN103980498A (en) * | 2014-05-27 | 2014-08-13 | 深圳市纳诺美生物科技有限公司 | Dendritic amphiphilic block copolymer H-PLA-b-TPGS as well as preparation method and application thereof |
| CN104177553A (en) * | 2014-08-25 | 2014-12-03 | 湖南科技大学 | Preparation method of ethylenediamine modified maleic anhydride polylactide-glycolide polymer |
| CN104710625A (en) * | 2015-03-19 | 2015-06-17 | 南京邮电大学 | Degradable water-soluble copolymer with near infrared response function, and efficient synthetic method of copolymer |
| WO2016197655A1 (en) * | 2015-06-11 | 2016-12-15 | 南京大学 | Process for controlled synthesis of polylactic acid through living ring-opening polymerization of lactide catalysed by organic guanidine-nontoxic alcohol |
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| CN114940746A (en) * | 2022-06-17 | 2022-08-26 | 山东采采医疗科技有限公司 | Star-shaped lactide-glycolide copolymer and application thereof as drug sustained-release carrier |
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| CN104177553A (en) * | 2014-08-25 | 2014-12-03 | 湖南科技大学 | Preparation method of ethylenediamine modified maleic anhydride polylactide-glycolide polymer |
| CN104177553B (en) * | 2014-08-25 | 2016-08-17 | 湖南科技大学 | The preparation method of poly-third co-glycolide polymers of ethylenediamine modified maleic anhydridization |
| CN104710625A (en) * | 2015-03-19 | 2015-06-17 | 南京邮电大学 | Degradable water-soluble copolymer with near infrared response function, and efficient synthetic method of copolymer |
| CN104710625B (en) * | 2015-03-19 | 2017-03-08 | 南京邮电大学 | A kind of near-infrared response degradable water soluble copolymer and its high-efficiency synthesis method |
| WO2016197655A1 (en) * | 2015-06-11 | 2016-12-15 | 南京大学 | Process for controlled synthesis of polylactic acid through living ring-opening polymerization of lactide catalysed by organic guanidine-nontoxic alcohol |
| JP2018513902A (en) * | 2015-06-11 | 2018-05-31 | 南京大学Ｎａｎｊｉｎｇ Ｕｎｉｖｅｒｓｉｔｙ | Process to synthesize polylactic acid controlled by active lactide ring-opening polymerization of organoguanidine-non-toxic alcohol catalyst |
| CN112226191A (en) * | 2020-08-24 | 2021-01-15 | 江苏美境新材料有限公司 | Biodegradable adhesive and preparation method thereof |
| CN114940746A (en) * | 2022-06-17 | 2022-08-26 | 山东采采医疗科技有限公司 | Star-shaped lactide-glycolide copolymer and application thereof as drug sustained-release carrier |
| CN114940746B (en) * | 2022-06-17 | 2024-04-26 | 山东采采医疗科技有限公司 | Star-shaped lactide-glycolide copolymer and application thereof as drug slow-release carrier |
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