CN102807677B - CA-PLGA-TPGS (Cholic Acid-Poly-Lactic-co-Glycolic Acid copolymer-Tocopherol Polyethylene Glycol Succinate) star copolymer as well as preparation method and application thereof - Google Patents
CA-PLGA-TPGS (Cholic Acid-Poly-Lactic-co-Glycolic Acid copolymer-Tocopherol Polyethylene Glycol Succinate) star copolymer as well as preparation method and application thereof Download PDFInfo
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- CN102807677B CN102807677B CN201210292220.7A CN201210292220A CN102807677B CN 102807677 B CN102807677 B CN 102807677B CN 201210292220 A CN201210292220 A CN 201210292220A CN 102807677 B CN102807677 B CN 102807677B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 229920001577 copolymer Polymers 0.000 title abstract description 23
- 239000002202 Polyethylene glycol Substances 0.000 title abstract description 3
- 229920001223 polyethylene glycol Polymers 0.000 title abstract description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 title abstract description 3
- 229960001295 tocopherol Drugs 0.000 title abstract 2
- 239000011732 tocopherol Substances 0.000 title abstract 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims abstract description 48
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 7
- 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 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 3
- 230000000259 anti-tumor effect Effects 0.000 claims abstract 2
- 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 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 21
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- 238000001556 precipitation Methods 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000000178 monomer Substances 0.000 claims description 15
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 14
- 239000004380 Cholic acid Substances 0.000 claims description 14
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 14
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- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 14
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- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims description 10
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- -1 nano zine oxide Chemical compound 0.000 claims description 7
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 4
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- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- GCTFWCDSFPMHHS-UHFFFAOYSA-M Tributyltin chloride Chemical compound CCCC[Sn](Cl)(CCCC)CCCC GCTFWCDSFPMHHS-UHFFFAOYSA-M 0.000 claims description 3
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- 239000003999 initiator Substances 0.000 claims description 3
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- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 2
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- CANRESZKMUPMAE-UHFFFAOYSA-L Zinc lactate Chemical compound [Zn+2].CC(O)C([O-])=O.CC(O)C([O-])=O CANRESZKMUPMAE-UHFFFAOYSA-L 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 150000001336 alkenes Chemical class 0.000 claims description 2
- VIBFDCIENRJBCC-UHFFFAOYSA-N butan-1-ol;iron Chemical compound [Fe].CCCCO VIBFDCIENRJBCC-UHFFFAOYSA-N 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 2
- 239000013583 drug formulation Substances 0.000 claims description 2
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a CA-PLGA-TPGS (Cholic Acid-Poly-Lactic-co-Glycolic Acid copolymer-Tocopherol Polyethylene Glycol Succinate) star copolymer as well as a preparation method and an application thereof. A structural formula of the CA-PLGA-TPGS star segmented copolymer is as shown in a formula 1. The preparation method comprises the steps as follows: 1) preparing a CA-PLGA; 2) carrying out carboxylation on a TPGS; and 3) preparing the CA-PLGA-TPGS star copolymer. The CA-PLGA-TPGS star copolymer has the advantages of good biocompatibility and biodegradability and is applied to the field of pharmaceutical preparations and tissue engineering, in particular to the field of pharmaceutical preparations for anti-tumor treatment or anti-cardiovascular diseases.
Description
Technical field
The present invention relates to a kind of CA-PLGA-TPGS star copolymer and preparation method thereof and application.
Background technology
Due to it, good biocompatibility and degradability are widely used in target slow-release, controlled release research as drug administration system carrier to Biodegradable polymer material in vivo.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, by rac-Lactide and glycollide copolymerization according to a certain ratio, obtained, 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, nontoxic at human body, and without accumulation, so it has very tempting application prospect and high commercial value at biomedical sector.
Vitamin E TPGS (TPGS) is the abbreviation of TPGS (D-α-tocopherol polyethylene glycol 1000succinate), it is the soluble derivative of vitamin-E, carboxyl and polyoxyethylene glycol esterification by VE-succinate (TOS) form, 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, there are a hydrophilic polar head and a hydrophobic aliphatic carbon chain afterbody molecule, can be water-soluble, also can be dissolved in most of polar organic solvents.Cholic acid (Cholic Acid, CA) be a kind of main elementary bile acide, it is as emulsifying agent synthetic biomolecules of biology on mammiferous lung in fatty digestive process, having a hard steroid skeleton structure and four can reactive group, has in vivo good Bc.Its molecular structural formula is as follows:
Than single linear polymeric, the star-like improvement that the high molecular polymer of design shape has brought the performances such as many physics, chemistry, biology in advance such as grade.Compare with the linear polymeric of same molecular amount, star-like polymer has less hydrodynamic volume, and the viscosity in solution is little, is difficult for blockedly in blood, and medicine is had to higher encapsulation rate and drug loading.(Mohammad R N, et al.Polymer 52 (2011) 2799 and Giovanni M, et al.Macromol.Rapid Commun.25 (2004) 1139).
Summary of the invention
The object of this invention is to provide a kind of star-like biodegradable CA-PLGA-TPGS star copolymer and preparation method thereof.
CA-PLGA-TPGS star copolymer provided by the present invention, its structural formula is suc as formula shown in I:
Wherein: m=5-260, n=1-200.
TPGS described in formula I represents the group shown in formula II:
Wherein: p=23-115.
The method of preparing above-mentioned CA-PLGA-TPGS star copolymer, comprises the steps:
(1) preparation of CA-PLGA: according to feed molar per-cent, the cholic acid initiator of the lactide monomer of 2%-95%, the glycolide monomer of 2%-95% and 0.1%-20% of take is raw material, under the condition of anhydrous and oxygen-free and catalyzer existence, carry out polyreaction, obtain CA-PLGA multipolymer;
(2) TPGS's is carboxylated: according to feed molar per-cent, take the Succinic anhydried (SA) of TPGS (TPGS), 5%-90% of 5%-90% or the catalyzer of maleic anhydride and 5%-50% reacts as raw material, reaction finishes rear the reaction solution obtaining to be precipitated with precipitation agent, filter, to precipitate and be dried, obtain carboxylated TPGS (CTPGS);
(3) preparation of CA-PLGA-TPGS star-type polymer: CA-PLGA, CTPGS and dehydrating condensation agent are reacted under the effect of catalyzer, reaction finishes rear the reaction solution obtaining to be precipitated with precipitation agent, filter, to precipitate and be dried, obtain star-like amphipathic nature block polymer CA-PLGA-TPGS; The mol ratio of described CTPGS and CA-PLGA is 1-15.
Wherein, catalyzer step 1) be selected from following at least one: stannous octoate, stannous iso caprylate, organic guanidine (as acetic acid tetramethyl-dibutyl guanidine), metallic zinc, tributyltin chloride, ferric acetyl acetonade, zinc lactate, nano zine oxide, taurine, ethanol iron, n-propyl alcohol iron, Virahol iron and propyl carbinol iron.The consumption of described catalyzer is the 0.01%-1% of described monomer molar total amount.
Step 1) in, the temperature of reaction of described polyreaction is 120-180 ℃, and the reaction times is 6-24 hour.The number-average molecular weight Mn of the CA-PLGA multipolymer obtaining is 3000-50000.
In step 1) rear step 2) front, described method also comprises that the CA-PLGA multipolymer to obtaining carries out the step of purifying, method is as follows: CA-PLGA multipolymer crude product is dissolved in methylene dichloride or ethyl acetate, add methyl alcohol or sherwood oil to make CA-PLGA multipolymer precipitation, filter, to be deposited in 30-50 ℃ of vacuum-drying, the CA-PLGA multipolymer that the number-average molecular weight Mn that obtains purifying is 3000-50000.
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 forming: 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 5-60 ℃, reacts for 8-48 hour.Described precipitation agent can be ether, normal heptane, sherwood oil or their any mixture.To being deposited under vacuum condition, be dried, dry temperature is 30-50 ℃, and the time is 12-48h.
Step 3), in, described dehydrating condensation agent can be N, N-dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC), and its add-on is 1-15 times of CA-PLGA molar weight.
Described catalyzer is pyridine, 2-picoline, 4-picoline or DMAP (DMAP), and its add-on is 0.01-10 times of CA-PLGA molar weight.
Step 3) described in, the reaction solvent of reaction can be methylene dichloride (DCM), toluene, DMF (DMF), dioxane or tetrahydrofuran (THF), and its consumption is 2-20 times of reactant quality.
Step 3) described in, the temperature of reaction of reaction is 5-60 ℃, reacts for 8-48 hour.Described precipitation agent can be ether, normal heptane, sherwood oil, methyl alcohol, ethanol, or the mixed solvent of these solvents.To being deposited under vacuum condition, be dried, dry temperature is 30-50 ℃, and the time is 12-48h.
Step 3) molecular weight of the star-like amphipathic nature block polymer CA-PLGA-TPGS obtaining is 5000-80000.
A further object of the present invention is to provide the application of above-mentioned CA-PLGA-TPGS star copolymer.
This CA-PLGA-TPGS star copolymer can be used as on the one hand pharmaceutical excipient and applies 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 tissue engineering material and be applied to field of tissue engineering technology (for example artificial organs, sutures and intravascular stent etc.).
CA-PLGA-TPGS star copolymer of the present invention is also specially adapted to the pharmaceutical excipient of antitumor drug and cardiovascular disease resistant pharmaceutical preparation.
The method that the present invention prepares CA-PLGA-TPGS star copolymer is simple, pollution-free.The multipolymer obtaining has good biocompatibility, biodegradability, is a kind of up-and-coming material.
Accompanying drawing explanation
Fig. 1 is the synthetic schematic diagram of star-like amphipathic nature block polymer CA-PLGA-TPGS.
Fig. 2 be multipolymer CA-PLGA and CA-PLGA-TPGS nucleus magnetic resonance figure (
1hNMR).
Fig. 3 is the gel permeation chromatography figure (GPC) of multipolymer CA-PLGA and CA-PLGA-TPGS.
Fig. 4 is the thermogravimetric analysis curve (TGA) of multipolymer CA-PLGA, CTPGS, CA-PLGA-TPGS.
Fig. 5 is field emission scanning electron microscope collection of illustrative plates (FESEM) collection of illustrative plates of carrying docetaxel CA-PLGA-TPGS nanoparticle.
Fig. 6 is particle diameter and the size distribution result that laser particle analyzer detects medicine carrying CA-PLGA-TPGS nanoparticle.
Fig. 7 is the result that zeta potential instrument is measured medicine carrying CA-PLGA-TPGS nanoparticle.
Fig. 8 is the result that differential scanning calorimeter characterizes Docetaxel crystal and carrying docetaxel PLGA and CA-PLGA-TPGS nanoparticle.
Fig. 9 is the vitro drug release curve of carrying docetaxel PLGA and CA-PLGA-TPGS nanoparticle.
Figure 10 is carrying docetaxel CA-PLGA-TPGS nanoparticle and the cell viability experimental result of blank CA-PLGA-TPGS nanoparticle (the identical nanoparticle suspension concentration with drug-carrying nanometer particle) to MCF-7 cell.
Figure 11 be laser confocal scanning electron microscope observation with CA-PLGA-TPGS copolymer material, prepare carry the MCF-7 cell that Coumarin-6 nanoparticle is hatched 4 hours at 37 ℃.Nucleus is dyed blueness with DAPI, and it is green carrying Coumarin-6 nano particle, respectively by EGFP passage and DAPI passage observation of cell picked-up situation: figure A is the situation of observing by DAPI passage; Figure B is the situation of observing by EGFP passage; Figure C is by the result after EGFP passage and the doubling of the image observed by DAPI passage.
Figure 12 is for carrying the Electronic Speculum figure of taxol CA-PLGA-TPGS microball preparation.
Embodiment
Below by specific embodiment, the present invention will be described, 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 CA-PLGA-TPGS star copolymer, comprises the steps:
(1) by molar content get 95% lactide monomer, 4% glycolide monomer and 1% cholic acid (CA) is raw material, put into polymerizing pipe, the 0.5% acetic acid tetramethyl-dibutyl guanidine that adds monomer molar amount, vacuumizes inflated with nitrogen, in triplicate, when vacuum tightness polymerizing pipe tube sealing during higher than 70pa, 145 ℃ of heating, react 12 hours, obtaining number-average molecular weight is the multipolymer CA-PLGA of 32000 (m=140, n=8).
(2) by mole% the TPGS (Mn=1500) that gets 30%, 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, 30 ℃ of temperature of reaction, react and after 24 hours, product is precipitated out, precipitation agent is the mixed solvent that ether and methyl alcohol volume ratio are 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 CA-PLGA-TPGS star-type polymer.Reactant CA-PLGA and CTPGS, the molar ratio of CTPGS is CA-PLGA 5 times; N, N-dicyclohexylcarbodiimide (DCC) is dehydrating condensation agent, 3 times of the molar weight that add-on is CA-PLGA; DMAP is catalyzer, 0.2 times of the molar weight that catalytic amount is CA-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 24h, product is precipitated out, precipitation agent is the mixed solvent that sherwood oil and methyl alcohol volume ratio are 2: 1, filter, to be deposited in 40 ℃ of vacuum-drying 24h, can obtain molecular weight is the star-like amphipathic nature block polymer CA-PLGA-TPGS of 36580 (m=140, n=8, p=23).
The preparation method of CA-PLGA-TPGS star copolymer, comprises the steps:
(1) take the lactide monomer of 17.28g (0.12mol), glycolide monomer and 0.54 (0.0013mol) cholic acid (CA) of 4.64g (0.04mol) is raw material, put into polymerizing pipe, add 1-2 to drip stannous iso caprylate as catalyzer, vacuumize, inflated with nitrogen, in triplicate, with alcohol blast burner to polymerizing pipe tube sealing, 145 ℃ of reacting by heating 12 hours, obtaining number-average molecular weight was the multipolymer CA-PLGA of 21307 (m=78, n=26).
(2) by quality, be the TPGS (Mn=1500) of 3g (2mmol), 0.26g (2.6mmol) Succinic anhydried, 0.348g (2.8mmol) DMAP (DMAP) and 0.256g (2.5mmol) triethylamine.50ml (51g) dioxane is as reaction solvent, and 30 ℃ of temperature of reaction, react and after 24 hours, product is 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 CA-PLGA-TPGS star-type polymer.Reactant CA-PLGA and CTPGS are respectively 3.5g (0.16mmol) and 1.1g (0.68mmol).Dehydrating condensation agent N, N-dicyclohexylcarbodiimide (DCC) 0.125g (0.6mmol), catalyzer DMAP (DMAP) 0.015g (0.12mmol).The methylene dichloride of 50ml is reaction solvent.30 ℃ of temperature of reaction, after reaction 24h, product is precipitated out, precipitation agent is the mixed solvent that anhydrous diethyl ether and methyl alcohol volume ratio are 2: 1, filter, to be deposited in 40 ℃ of vacuum-drying 24h, can obtain number-average molecular weight is the star-like amphipathic nature block polymer CA-PLGA-TPGS of 26198 (m=78, n=26, p=23).Figure 1 shows that the building-up reactions formula of the star-like amphipathic nature block polymer of CA-PLGA-TPGS.
Proton nmr spectra (
1hNMR), gel permeation chromatography (GPC) and thermogravimetric analysis (TGA) result prove that star-like amphipathic nature block polymer CA-PLGA-TPGS synthesizes successfully.Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of polymkeric substance CA-PLGA and CA-PLGA-TPGS.Methyl (CH in rac-Lactide in PLGA segment
3) signal of hydrogen and methyne (CH) hydrogen appears at respectively 1.62ppm (a peak) and 5.21ppm (b peak) locates, and is arranged in the methylene radical (CH that fignal center that 4.62-4.82ppm (c peak) locates belongs to glycollide
2) proton.Methylene radical (CH in TPGS polyoxyethylene glycol
2) absorption peak appear at 3.65ppm (h peak) and locate, this is the characteristic peak of TPGS.4.41ppm place occurred representing PLGA segment end connect hydroxyl-CH-peak, show that rac-Lactide and glycollide open loop form polymer segment; Script connects three hydroxyls-CH-peak and moves on to 3.80ppm from 3.21ppm on CA molecule, shows that hydroxyl and the second rac-Lactide on CA reacts, and changes ester bond structure into.Proton nmr spectra (
1hNMR) analytical results also illustrates that CA-PLGA-TPGS multipolymer synthesizes successfully.Fig. 3 is the gel permeation chromatography figure (GPC) of polymkeric substance CA-PLGA and CA-PLGA-TPGS.As can be seen from the figure, polymkeric substance CA-PLGA and CA-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 CA-PLGA is not the physical mixed of glycolide monomer, lactide monomer and cholic acid initiator; This reaction product of unimodal explanation of polymkeric substance CA-PLGA-TPGS is not the physical mixed of CA-PLGA and TPGS.Wherein, the appearance time of CA-PLGA is 20.5min, and CA-PLGA-TPGS multipolymer appearance time be 19.3min.In the GPC result of multipolymer CA-PLGA-TPGS, can't detect the peak of TPGS, and only occur one unimodal.By GPC result, show that the number-average molecular weight Mn of multipolymer CA-PLGA is 21307, multipolymer CA-PLGA-TPGS number-average molecular weight Mn is 26198.Molecular weight by polymkeric substance CA-PLGA and CA-PLGA-TPGS also can show that TPGS is successfully coupled to CA-PLGA and forms amphipathic nature block polymer.Fig. 4 is carboxylated TPGS, the thermogravimetric analysis curve (TGA) of polymkeric substance CA-PLGA and CA-PLGA-TPGS.What TGA detected is variation with temperature, and in sample, composition causes the situation of changes in weight because of evaporation cracking etc.As can be seen from the figure, carboxylated TPGS only has a flex point at 300-420 ℃, CA-PLGA has only located a flex point at 250-360 ℃, and the figure of CA-PLGA-TPGS has three flex points, a composition in each flex point representation polymer is because of heating weightlessness, the weightless peak of 250-340 ℃ and 330-420 ℃ is respectively that PLGA and the TPGS in polymkeric substance partly causes, and wherein the weightless temperature of PGA and PLA overlaps to some extent.Thermogravimetric analysis detected result further proves that multipolymer CA-PLGA-TPGS synthesizes successfully.
Embodiment 3, preparation CA-PLGA-TPGS star copolymer
The preparation method of CA-PLGA-TPGS star copolymer, comprises the steps:
(1) by molar content get 75% lactide monomer, 10% glycolide monomer and 15% cholic acid (CA) is raw material, put into polymerizing pipe, adding feed molar amount is 0.5% catalyzer tributyltin chloride, vacuumize, inflated with nitrogen, repeats 3 times, tube sealing under vacuum state, at 155 ℃, frit reaction is 12 hours, and obtaining number-average molecular weight is the multipolymer CA-PLGA of 4600 (m=19, n=3).
(2) by mole% the TPGS (Mn=1500) that gets 40%, 45% maleic anhydride, 15% catalyzer pyridine and diethylenetriamine, wherein the molar ratio of pyridine and diethylenetriamine is 1: 1.Add the solvent toluene that is equivalent to 8 times of quality of raw material, 25 ℃ of temperature of reaction, react and after 40 hours, product are precipitated out, precipitation agent is 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 CA-PLGA-TPGS star-type polymer.Reactant CA-PLGA and CTPGS, the molar ratio of CTPGS is CA-PLGA 4 times.N, N-dicyclohexylcarbodiimide (DCC) is dehydrating condensation agent, 2 times of the molar weights that add-on is CA-PLGA.DMAP is catalyzer, 0.3 times of the molar weight that catalytic amount is CA-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 40h 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 is 9250 (m=19, n=3, p=23) star-like amphipathic nature block polymer CA-PLGA-TPGS.
Embodiment 4, prepare the CA-PLGA-TPGS nanoparticle of carrying docetaxel (Docetaxel)
Utilize ultrasonic emulsification/solvent evaporation method to prepare carrying docetaxel (Docetaxel) CA-PLGA-TPGS nanoparticle.Preparation method is as follows: accurately take CA-PLGA-TPGS multipolymer and a certain amount of Docetaxel powder of 200mg embodiment 2 preparations, be dissolved in 12ml methylene dichloride.Under agitation condition, the massfraction that this solution is joined to 240ml is in the 0.03%TPGS aqueous solution.Under condition of ice bath, with 25w power ultrasonic, disperse 120s, form emulsion oil-in-water, organic solvent is removed in decompression volatilization.The centrifugal 15min of 20000rpm, uses deionized water wash three times, to remove TPGS and free Docetaxel medicine.Gained precipitation is resuspended in 10ml deionized water, and lyophilize obtains carrying docetaxel CA-PLGA-TPGS nanoparticle product.Utilize same method to prepare carrying docetaxel PLGA nanoparticle.The scanning electron microscope of carrying docetaxel CA-PLGA-TPGS nanoparticle the results are shown in Figure 5, and Nanoparticle Size is compared with homogeneous, and smooth in appearance is spherical in shape, and particle diameter is greatly about 200nm left and right.As shown in Figure 6, nanoparticle narrower particle size distribution, particle diameter, greatly about 200nm left and right, has further confirmed the observations of scanning electron microscope.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 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, can make encapsulation rate reach and approach 100%.As shown in Figure 8, the endotherm(ic)peak of Docetaxel crystal is at 173 ℃, and carrying docetaxel PLGA and CA-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 CA-PLGA-TPGS nanoparticle, is two-phase release characteristic and follows initial " burst effect ".CA-PLGA-TPGS nanoparticle release rate is faster, easily meets clinical requirement.As shown in figure 10, the blank CA-PLGA-TPGS nanoparticle of medicine carrying does not have good biocompatibility, because it does not all have obvious toxicity to MCF-7 cell under different nanoparticle suspension concentration; And carrying docetaxel CA-PLGA-TPGS nanoparticle has obvious cytotoxicity.In addition, MTT experimental result explanation carrying docetaxel CA-PLGA-TPGS nanoparticle has time and concentration dependent to the toxicity of MCF-7 cell.
Table 1. is prepared in polyene-containing taxol nanoparticle process with CA-PLGA-TPGS copolymer material, the impact on the particle diameter of nanoparticle, Zeta potential and encapsulation rate of drug loading and emulsifying agent
The CA-PLGA-TPGS nanoparticle of Coumarin-6 is carried in embodiment 5, preparation
Utilize the preparation of ultrasonic emulsification/solvent evaporation method to carry the CA-PLGA-TPGS nanoparticle of Coumarin-6.Preparation method is as follows: accurately take the CA-PLGA-TPGS star copolymer of 100mg embodiment 2 preparations and the Coumarin-6 of 12mg, be dissolved in 8ml methylene dichloride.Under agitation condition, this solution is joined in the 0.03%TPGS aqueous solution of 120ml.Under condition of ice bath, with 25w power ultrasonic, disperse 120s, form emulsion oil-in-water, organic solvent is removed in decompression volatilization.The centrifugal 15min of 20000rpm, uses deionized water wash three times, to remove de-emulsifier TPGS and free Coumarin-6.Gained precipitation is resuspended in 10ml deionized water, and lyophilize must be carried the CA-PLGA-TPGS nanoparticle product of Coumarin-6.Nanoparticle particle diameter is in 220 nanometer left and right.Utilize DAPI to dye to nucleus, can in cellular uptake experiment, by nuclear location is determined, carry the position of Coumarin-6 nanoparticle in cell.Figure 11 is to the picked-up result of carrying Coumarin-6 nano particle of being prepared by CA-PLGA-TPGS with laser confocal scanning electron microscope observation MCF-7 cell.As can be seen from the figure, only hatching after 2h with cell, nanoparticle is just absorbed by cell.From figure A, merge with figure B the figure C obtaining and can know to such an extent that see, greeny nanoparticle great majority are arranged in tenuigenin, tightly surround the nucleus that is blue.
Taxol (Paclitaxel) CA-PLGA-TPGS microballoon is carried in embodiment 6, preparation
Utilize solvent evaporation method preparation to carry taxol (Paclitaxel) CA-PLGA-TPGS microballoon.Preparation method is as follows: accurately take the CA-PLGA-TPGS multipolymer of 150mg embodiment 2 preparations and the taxol powder of 50mg, be dissolved in 16ml methylene dichloride.Under agitation condition, this solution is joined in 0.2% polyvinyl alcohol (PVA) aqueous solution of 500ml.Under 800rpm rotating speed, stir two hours, form emulsion oil-in-water, under 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.Gained precipitation is resuspended in 10ml deionized water, and lyophilize must be carried taxol CA-PLGA-TPGS microball preparation.As shown in figure 12, carry taxol CA-PLGA-TPGS microsphere features smooth surface, particle diameter is 15 microns of left and right.The drug loading that carries taxol CA-PLGA-TPGS microballoon is about 25%, and encapsulation rate is more than 80%.
Claims (9)
1. a CA-PLGA-TPGS star block copolymer, its structural formula is suc as formula shown in I:
Wherein: m=5-260, n=1-200; (formula I)
TPGS represents the group shown in formula II:
Wherein: p=23-115.(formula II)
2. the method for preparing the star block copolymer of CA-PLGA-TPGS described in claim 1, comprise the steps: the preparation of (1) CA-PLGA: according to feed molar per-cent, the cholic acid initiator of the lactide monomer of 2%-95%, the glycolide monomer of 2%-95% and 0.1%-20% of take is raw material, under the condition of anhydrous and oxygen-free and catalyzer existence, carry out polyreaction, obtain CA-PLGA multipolymer;
(2) TPGS's is carboxylated: according to feed molar per-cent, the catalyzer of the TPGS of 5%-90%, the Succinic anhydried of 5%-90% or maleic anhydride and 5%-50% of take reacts as raw material, reaction finishes rear the reaction solution obtaining to be precipitated with precipitation agent, filter, to precipitate and be dried, obtain carboxylated TPGS;
(3) preparation of CA-PLGA-TPGS star-type polymer: CA-PLGA, CTPGS and dehydrating condensation agent are reacted under the effect of catalyzer, reaction finishes rear the reaction solution obtaining to be precipitated with precipitation agent, filter, will precipitate and be dried, obtain star block copolymer CA-PLGA-TPGS; Wherein, the mol ratio of described CTPGS and CA-PLGA is 1-15.
3. method according to claim 2, is characterized in that: catalyzer described in step 1) be selected from following at least one: stannous octoate, stannous iso caprylate, organic guanidine, metallic zinc, tributyltin chloride, ferric acetyl acetonade, zinc lactate, nano zine oxide, taurine, ethanol iron, n-propyl alcohol iron, Virahol iron and propyl carbinol iron; The consumption of described catalyzer is the 001%-1% of described monomer molar amount
In step 1), the temperature of reaction of described polyreaction is 120-180 ℃, and the reaction times is 6-24 hour.
4. according to the method in claim 2 or 3, it is characterized in that: described method is also included in step 2 after step 1)) front step of the CA-PLGA multipolymer obtaining being carried out to purifying, method is as follows: CA-PLGA multipolymer crude product is dissolved in methylene dichloride or ethyl acetate, add methyl alcohol or sherwood oil to make CA-PLGA multipolymer precipitation, filter, to be deposited in 30-50 ℃ of vacuum-drying, obtain the CA-PLGA multipolymer of purifying.
5. it is characterized in that: step 2 according to the method in claim 2 or 3) described in catalyzer be selected from following a) and b) in any one or a) and b) mixture that forms according to mol ratio 0.1-2:1: a) pyridine, 2-picoline, 4-picoline or DMAP (DMAP); B) triethylamine quadrol, triethylene diamine or tetrem alkene triamine;
Step 2) reaction solvent of reaction described in be selected from following at least one: dioxane, methylene dichloride, toluene, tetrahydrofuran (THF) and DMF, its consumption be raw material total mass 2-20 doubly;
Step 2) described in, the temperature of reaction of reaction is 5-60 ℃, reacts for 8-48 hour;
Step 2) precipitation agent described in be selected from following at least one: ether, normal heptane and sherwood oil;
Step 2) in, described being deposited under vacuum condition is dried, dry temperature is 30-50 ℃, and the time is 12-48h.
6. according to the method in claim 2 or 3, it is characterized in that: in step 3), described dehydrating condensation agent is N, N-dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, and its consumption is 1-15 times of described CA-PLGA molar weight;
Catalyzer described in step 3) is pyridine, 2-picoline, 4-picoline or DMAP, and its add-on is 0.01-10 times of described CA-PLGA molar weight;
The reaction solvent reacting described in step 3) be selected from following at least one: methylene dichloride, toluene, DMF, dioxane and tetrahydrofuran (THF), its consumption be raw material total mass 2-20 doubly;
The temperature of reaction of reacting described in step 3) is 5-60 ℃, reacts for 8-48 hour;
Precipitation agent described in step 3) be selected from following at least one: ether, normal heptane, sherwood oil, methyl alcohol and ethanol; In step 3), described being deposited under vacuum condition is dried, dry temperature is 30-50 ℃, and the time is 12-48h.
7. CA-PLGA-TPGS star block copolymer claimed in claim 1 application in useful in preparing drug formulations as pharmaceutical excipient.
8. application according to claim 7, is characterized in that: described pharmaceutical preparation is microparticle formulation, and described microparticle formulation is 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.
9. CA-PLGA-TPGS star block copolymer claimed in claim 1 is as the application of tissue engineering material.
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| Doxorubicin conjugated to D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS): Conjugation chemistry, characterization, in vitro and in vivo evaluation;Na Cao et al.;《Biomaterials》;20081031;第29卷(第28期);3856-3865 * |
| Na Cao et al..Doxorubicin conjugated to D-a-tocopheryl polyethylene glycol 1000 succinate (TPGS): Conjugation chemistry, characterization, in vitro and in vivo evaluation.《Biomaterials》.2008,第29卷(第28期),3856-3865. |
| 星形PLA-PEG嵌段共聚物胶束的制备与表征;陈一纾等;《化学研究与应用》;20101015;第22卷(第10期);1225～1230 * |
| 陈一纾等.星形PLA-PEG嵌段共聚物胶束的制备与表征.《化学研究与应用》.2010,第22卷(第10期),1225～1230. |
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