CN102504267A - Paclitaxel bonded amphipathic aliphatic polyester-b-polyphosphate high polymer and preparation thereof - Google Patents
Paclitaxel bonded amphipathic aliphatic polyester-b-polyphosphate high polymer and preparation thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicament control release, and in particular relates to a paclitaxel bonded amphipathic aliphatic polyester-b-polyphosphate high polymer. The high polymer comprises a polyphosphate chain segment, an aliphatic polyester chain segment and a paclitaxel group, wherein the two ends of the aliphatic polyester chain segment are respectively connected with the paclitaxel group and the polyphosphate chain segment by virtue of ester bonds; the aliphatic polyester chain segment is selected from a poly(epsilon-caprolactone) chain segment or a polyactic acid segment. The high polymer can perform self-assembly in a phosphoric acid buffer solution PBS to form a hydrophobic medicament and a micelle in which lipophilic aliphatic polyester is used as a core and water-soluble polyphosphate is used as a shell. Through the preparation, on one hand, the strong hydrophobicity of a paclitaxel medicament is improved so as to avoid the rejection reaction of the medicament in the in vivo transportation process, and on the other hand, the medicament is slowly released through degradation of polyester so as to avoid the harmfulness of sharp increase of medicament concentration on other normal cells of tissue organs, thereby reaching the effect that an anti-tumor medicament is released controllably.
Description
Technical field
The invention belongs to medicine sustained release field, but relate to a kind of polymer drug and compound method thereof of treating hydrophobic drug taxol with the physiologically acceptable and the biodegradable amphipathic aliphatic polyester-b-poly phosphate segmented copolymer bonding of tumour.
Background technology
Taxol (Paclitaxel, trade(brand)name Taxol) is a kind of tricyclic diterpene material that from Chinese yew genus plants, extracts, and has antitumor action.Since 1992 were used to treat advanced ovarian cancer by FDA (Food and Drug Adminstration) (FDA) approval listing, research found that gradually it all has very high curative effect to mammary cancer, ovarian cancer and lung cancer.Because taxol is made up of a huge ring texture and numerous hydrophobic groups, its solvability in water is very poor, and making it be prepared into injection has certain difficulty.Water-soluble in order to improve it; Minimizing is by the discharge of P-gp; Enhancing is for the anti-cancer ability of colorectal carcinoma, carcinoma of the pancreas, melanoma and renal cancer; Clinical application at present mainly be paclitaxel injection, the colourless sticky shape solution of promptly processing by cremophor EL (Cremophor EL contains Witconol 5909)/absolute ethyl alcohol (50: 50).But big quantity research shows that Witconol 5909 can impel a large amount of I4EAs to discharge in vivo, produces anaphylaxis such as fluid retention, and the clinical safety that has influenced taxol is greatly used.
Directly be used for clinical untoward reaction in order to improve taxol, investigators are through amphipathic nature polyalcohol is bonded on the taxol, and are water-soluble to improve it, for example: bonding biodegradable polyester material on taxol.Through the polyester degraded, can control anticarcinogen and discharge in vivo.This method not only reduced taxol in vivo in the course of conveying to the injury of healthy tissues, and can slowly discharge in vivo, avoided drug level sharply to increase the damage of bringing for tissue and organ.
Amphipathic nature polyalcohol is meant and in same macromolecular chain, contains hydrophilic and the different segmental polymkeric substance of two kinds of chemical property of oleophylic simultaneously.Because have the segment of two kinds of chemical structures, amphipathic nature polyalcohol can be assembled into various forms in elective medium, like micella, vesica etc.At biomedical sector, kernel is hydrophobic, the hydrophilic polymer/nanometer particle of shell because amphipathic multipolymer is assembled at aqueous phase, and the efficient drug delivery system of these nanoparticles causes scientific worker's extensive interest.Introduce in the amphipathic nature polyalcohol structure Biodegradable high-molecular and the research that is used to make up drug delivery system has the potential using value; Because solid support material was organized accumulated at human organ after the use of Biodegradable material can be avoided drug release, produce toxic side effect.
The patent No. is 200610016559.9 Chinese disclosure of the Invention a kind of biodegradable amphiphilic tri-block copolymer-paclitaxel bonded drug and preparation method thereof, the molecular structure of said amphiphilic tri-block copolymer-paclitaxel bonded drug is:
Wherein the wetting ability mid-block is a molecular weight less than 10000 polyoxyethylene glycol; Hydrophobic two ends block is the ring-opening polymerization product polyesteramide of the morpholine diketone of aliphatics cyclic ester and band carboxylic acid side group, molecular weight 2000～50000; Taxol through its 2 '-position or the carboxyl of 7-position link to each other with side carboxyl on the main chain; The mass content of taxol in the bonding medicine is 1～15%.Its preparation method is: polyoxyethylene glycol (PEG) is as macromole evocating agent, through the L-rac-Lactide, and the morpholine-2 of NSC 403079 or 6-caprolactone and functionalization, the random copolymerization of 5-derovatives obtains having the triblock copolymer of side benzyl ester; Through catalytic hydrogenation the benzyl ester is converted into carboxyl; 2 of the side carboxyl of multipolymer and taxol '-or the 7-hydroxyl reaction obtain amphiphilic tri-block copolymer-paclitaxel bonded drug.This bonding medicine can be self-assembled into nano-micelle in water, nanoparticle is expected in blood circulation, (EPR) to assemble at tumor locus through " enhanced infiltration and retention effect ", improves the targeting of taxol to tumor locus.Therefore, this amphipathic nature polyalcohol-paclitaxel bonded drug and the nano-micelle that in the aqueous solution, is self-assembled into thereof are expected to become problem that solves the taxol soluble difference and the effective way that improves the taxol bioavailability.
The patent No. is that 200410002722.7 Chinese invention patent discloses a kind of taxol soluble derivative, comprising: galactosylation taxol, AGMT base taxol, heparin modified taxol and taxol dimer; Its preparation method is: after making taxol and corresponding acid anhydrides and the reaction of dicarboxylicacid carboxylic acid halides generate the carboxylic acyloxy taxol; Respectively with galactosylation reagent or AGMT amidation; Or react with heparin more earlier and after the diamine amidation, generate corresponding water soluble taxad alcohol derivative respectively.Said taxol dimer is formed by carboxylic acyloxy taxol and the reaction of amino polyoxyethylene glycol generation acid amides.Taxol is after above-mentioned modification, and its water-soluble having is considerably improved.And the taxol molecule has possessed certain tissue target tropism after connecting galactosyl, AGMT base or heparin; Can be after administration through the blood circulation directive action in target tissue; Thereby improved local drug concentration greatly, also greatly reduced the toxic side effect of taxol simultaneously other organs of health.In addition, in the prior art, mainly contain for paclitaxel bonded research:
(1) Paul C.Ho etc. through the amphipathic block of monomethyl polyethylene glycol-lactic acid earlier with the succinyl oxide reaction; Again at N-hydroxyl amber imines and N; Utilize the hydroxy esterification effect bonding of carboxyl and the taxol of succinyl oxide to get under the effect of N-dicyclohexyl diimine (referring to: Zhe Wang, Paul C.Ho, Biomaterials2010; 31,7115-7123).
(2) people such as Sun Jian utilizes taxol to convert the hydroxyl of taxol to the end carboxyl with the succinyl oxide reaction earlier, be prepared into the PTX-NHS Acibenzolar with the effect of N-hydroxyl amber imines again, is getting on (referring to Guolin Li through carrying out the transesterification reaction bonding with ultra-branching polyether ester (HPEE); Jinyao Liu, Yan Pang, Ruibin Wang; Limin Mao, Deyue Yan, Xinyuan Zhu; Jian Sun.Biomacromolecules 2011,12,2016-2026).
(3) people such as Jih Ru Hwu is through (MeO) PCl
2With single sulfydryl end capped Tetraglycol 99 list mercaptan and paclitaxel bonded after, again with red stone or gold nano grain addition, the paclitaxel carrier of preparation target is (referring to Jih Ru Hwu, Yu Sern Lin; Thainashmuthu Josephrajan, Ming-Hua Hsu, Fong-Yu Cheng; Chen-Sheng Yeh, Wu-Chou Su, Dar-Bin Shieh; J.Am.Chem.Soc.2009,131,66-68).
(4) people such as Shui-Tein Chen utilize succinyl oxide with taxol and glucuronic acid or 2 '-glucose links, preparation based on the prodrugs of paclitaxel of saccharan (referring to Yih-Shyan Lin, Rudeewan Tungpradit; Supachok Sinchaikul, Feng-Ming An, Der-Zen Liu; Suree Phutrakul, Shui-Tein Chen, J.Med.Chem.2008; 51,7428-7441).
In the above-mentioned document, all be, by the conversion of other molecules or connect with bonding paclitaxel through esterification comparatively loaded down with trivial details and that reaction efficiency is not high.The introducing of more other compounds changes medicines structure on the one hand, and then possibly influence drug effect; On the other hand, preparation process is comparatively complicated to have the potential influence to medicines structure.
Aliphatic polyester such as polycaprolactone (PCL), POLYACTIC ACID (PLA), lactic acid-glycolide copolymer (PLGA) and polycarbonate such as polytrimethylene cyclic carbonate ester (PTMC) etc. are the most frequently used synthesising biological degradable macromolecules.Yet traditional biodegradable polymer also has some self deficiency, and for example: strong excessively hydrophobicity, texture ratio be more single, lack modifiable functional group or reaction site etc.
Poly phosphate (Polyphosphoester) is one type and connects the unitary Biodegradable polymer material of backbone structure by the phosphoric acid ester bond; Its structure and biomacromolecule nucleic acid are similar; Penetrating ability with good water-solubility, stronger biocompatibility, cellular affinity and cytolemma, in biomedical sector, more and more receive publicity (referring to: Macromol.Biosci., 2009; 9,1154-1164.).
According to investigation, the bibliographical information that directly will be paclitaxel bonded prepares anticarcinogen through ring-opening polymerization on poly-epsilon-caprolactone and the poly phosphate amphipathic nature block polymer is not arranged so far.
Summary of the invention
Goal of the invention of the present invention provides polymer drug of a kind of paclitaxel bonded physiologically acceptable and biodegradable amphipathic polyester and preparation method thereof.
For reaching the foregoing invention purpose; The technical scheme that the present invention adopts is: the polymer of a kind of paclitaxel bonded amphipathic aliphatic polyester-b-poly phosphate; Comprise poly phosphate segment, aliphatic polyester segment and Japanese yew alcohol radical, wherein aliphatic polyester segmental two ends link to each other with Japanese yew alcohol radical, poly phosphate segment with ester bond respectively.
In the technique scheme; Said aliphatic polyester segment is selected from: gather (6-caprolactone) segment or polylactic acid chain segment; When the aliphatic polyester segment when gathering (6-caprolactone) segment, the high molecular chemical structural formula of said paclitaxel bonded amphipathic aliphatic polyester-b-poly phosphate is:
When the aliphatic polyester segment was polylactic acid chain segment, the high molecular chemical structural formula of said paclitaxel bonded amphipathic aliphatic polyester-b-poly phosphate was:
Wherein, polycaprolactone segmental number-average molecular weight
Be 2900～5000g/mol, m is 15～40; The number-average molecular weight of polylactic acid chain segment
Be 3000～6000g/mol, x is 30～80; Poly phosphate segmental number-average molecular weight
Be 2300～6100g/mol, n is 15～30; R
1Be selected from: oxyethyl group-OCH
2CH
3, methoxyl group-OCH
3, dimethylamino-N [(CH
3)
2], diethylin-N [(CH
2CH
3)
2] or methylamino--NH (CH
3) in a kind of.
The high molecular preparation method of above-mentioned paclitaxel bonded amphipathic aliphatic polyester-b-poly phosphate may further comprise the steps: at first under the katalysis of stannous octoate; Utilize the hydroxyl of taxol 2 '-position to cause the ring-opening polymerization of aliphatic cyclic ester class monomer, obtain the hydrophobic polymer of paclitaxel bonded polyester; And then utilize the terminal hydroxyl of polyester in the hydrophobic polymer of paclitaxel bonded polyester, and under the stannous octoate katalysis, cause the ring-opening polymerization of annular phosphate monomer, obtain the polymer drug of paclitaxel bonded amphipathic polyester-b-poly phosphate; Wherein, the monomeric structure of said annular phosphate is:
In the formula, R
1Be selected from-OCH
2CH
3,-OCH
3,-N [(CH
3)
2] ,-N [(CH
2CH
3)
2], or-NH (CH
3) in a kind of.
In the technique scheme, the purity of said taxol is more than 99.5%, is the commodity that can buy.
In the technique scheme, the hydrophobic polymer of said paclitaxel bonded polyester is: paclitaxel bonded gathering (6-caprolactone) or paclitaxel bonded POLYACTIC ACID, wherein, paclitaxel bonded gathering (6-caprolactone) chemical structural formula be:
The structural formula of paclitaxel bonded POLYACTIC ACID is:
Wherein, polycaprolactone segmental number-average molecular weight
Be 2900～5000g/mol, m is 15～40; The number-average molecular weight of POLYACTIC ACID
Be 3000～6000g/mol, x is 30～80; Poly phosphate segmental number-average molecular weight
Be 2300～6100g/mol, n is 15～30; R
1Be selected from: oxyethyl group-OCH
2CH
3, methoxyl group-OCH
3, dimethylamino-N [(CH
3)
2], diethylin-N [(CH
2CH
3)
2] or methylamino--NH (CH
3) in a kind of.
Further in the technical scheme, for guaranteeing degree of purity of production, need make with extra care the reaction product in each step, its method is:
(1) purification process to paclitaxel bonded aliphatic polyester polymer is: (a) reaction product is concentrated with rotary evaporation, liquid concentrator is dropwise added in the anhydrous diethyl ether under stirring again, remove catalyzer and unreacted raw material through deposition; A large amount of white precipitates that (b) will produce obtain white solid product with the B suction filtration; (c) solid product is precipitated with anhydrous diethyl ether after with the dissolving of a small amount of trichloromethane once more; Obtain white solid matter; (d) with behind the B suction filtration; With gained white solid matter in vacuum drying oven dry 12～24 hours, obtain the exsiccant white powder, be the polymer of paclitaxel bonded polyester.
(2) purification process to the polymer drug of paclitaxel bonded amphipathic polyester-b-poly phosphate is: (a) reaction product is concentrated with rotary evaporation; Again liquid concentrator is dropwise added in the anhydrous diethyl ether under stirring, remove catalyzer and unreacted raw material through deposition; A large amount of white precipitates that (b) will produce obtain white solid product with the B suction filtration; (c) with after a little trichloromethane dissolving of solid product usefulness, with the anhydrous diethyl ether deposition, obtain white solid matter once more; (d) behind the B suction filtration with gained white solid matter in vacuum drying oven dry 12～24 hours, obtain slightly agglutinating exsiccant white solid, be the polymer of paclitaxel bonded amphipathic aliphatic polyester-b-poly phosphate.
In the technique scheme; The drug effect of the existing treatment tumour of polymer drug of said paclitaxel bonded amphipathic polyester-b-poly phosphate; Good amphipathic aliphatic polyester of easy formation micella, biocompatibility and biological degradability and poly phosphate segmented copolymer are arranged as carrier again; Can reduce taxol direct toxicity in vivo, reach the purpose of slow releasing pharmaceutical.
Particularly, the high molecular preparation method of above-mentioned paclitaxel bonded amphipathic caprolactone-b-poly phosphate may further comprise the steps:
(1) under anhydrous and oxygen-free and protection of inert gas, be solvent with the orthodichlorobenzene, be reaction substrate with 6-caprolactone monomer and taxol, at stannous octoate Sn (Oct)
2Under the catalysis, ring-opening polymerization is 20～24 hours in 90～110 ℃ temperature, obtains the hydrophobic polymer (PTX-APE) of paclitaxel bonded polyester; Behind the stopped reaction; Earlier reaction product is concentrated, liquid concentrator is dropwise added in the anhydrous diethyl ether under stirring precipitate again, filter and obtain solid product; Precipitate with anhydrous diethyl ether once more after again solid product being dissolved with trichloromethane; With gained solid matter Air drying 12～24 hours in vacuum drying oven, obtain loose exsiccant white powder after the filtration, be the hydrophobic polymer of paclitaxel bonded polyester;
Above-mentioned reaction process is as follows:
(2) the high molecular preparation of paclitaxel bonded amphipathic polyester-b-poly phosphate: the hydrophobic polymer of the paclitaxel bonded polyester of product that utilizes step (1) is as macromole evocating agent; With the THF is solvent; Under the catalysis of stannous octoate; Utilize paclitaxel bonded polyester chain terminal hydroxyl to cause annular phosphate monomer
ring-opening polymerization; 40～50 ℃ of temperature of reaction were reacted 5～7 hours; After reaction finishes, earlier reaction product is concentrated, under agitation liquid concentrator is dropwise added in the anhydrous diethyl ether again and precipitate; After the filtration; Solid product is dissolved with trichloromethane,, filter and gained solid matter Air drying 12～24 hours in vacuum drying oven once more with anhydrous diethyl ether deposition; Obtain the exsiccant white solid, be the polymer of paclitaxel bonded amphipathic polyester-b-poly phosphate;
Above-mentioned reaction process is as follows:
In the formula, poly phosphate segmental number-average molecular weight
Be 2300～6100g/mol, n is 15～35; Preferably, R in the formula
1Be selected from: oxyethyl group-OCH
2CH
3, methoxyl group-OCH
3, dimethylamino-N [(CH
3)
2], diethylin-N [(CH
2CH
3)
2] or methylamino--NH (CH
3) in a kind of.
In the technique scheme, in the step (1), the consumption of stannous octoate is 1/2～1 times of the hydroxyl molar mass of participating in initiation reaction; The feed ratio of 6-caprolactone monomer and initiator precursor taxol is 30～60: 1.
In the technique scheme, in the step (2), the feed ratio of phosphate ester monomer and macromole evocating agent (1) is 40～80: 1.
The present invention requires to protect above-mentioned various ring-type poly phosphate monomer and the application in preparation dependency structure polymer thereof simultaneously.
The present invention requires to protect the initiator precursor of above-mentioned taxol as ring-opening polymerization simultaneously, is used for ring-opening polymerization and in the application of preparation dependency structure medicine.
The present invention requires to protect above-mentioned paclitaxel bonded aliphatic polyester polymer medicine and the application in preparation dependency structure polymer drug thereof simultaneously.
The present invention requires to protect the application of above-mentioned paclitaxel bonded amphipathic polyester-b-poly phosphate in preparation medicine for treating tumor thing simultaneously.
The present invention requires to protect a kind of medicine of treating tumour simultaneously, and its main active ingredient is above-mentioned paclitaxel bonded amphipathic polyester-b-poly phosphate or acceptable salt of its medical science.
Because the technique scheme utilization, the present invention compared with prior art has advantage:
1. the invention provides a kind of polymer drug that contains anti-carcinogenic property medicine, physiologically acceptable and biodegradable amphipathic nature block polymer simultaneously; Overcome and utilized the caused bag of amphipathic nature polyalcohol micella bag loaded with anti-cancer medicine to carry the low deficiency of rate in the prior art, expanded the range of application of taxol drug.Owing in final product, have hydrophobic paclitaxel bonded polyester construction and hydrophilic poly phosphate structure; This polymer drug can be self-assembled in simulation human body environment and be micella; With the paclitaxel bonded aliphatic polyester of hydrophobicity (PTX-APE) is that nuclear, wetting ability poly phosphate (PPE) are shell; Can improve the caused rejection of hydrophobic drug poorly water-soluble in course of conveying and, reach the purpose of effective control drug release Normocellular toxic side effect.
2. the present invention is an initiator precursor with the commercialization drug taxol; Utilize in the taxol molecular structure 2 '-selective reaction of position; Through the change of aliphatics cyclic ester and a series of annular phosphate monomer structures, regulate [monomer]/[initiation precursor] volumetric molar concentration proportioning, as required; Can prepare the polymer drug of the paclitaxel bonded amphipathic aliphatic polyester-b-poly phosphate with different aliphatic polyesters and poly phosphate chain length, different chain structures, product has variety.
3. aliphatic polyester used in the present invention comprises (poly-epsilon-caprolactone) and POLYACTIC ACID, all has good bag to carry efficient to fat-soluble medicine, and this polymer drug also can be used for bag and carry other fat-soluble medicines, realizes dual pharmaceutical carrier.Because (poly-epsilon-caprolactone) and poly phosphate all have favorable biological degradability, especially poly phosphate can be degraded under the effect of phosphodiesterase sooner, and its degraded product is the compound to the life entity toxicological harmless such as phosphoric acid salt, ethanol, glycol.Through the degraded of polymkeric substance, can be after arriving cancer cells in the short period (about 5～15 days) drug release is reached the effect of treatment tumour.
4. synthesis step of the present invention is simple, and through ring-opening polymerization, with aliphatic polyester (comprising poly-epsilon-caprolactone and POLYACTIC ACID) and water-soluble poly SULPHOSUCCINIC ACID ESTER block and paclitaxel bonded, bonding reaction efficient is higher, and product is pure.It is tediously long to have overcome the additive method reactions step, shortcomings such as aftertreatment complicacy.
5. the present invention makes the medicine sustained release through having the poly phosphate of biocompatibility and biodegradability, reaches the purpose of regulating drug release rate, increases suddenly the infringement of organizing and organ brings to reduce drug level.
Description of drawings
Fig. 1 for the proton nmr spectra of ring-opening polymerization initiator precursor taxol (
1H NMR) spectrogram, solvent are deuterochloroform (CDCl
3);
Fig. 2 among the embodiment one paclitaxel bonded gathering (6-caprolactone) polymer drug proton nmr spectra (
1H NMR) spectrogram, solvent are deuterochloroform (CDCl
3);
Fig. 3 be the polymer drug of paclitaxel bonded amphipathic caprolactone-b-poly phosphate among the embodiment two proton nmr spectra (
1H NMR) spectrogram, solvent are deuterochloroform (CDCl
3);
Fig. 4 among the embodiment one paclitaxel bonded gathering (6-caprolactone) polymer drug gel permeation chromatography (GPC) elution curve, be moving phase with the THF;
Fig. 5 is that polymer drug self-assembly in the phosphoric acid buffer of pH 7.4 of paclitaxel bonded amphipathic caprolactone-b-poly phosphate among the embodiment three forms micellar transmission electron microscope (TEM) photo; Wherein (a) and (b) are same sample, (b) are the enlarged view of (a);
Fig. 6 is the polymer drug of paclitaxel bonded polycaprolactone-b-poly phosphate among the embodiment four cumulative in vitro releasing curve diagram under 37.4 ℃ of water bath with thermostatic control conditions in the phosphoric acid buffer of pH5.0.
Embodiment
Below in conjunction with accompanying drawing and embodiment the present invention is further described:
Embodiment one: the preparation of the polymer drug of taxol-poly-epsilon-caprolactone bonding
After the side tube flask that stirrer is housed, glass syringe, syringe needle and glass stopper be put in 120 ℃ of baking ovens dry 12 hours, take out the needle and syringe head and put into the exsiccator internal cooling, side tube flask is connected to behind the ground glass stopper on the biexhaust pipe to take out with oil pump beyond the Great Wall is chilled to room temperature; Charge into high-purity argon gas again; And substitute gas three times, and be full of argon gas at last, under the condition of logical argon gas, add taxol white powder (0.20g; 0.23mmol) and stannous octoate (0.047g, 0.12mmol) thick liquid.Substitute gas twice, after substituting argon gas, extract the solvent orthodichlorobenzene with dried syringe and add in the side tube flask stirring and dissolving to system clear.(1.33g, 0.012mol), the mol ratio of its consumption and initiator taxol is 40～60: 1 to add the 6-caprolactone monomer with the exsiccant syringe again.Reaction flask is put into 90～110 ℃ of oil baths of setting, stir reaction down 20～24 hours.Elder generation concentrates about 60 ℃ with Rotary Evaporators with reaction product, liquid concentrator is dropwise added in a large amount of anhydrous diethyl ethers under stirring to produce white precipitate again, removes catalyzer and unreacted raw material through deposition.Obtain white solid product with the B suction filtration.Solid product is precipitated with anhydrous diethyl ether after with the dissolving of a small amount of trichloromethane once more; Obtain white solid; Behind the B suction filtration; With gained white solid matter in vacuum drying oven dry 12～24 hours, obtain the exsiccant white powder, be the polymer drug PTX-PCL of (6-caprolactone) bonding of paclitaxel bonded gathering
35Through proton nmr spectra (
1H NMR) and gel permeation chromatography (GPC) its chemical structure and molecular weight and MWD are characterized; In the nucleus magnetic hydrogen spectrum spectrogram, chemical shift δ 1.35, δ 1.65, δ 2.33ppm place are the methene proton on the polycaprolactone main chain, have proved that thus taxol successfully causes the caprolactone ring-opening polymerization; The elution curve of gel permeation chromatography is unimodal; Explain and have only a hydroxyl to participate in ring-opening polymerization on the taxol, its nucleus magnetic hydrogen spectrum spectrogram is seen Fig. 2, and the GPC elution curve is seen Fig. 4.
Embodiment two: the preparation of the polymer drug (PTX-PCL-b-PEEP) of taxol-poly-epsilon-caprolactone-poly phosphate bonding
After the side tube flask that stirrer is housed, glass syringe, syringe needle and ground glass stopper be put in 120 ℃ of baking ovens dry 12 hours; Take out the needle and syringe head and put into the exsiccator internal cooling; Side tube flask is connected to behind the ground glass stopper on the biexhaust pipe to take out with oil pump beyond the Great Wall is chilled to room temperature, charge into high-purity argon gas again, and substitute gas three times; Be full of argon gas at last, under the condition of logical argon gas, add number-average molecular weight and be about the paclitaxel bonded poly-epsilon-caprolactone (PTX-PCL of 4800g/mmol
35) macromole evocating agent (0.58g, 0.12mmol) and stannous octoate (0.024g, 0.06mmol) thick liquid.Substitute gas twice, after substituting argon gas, extract solvents tetrahydrofurane with dried syringe and add in the side tube flask stirring and dissolving to system clear.(0.77g, 5.1mmol), the mol ratio of its consumption and initiator taxol is 50～80: 1 to add phosphate ester monomer with syringe again.Reaction system stirs reaction down 20～24 hours in 45～50 ℃ of oil baths.Reaction product concentrates with rotary evaporation earlier, liquid concentrator is dropwise added in a large amount of anhydrous diethyl ethers under stirring again, and removes catalyzer and unreacted raw material through deposition.The white precipitate that produces is used the B suction filtration, obtain white solid product.With solid product with the dissolving of a small amount of trichloromethane after once more with the anhydrous diethyl ether deposition, behind the B suction filtration, the gained white solid matter is dried to constant weight in vacuum drying oven, obtain the exsiccant white solid, be PTX-PCL
35-b-PEEP
16Through proton nmr spectra (
1H NMR) and gel permeation chromatography (GPC) its chemical structure and molecular weight and MWD are characterized; In the nucleus magnetic hydrogen spectrum spectrogram; Chemical shift δ 4.16ppm and δ 4.26ppm place are the proton of the methylene radical on the poly phosphate main chain; Proved that the poly phosphate section successfully prepares, wherein the mass content of taxol in the bonding medicine is 11.70%.Its nucleus magnetic hydrogen spectrum spectrogram is seen Fig. 3.
Embodiment three: adopt the preparation of film forming method to contain the polymer micelle of cancer therapy drug
Get 5mg sample P TX-PCL with round-bottomed flask
35-b-PEEP
16In the 5mL THF, stir fully dissolving, revolve steaming then and remove THF fully, add 5mL pH value again and be 7.4 phosphate buffer solution, stirred overnight.Its pattern and micellar size are seen Fig. 5 by transmission electron microscope observation.
Above-mentioned PTX-PCL
35-b-PEEP
16Self-assembly in phosphate buffer solution, forming dewatering medicament and oleophilicity aliphatic polyester is the micella of shell for nuclear, water-soluble poly SULPHOSUCCINIC ACID ESTER.On the one hand, can improve the strong-hydrophobicity of taxol drug, thereby avoid the medicine rejection in the course of conveying in vivo; On the other hand, through the degraded of polyester, slowly discharge medicine; Avoided drug level sharply to increase, reached the effect of sustained release antitumor drug, avoided medicine other Normocellular injuries of histoorgan to other Normocellular injuries of histoorgan; After in medicine arrives cancer cells, because the pH value descends and the existence of the interior enzyme of body, poly phosphate will be accelerated degraded; Discharge medicine, reach the effect of treatment tumour.
Embodiment four: the extracorporeal releasing experiment of the polymer drug of paclitaxel bonded amphipathic caprolactone-b-poly phosphate
With 25mg PTX-PCL
35-b-PEEP
16Stir down and fully is dissolved in the 5mL THF, use molecular weight cut-off in pH value is 7.4 phosphate buffer soln, to dialyse 20 hours again, it is mixed with the polymers soln of 1mg/mL with 25mL volumetric flask constant volume as the dialysis tubing of 3500g/mol.Transferase 45 mL is in the dialysis tubing of 3500g/mol to molecular weight cut-off again, and this dialysis tubing is put into the centrifuge tube of 30mL capacity, adds 20mL pH value in addition and be 5.0 phosphate buffer soln.Place about 37.4 ℃ of constant temperature shaking tables to carry out release experiment centrifuge tube.Whenever from centrifuge tube, took out 5mL liquid at a distance from 5～24 hours with liquid-transfering gun, the pH value of putting into equal volume again is 5.0 phosphate buffer soln.Discharge 8 days continuously.Releasing structure is through the ultraviolet-visible light spectroscopic analysis, and the cumulative release curve is seen Fig. 6, and visible slow release effect is good.
Claims (7)
1. the polymer of paclitaxel bonded amphipathic aliphatic polyester-b-poly phosphate; It is characterized in that; The polymer of said paclitaxel bonded amphipathic aliphatic polyester-b-poly phosphate comprises: poly phosphate segment, aliphatic polyester segment and Japanese yew alcohol radical, wherein aliphatic polyester segmental two ends link to each other with Japanese yew alcohol radical, poly phosphate segment with ester bond respectively.
2. according to the polymer of the said paclitaxel bonded amphipathic aliphatic polyester of claim 1-b-poly phosphate; It is characterized in that; Said aliphatic polyester segment is selected from: gather (6-caprolactone) segment or polylactic acid chain segment; When the aliphatic polyester segment when gathering (6-caprolactone) segment, the high molecular chemical structural formula of said paclitaxel bonded amphipathic aliphatic polyester-b-poly phosphate is:
When the aliphatic polyester segment was polylactic acid chain segment, the high molecular chemical structural formula of said paclitaxel bonded amphipathic aliphatic polyester-b-poly phosphate was:
Wherein, polycaprolactone segmental number-average molecular weight
Be 2900～5000g/mol, m is 15～40; The number-average molecular weight of polylactic acid chain segment
Be 3000～6000g/mol, x is 30～80; Poly phosphate segmental number-average molecular weight
Be 2300～6100g/mol, n is 15～30; R
1Be selected from: oxyethyl group-OCH
2CH
3, methoxyl group-OCH
3, dimethylamino-N [(CH
3)
2], diethylin-N [(CH
2CH
3)
2] or methylamino--NH (CH
3) in a kind of.
3. the high molecular preparation method of the said paclitaxel bonded amphipathic aliphatic polyester of claim 1-b-poly phosphate; It is characterized in that; May further comprise the steps: at first under the katalysis of stannous octoate; Utilize taxol 2 '-hydroxyl of position causes the ring-opening polymerization of aliphatic cyclic ester class monomer, obtains the hydrophobic polymer of paclitaxel bonded polyester; And then utilize the terminal hydroxyl of polyester in the hydrophobic polymer of paclitaxel bonded polyester, and under the stannous octoate katalysis, cause the ring-opening polymerization of annular phosphate monomer, obtain the polymer drug of paclitaxel bonded amphipathic polyester-b-poly phosphate; Wherein, the monomeric structure of said annular phosphate is:
In the formula, R
1Be selected from oxyethyl group-OCH
2CH
3, methoxyl group-OCH
3, dimethylamino-N [(CH
3)
2], diethylin-N [(CH
2CH
3)
2], or methylamino--NH (CH
3) in a kind of.
4. the high molecular preparation method of the said paclitaxel bonded amphipathic aliphatic polyester of claim 3-b-poly phosphate is characterized in that said aliphatic cyclic ester class monomer is selected from: 6-caprolactone or rac-Lactide.
5. the high molecular preparation method of the said paclitaxel bonded amphipathic aliphatic polyester of claim 3-b-poly phosphate; It is characterized in that; The hydrophobic polymer of said paclitaxel bonded polyester is: paclitaxel bonded gathering (6-caprolactone) or paclitaxel bonded POLYACTIC ACID; Wherein, the chemical structural formula of paclitaxel bonded gathering (6-caprolactone) is:
The structural formula of paclitaxel bonded POLYACTIC ACID is:
Wherein, polycaprolactone segmental number-average molecular weight
Be 2900～5000g/mol, m is 15～40; The number-average molecular weight of POLYACTIC ACID
Be 3000～6000g/mol, x is 30～80; Poly phosphate segmental number-average molecular weight
Be 2300～6100g/mol, n is 15～30; R
1Be selected from: oxyethyl group-OCH
2CH
3, methoxyl group-OCH
3, dimethylamino-N [(CH
3)
2], diethylin-N [(CH
2CH
3)
2] or methylamino--NH (CH
3) in a kind of.
6. claim 1 or the 2 said paclitaxel bonded amphipathic polyester-b-poly phosphates application in preparation medicine for treating tumor thing.
7. medicine of treating tumour, its main active ingredient is claim 1 or 2 said paclitaxel bonded amphipathic polyester-b-poly phosphate or acceptable salt of its medical science.
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|---|---|---|---|---|
| CN105688225A (en) * | 2014-11-27 | 2016-06-22 | 黑龙江鑫达企业集团有限公司 | Biodegradable polymer-docetaxel bonding drug and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101679021A (en) * | 2007-03-02 | 2010-03-24 | 伊利诺伊大学评议会 | Particulate drug delivery |
-
2011
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101679021A (en) * | 2007-03-02 | 2010-03-24 | 伊利诺伊大学评议会 | Particulate drug delivery |
Non-Patent Citations (3)
| Title |
|---|
| 《Macromolecules》 20090331 Yu-Cai Wang等 Tunable Thermosensitivity of Biodegradable Polymer Micelles of Poly(epsilon-caprolactone) and Polyphosphoester Block Copolymers 3026-3032 1-4,6-7 第42卷, * |
| 《Macromolecules》 20090331 Yu-Cai Wang等 Tunable Thermosensitivity of Biodegradable Polymer Micelles of Poly(epsilon-caprolactone) and Polyphosphoester Block Copolymers 3026-3032 5 第42卷, * |
| YU-CAI WANG等: "Tunable Thermosensitivity of Biodegradable Polymer Micelles of Poly(ε-caprolactone) and Polyphosphoester Block Copolymers", 《MACROMOLECULES》, vol. 42, 31 March 2009 (2009-03-31), pages 3026 - 3032 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105688225A (en) * | 2014-11-27 | 2016-06-22 | 黑龙江鑫达企业集团有限公司 | Biodegradable polymer-docetaxel bonding drug and preparation method thereof |
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