CN102552930B - Water-soluble paclitaxel derivative with cell targeting effect and preparation thereof - Google Patents
Water-soluble paclitaxel derivative with cell targeting effect and preparation thereof Download PDFInfo
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- 0 CCOCCOP(*)(C(C)(C)O[C@]([C@](c1ccccc1)NC(c1ccccc1)=O)C(O[C@@](C1)C(C)=C([C@](C([C@](C)([C@](C[C@]2OC3)O)[C@@]([C@@]4OC(c5ccccc5)=O)[C@@]23OC(C)=O)=O)OC(C)=O)C(C)(C)[C@@]14O)=O)=O Chemical compound CCOCCOP(*)(C(C)(C)O[C@]([C@](c1ccccc1)NC(c1ccccc1)=O)C(O[C@@](C1)C(C)=C([C@](C([C@](C)([C@](C[C@]2OC3)O)[C@@]([C@@]4OC(c5ccccc5)=O)[C@@]23OC(C)=O)=O)OC(C)=O)C(C)(C)[C@@]14O)=O)=O 0.000 description 1
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Abstract
The invention belongs to the field of high molecular medicaments, and discloses an anticancer medicament which has targeting properties on multiple cancer cells and contributes to bonding of polyphosphate ester with paclitaxel, and a preparation method thereof. The invention specifically discloses a paclitaxel-polyphosphate ester-folic acid bonded high molecular medicament which is self-assembledin a phosphoric acid buffer solution, so that a micelle in which folic acid is distributed on an outer layer is formed. On one hand, the high hydrophobic property of a paclitaxel medicament can be improved, so that the transplant reactions of a medicament in an in-vivo conveying process are avoided; and on the other hand, the accumulation of the medicament on cancer cells is enhanced, damages of the medicament to other normal cells of tissue organs are avoided, the degrading speed of a polymer in under an in-vivo circulating condition (the pH value is about 7.4) is slow, polyphosphate ester is degraded at a higher speed due to the falling of the pH value in the presence of in-vivo bio-enzymes after the medicament reaches the cancer cells, the medicament is released, and the effect of treating tumors is achieved.
Description
Technical field
The invention belongs to medicine control release field, relate to a kind of have medicine and synthetic method thereof folate-mediated cancerous cell targeting, good water solubility, good biocompatibility, biodegradable poly phosphate bonding anticarcinogen paclitaxel.
Background technology
Paclitaxel (Paclitaxel, trade name Taxol) is a kind of tricyclic diterpene material that extracts from Chinese yew genus plants, has unique active anticancer.Since in December, 1992 FDA (Food and Drug Adminstration) (FDA) approval paclitaxel is used for the treatment of advanced ovarian cancer, found that gradually it has very high curative effect to breast carcinoma, ovarian cancer and pulmonary carcinoma.
But, owing to paclitaxel is made of a huge circulus and numerous hydrophobic groups, so its dissolubility in water is very poor.In order to improve its water solublity, minimizing is discharged by the P-glycoprotein, enhancing is for the anti-cancer ability of colon cancer, cancer of pancreas, melanoma and renal cancer, clinical practice at present mainly be paclitaxel injection, the i.e. colourless sticky shape solution of being made by cremophor EL (Cremophor EL contains polyoxyethylene castor oil)/dehydrated alcohol (50: 50).But studies show that in a large number polyoxyethylene castor oil can impel a large amount of histamines to discharge in vivo, produces anaphylaxis, the clinical safety that has influenced paclitaxel is greatly used.
At this defective, researcheres are by being bonded to hydrophilic polymer on the paclitaxel to improve its water solublity, for example: by chemical reaction, with the biodegradable amphipathic nature polyalcohol that contains polyesters and water-soluble polymer of paclitaxel molecular linkage.Degraded control by polyester discharges anticarcinogen, this method not only reduced paclitaxel in vivo in the course of conveying to the injury of normal structure, and can slowly discharge in vivo, avoided the drug level sharply to increase the damage of bringing for tissue and organ.
The far refined seminar of scape reports amphipathic three block copolymer (aliphatic polyester-Polyethylene Glycol-aliphatic polyester) bonding paclitaxel medicine, can improve the problem of taxol soluble difference.(far refined referring to scape, Xie Zhigang, Lv Changhai, Chen Xuesi, Hu Xiuli, stone is complete, the village is beautiful, " amphiphilic tri-block copolymer-paclitaxel bonded drug and synthetic method thereof ", Chinese patent application 200610131690.X)
Above-mentioned patent does not relate to the cancerous cell targeting, and the aliphatic polyester degradation time is longer.
In addition, in the prior art, mainly contain for paclitaxel bonded research:
(1) Paul C.Ho etc. by the amphipathic block of monomethyl polyethylene glycol-lactide earlier with the succinic anhydrides reaction, at N-hydroxyl succinum imines and N, utilize the carboxyl of succinic anhydrides and the hydroxy esterification effect bonding of paclitaxel to get under the effect of N-dicyclohexyl diimine again.(Zhe?Wang，Paul?C.Ho，Biomaterials?2010，31，7115-7123)
(2) people such as Sun Jian utilize paclitaxel earlier with the succinic anhydrides reaction, convert the hydroxyl of paclitaxel to the end carboxyl, be prepared into the PTX-NHS Acibenzolar with the effect of N-hydroxyl succinum imines again, by carrying out ester exchange reaction with ultra-branching polyether ester (HPEE), obtain paclitaxel bonded polyether ester at last.(Guolin?Li，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 by (MeO) PCl
2With the single mercaptan of the tetraethylene glycol (TEG) of single sulfydryl end-blocking with paclitaxel bonded after, again with ferrum oxide or gold nano grain addition, prepare the paclitaxel carrier of targeting.(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 succinic anhydrides with paclitaxel and glucuronic acid or 2 '-glucose couples together, preparation is based on the prodrugs of paclitaxel of polysaccharide.(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, (1) and (2) institute reported method all is by esterification comparatively loaded down with trivial details and that reaction efficiency is not high, by other molecules paclitaxel and hydrophilic polymer bonding is got up.The introducing of more other chemical compounds changes medicines structure on the one hand, and then may influence drug effect; On the other hand, preparation process is comparatively complicated, and does not relate to the targeting in the medicines structure.Document (3) and (4) are though institute's reported method relates to the targeting of medicament transport, and not relating to has the folic acid of mediation and the water-soluble poly phosphate ester with biodegradability to various tumors.
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 described amphiphilic tri-block copolymer-paclitaxel bonded drug is:
Wherein, the hydrophilic mid-block is molecular weight less than 10000 Polyethylene Glycol; Hydrophobic two ends block is the ring-opening polymerisation product polyesteramide of the morpholine diketone of aliphatic cyclic ester and band carboxylic acid side group, molecular weight 2000～50000; Paclitaxel by its 2 '-position or the carboxyl of 7-position link to each other with side carboxyl on the main chain; The mass content of paclitaxel in the bonding medicine is 1～15%.Its preparation method is: Polyethylene Glycol (PEG) is as macromole evocating agent, by the L-lactide, and the morpholine-2 of Acetic acid, hydroxy-, bimol. cyclic ester or 6-caprolactone and functionalization, the random copolymerization of 5-derovatives obtains having the triblock copolymer of side benzyl ester; By catalytic hydrogenation the benzyl ester is converted into carboxyl; 2 of the side carboxyl of copolymer and paclitaxel '-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 (EPR) to assemble at tumor locus by " infiltration of enhancing and retention effect " in blood circulation, improves paclitaxel to the targeting of tumor locus.Therefore, this amphipathic nature polyalcohol-paclitaxel bonded drug and the nano-micelle that is self-assembled in aqueous solution thereof are expected to become the problem that solves the taxol soluble difference and the effective way that improves the paclitaxel bioavailability.
The patent No. is that 200410002722.7 Chinese invention patent discloses a kind of taxol soluble derivative, comprising: galactosylation paclitaxel, agmatine base paclitaxel, heparin modified paclitaxel and paclitaxel dimer; Its preparation method is: after making paclitaxel and corresponding anhydride and the reaction of dicarboxylic acids carboxylic acid halides generate the carboxylic acyloxy paclitaxel, respectively with galactosylation reagent or agmatine amidatioon, or react with heparin more earlier and after the diamine amidatioon, generate corresponding water soluble taxad alcohol derivative respectively.Described paclitaxel dimer is formed by carboxylic acyloxy paclitaxel and the reaction of amino Polyethylene Glycol generation amide.Paclitaxel is after above-mentioned modification, and its water solublity has considerably and improves.And the paclitaxel molecule has possessed certain tissue target tropism after connecting galactosyl, agmatine base or heparin, can after administration, pass through the blood circulation orientation in target tissue, thereby improved local drug concentration greatly, also greatly reduced the toxic and side effects of paclitaxel to other organs of health simultaneously.
Summary of the invention
Goal of the invention of the present invention provides a kind of water soluble taxad alcohol derivative with cell-targeting effect and its preparation method and application, make folate-mediated poly phosphate bonding anticarcinogen paclitaxel have good cancerous cell targeting, water solublity, biocompatibility, and biodegradable.
To achieve the above object of the invention, the technical solution used in the present invention is: a kind of water soluble taxad alcohol derivative with cell-targeting effect, described paclitaxel derivant are the macromolecule of paclitaxel-poly phosphate-folic acid bonding, and its chemical structural formula is:
Wherein, the number-average molecular weight of poly phosphate segment
Be 2300～6100g/mol, n is 15～35; R
1Be selected from ethyoxyl-OCH
2CH
3, methoxyl group-OCH
3, dimethylamino-N[(CH
3)
2], lignocaine-N[(CH
2CH
3)
2] or methylamino-NH (CH
3) in a kind of.
In the technique scheme, the high molecular preparation method of described paclitaxel-poly phosphate-folic acid bonding may further comprise the steps:
(1) the high molecular preparation of water-soluble paclitaxel bonding poly phosphate: under anhydrous and oxygen-free and inert gas shielding; mixture (2: 1～1: 2v/v%) be solvent with o-dichlorohenzene and oxolane; be reaction substrate with phosphate ester monomer and paclitaxel, with stannous octoate Sn (Oct)
2Be catalyst, in 40～50 ℃ temperature, carried out ring-opening polymerization 5～7 hours; Wherein, described phosphate ester monomer is
R
1Be selected from ethyoxyl-OCH
2CH
3, methoxyl group-OCH
3, dimethylamino-N[(CH
3)
2], lignocaine-N[(CH
2CH
3)
2] or methylamino-NH (CH
3) in a kind of;
(2) the high molecular preparation of water-soluble paclitaxel-poly phosphate-folic acid bonding, may further comprise the steps: (i) in the presence of triethylamine, with folic acid abundant stirring and dissolving in anhydrous dimethyl sulfoxide, add dicyclohexylcarbodiimide (DCC) and N-hydroxyl succinum imines (NHS), stir 12～24h, obtain folic acid solution; (ii) the macromolecule with the poly phosphate bonding paclitaxel is dissolved in the dimethylsulfoxide solvent, joins in the folic acid solution of step (i) again, at room temperature continues the lucifuge stirring reaction 24～36 hours, namely obtains the macromolecule of paclitaxel-poly phosphate-folic acid bonding structure.
In the technique scheme, in the step (1), the mol ratio of phosphate ester monomer and paclitaxel is 40～80: 1; The consumption of stannous octoate is 0.5～1 times of the mole of hydroxyl in the paclitaxel molecule that participate in to cause; The volume ratio of o-dichlorohenzene and oxolane is 2: 1～1: 2; The high molecular chemical structural formula of described paclitaxel bonded poly phosphate is:
The number-average molecular weight of described poly phosphate segment
Be 2300～6100g/mol, n is 15～35.The course of reaction of step (1) is as follows:
Wherein, described paclitaxel is commercial product, and purity is more than 99.5%.
In the technique scheme, the course of reaction of step (2) is as follows:
Wherein, in the above-mentioned reaction equation, FA represents
Carboxyl in the formula can with poly phosphate part bonding.
Further in the technical scheme, for guaranteeing degree of purity of production, need make with extra care the product in each step, its method is:
(1) the high molecular purification process of paclitaxel-poly phosphate is: earlier product is put in the bag filter that molecular cut off is 3500g/mol, with deionized water dialysis 48～60 hours; Be put in the freezer dryer after product after will dialysing again places and freezes under refrigerator-20～-25 ℃ and drain, obtain the water white transparency sticky solid, be paclitaxel bonded poly phosphate macromolecule;
(2) the high molecular purification process of paclitaxel-poly phosphate-folic acid is: remove by filter by-product of dicyclohexylurea white insoluble matter, after filtrate is concentrated, transfer in the bag filter that molecular cut off is 3500g/mol with deionized water dialysis 24～30 hours, changed water at interval in 3～4 hours, after lyophilization, the dissolving of reuse dichloromethane, centrifugally remove insoluble unreacted folic acid, remove a large amount of solvents again, transfer to again in the bag filter that molecular cut off is 3500g/mol at last, utilize deionized water dialysis 12～24 hours, through lyophilization, obtain solid product, be paclitaxel-poly phosphate-folic acid polymer drug.
The present invention is claimed above-mentioned various ring-type poly phosphate monomers and the application in preparation dependency structure macromolecule thereof simultaneously.
The present invention's claimed above-mentioned paclitaxel of while is as the initiator precursor of ring-opening polymerisation, for ring-opening polymerisation and in the application for preparing the dependency structure medicine.
The present invention is claimed above-mentioned paclitaxel-poly phosphate polymer drug and the application in preparation dependency structure polymer drug thereof simultaneously.
Above-mentioned paclitaxel-poly phosphate macromolecule, paclitaxel-poly phosphate-folic acid macromolecule all have antitumor action, wherein, paclitaxel-poly phosphate macromolecule has good water-solubility, paclitaxel-poly phosphate-folic acid macromolecule has good water-solubility, biocompatibility, tumor cell target function, and biodegradable.
Therefore, the present invention is claimed a kind of antitumor drug simultaneously, and the main active ingredient of described antitumor drug is above-mentioned paclitaxel-poly phosphate macromolecule or the acceptable salt of its medical science.
The present invention is claimed a kind of antitumor drug simultaneously, and the main active ingredient of described antitumor drug is above-mentioned paclitaxel-poly phosphate-folic acid macromolecule or the acceptable salt of its medical science.
The present invention's application of claimed above-mentioned paclitaxel-poly phosphate macromolecule in the preparation antitumor drug simultaneously.
The present invention's application of claimed above-mentioned paclitaxel-poly phosphate-folic acid macromolecule in the preparation antitumor drug simultaneously.
Because technique scheme is used, the present invention compared with prior art has following advantage:
1. the invention provides a kind of polymer drug that contains cancer resistance medicine, biodegradable and water-soluble polymer simultaneously and cancerous cell is had the multi-functional of targeting, overcome and only had cancer therapy drug and polymer-bound in the prior art, the perhaps deficiency of targeted molecular and hydrophobic drug bonding has been expanded the range of application of taxol drug.Owing in end product, have hydrophobic paclitaxel structure and hydrophilic poly phosphate and folic acid structure, this polymer drug can be self-assembled in simulation human body environment and be micelle, be that nuclear, hydrophilic poly phosphate are shell, have folate molecule to the cancerous cell mediation on the surface of micelle with the hydrophobicity paclitaxel, thereby can obtain a kind of water-soluble paclitaxel-poly phosphate-folic acid polymer drug with cancerous cell targeting.Can improve the targeting of medicine, improve the caused rejection of hydrophobic drug poorly water-soluble in course of conveying and to Normocellular toxic and side effects, reach the purpose of effective control drug release.
The present invention with the commercialization drug taxol as initiator precursor, utilize 2 in the paclitaxel molecular structure '-position selective reaction, by the change of a series of annular phosphate monomer structures and the change of [monomer]/[initiator precursor] molar concentration proportioning, as required, can prepare the polymer drug of the paclitaxel bonded poly phosphate with different poly phosphate chain lengths, different poly phosphate chain structures, product has multiformity.
3. synthesis step of the present invention is simple, and with poly phosphate and paclitaxel bonded, bonding reaction efficient is higher by ring-opening polymerisation, and product is pure.It is tediously long to have overcome the additive method reactions steps, shortcomings such as post processing complexity.
4. the present invention makes medicine control release by 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 open loop initiator precursor paclitaxel (
1H NMR) spectrogram, solvent are deuterochloroform (CDCl
3);
Fig. 2 be paclitaxel among the embodiment one-poly phosphate polymer drug proton nmr spectra (
1HNMR) spectrogram, solvent are deuterochloroform (CDCl
3);
Fig. 3 be paclitaxel-poly phosphate among the embodiment two-folic acid polymer drug proton nmr spectra (
1H NMR) spectrogram, solvent are deuterated dimethyl sulfoxide (DMSO-d
6);
Fig. 4 is transmission electron microscope (TEM) photo that paclitaxel-poly phosphate-folic acid polymer drug self assembly forms micelle, and wherein (a) and (b) are same sample, (b) are the enlarged drawing of (a);
Fig. 5 is that paclitaxel-poly phosphate-folic acid polymer drug adds up releasing curve diagram in 37.4 ℃ of waters bath with thermostatic control in the phosphate buffer of pH 5.0.
The specific embodiment
Below in conjunction with drawings and Examples the present invention is further described:
Embodiment one: the preparation method of paclitaxel bonded poly phosphate medicine
After glass syringe, syringe needle, glass stopper, side tube flask that stirrer is housed placed 120 ℃ of dry 12h of baking oven, take out the needle and syringe head and put into the desiccator internal cooling, side tube flask is connected to behind the 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 at last, adding molecular weight under the condition of logical argon is the paclitaxel white powder (0.30g of 853.9g/mol, 0.35mmol) and stannous octoate (0.07g, 0.18mmol) thick liquid of distilling under reduced pressure.Substitute gas twice, extract solvent o-dichlorohenzene 2mL and oxolane 4mL (volume ratio is 1: 2) injection side tube flask with dried syringe after substituting argon, stirring and dissolving is to the system clear.It is the phosphate ester monomer 2-ethoxy-2-oxo-1 of 151g/mol that the reuse syringe adds molecular weight, 3,2-dioxaphospholane (EOP), with the mol ratio of initiator precursor paclitaxel be 40～80: 1.Reaction bulb is put into 45 ℃ of oil baths of setting, under stirring under this temperature, reacting 5～7h.
The reaction back is directly transferred to product in the bag filter that molecular cut off is 3500g/mol, with deionized water dialysis 48～60h; The afterproduct of will dialysing is put in the freezer dryer after refrigerator lower floor freezes to be drained, and obtains the water white transparency sticky solid, is paclitaxel-poly phosphate polymer drug PTX-PEEP
25Its number-average molecular weight is about 4600g/mol.
Products therefrom through proton nmr spectra (
1H NMR) checking, chemical shift is the proton of two methylene on the phosphate ester δ 4.25ppm and 4.16ppm's, proves that the product that is synthesized is paclitaxel bonded poly phosphate PTX-PEEP
25, the proton nmr spectra spectrogram is seen Fig. 2.
Embodiment two: paclitaxel-poly phosphate-folic acid polymer drug (PTX-PEEP-FA) preparation method
Be put in desiccator and cool off taking out behind the band side tube flask of stirrer and stopper and syringe and the 120 ℃ of oven dryings, adding molecular weight in being full of the side tube flask of argon is the folic acid (0.024g of 441g/mol, 0.054mmol), extract dimethyl sulfoxine 5mL and the triethylamine 0.5mL (volume ratio is 10: 1) that distillation purifying is crossed with the dry injection device, fully stirring and dissolving is to yellow transparent solution, add dicyclohexylcarbodiimide (0.014g, 0.070mmol) and N-hydroxyl succinum imines (0.008g, 0.070mmol), be 1: 1.3 with the mol ratio of folic acid, under the room temperature lucifuge, stir 12～24h earlier.(0.20g 0.043mmol) joins in the reaction system of this folic acid, continues stirring reaction 24～48h under the room temperature lucifuge number-average molecular weight to be about the medicine macromole PTX-PEEP25 of the poly phosphate bonding paclitaxel of 4600g/mol again.
The reaction back is earlier with product buchner funnel sucking filtration, remove the byproduct of reaction 1,3-Dicyclohexylurea white insoluble matter of dicyclohexylcarbodiimide, then behind the concentrating part dimethyl sulfoxine, transfer in the bag filter that molecular cut off is 3500g/mol with deionized water dialysis 24～30 hours, changed water at interval in 3～4 hours, after lyophilization, the dissolving of reuse dichloromethane, centrifugally remove insoluble unreacted folic acid, revolve again to steam and remove a large amount of solvents, utilize deionized water dialysis 12～24 hours at last, namely obtain the polymer drug PTX-PEEP of paclitaxel-poly phosphate-folic acid bonding again through lyophilization
25-FA.
Product through proton nmr spectra (
1H NMR) characterizes, verified polymer architecture, chemical shift δ 11.45ppm place is for having neither part nor lot in the proton of the carboxylic hydroxyl of reaction in the folate molecule, chemical shift δ 9.25ppm place be in the folic acid with the secondary amine proton on the carbonyl of phenyl ring conjugation next door, prove the polymer drug (PTX-PEEP of taxol biosynthesis-poly phosphate-folic acid bonding
25-FA).The proton nmr spectra spectrogram is seen Fig. 3.
Embodiment three: adopt the dialysis preparation to contain the polymer micelle of cancer therapy drug
Get 5mg sample P TX-PEEP with round-bottomed flask
25-FA stirs fully dissolving in the 3mL oxolane, under stirring, drip after pH value is 7.4 phosphate buffered solution 8mL with the speed of 0.5mL/min with the micro-sampling pump then, be that oxolane was removed in the dialysis of 7.4 phosphate buffered solution in 24～30 hours with pH value, the reuse pH value is phosphate buffered solution standardize solution in the volumetric flask of 25mL of 7.4, fully stirs 48～72 hours.Adopt the size of transmission electron microscope observation micelle pattern and micelle, can see, the polymer drug of paclitaxel-poly phosphate-folic acid bonding is self-assembled into the micelle that particle diameter is 80～100nm under the simulation physiological condition, see Fig. 4.
Embodiment four: the extracorporeal releasing experiment of paclitaxel bonded polymeric medicine
With 25mg sample P TX-PEEP
25Stir down and fully is dissolved in the 5mL oxolane, the reuse molecular cut off is that the bag filter of 3500g/mol is dialysis 20 hours in 7.4 the phosphate buffered solution in pH value, with 25mL volumetric flask standardize solution, it is mixed with the phosphate-buffered liquor of 1mg/mL.Pipetting this polymeric medicine solution of 5mL again is in the bag filter of 3500g/mol to molecular cut off, and this bag filter is put into the centrifuge tube of 30mL capacity, is 5.0 phosphate buffered solution at the outside 20mL pH value that adds of bag filter again.Place about 37.4 ℃ of constant temperature shaking tables to carry out release experiment centrifuge tube.Take out 5mL liquid every 5～24 hours (namely 5,20,24 hours) with liquid-transfering gun bag filter outside from centrifuge tube, the pH value of putting into equal volume again is 5.0 phosphate buffered solution.Discharge 9 days continuously.Discharge the result through the ultraviolet spectrophotometer analysis, release profiles is seen Fig. 5.
From embodiment three and embodiment four as can be known: the self assembly phosphate buffer solution of the macromolecule of above-mentioned paclitaxel-poly phosphate-folic acid bonding forms folic acid and is distributed in outer field micelle.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, because having in a series of malignant tumor highly, folacin receptor expresses, comprise pulmonary carcinoma, ovarian cancer, breast carcinoma, the brain cancer, renal carcinoma, colon cancer, cervical cancer, nasopharyngeal carcinoma, so folic acid is bonded on the medicine, can realize the identification of kinds of tumors and the mediation of cancer therapy drug efficiently, can increase the gathering of medicine at the cancerous cell place, avoided medicine to other Normocellular injuries of histoorgan, and polymer in vivo under the cycling condition (pH value is about 7.4) degradation speed slow, after in medicine arrives cancerous cell, because pH value descends and the existence of the interior enzyme of body, poly phosphate will be accelerated degraded, discharge medicine, reach the effect for the treatment of tumor.
Claims (5)
1. the water soluble taxad alcohol derivative with cell-targeting effect is characterized in that, described paclitaxel derivant is the macromolecule of paclitaxel-poly phosphate-folic acid bonding, and its chemical structural formula is:
Wherein, the number-average molecular weight of poly phosphate segment
Be 2300 ~ 6100 g/mol, n is 15 ~ 35; R
1Be selected from ethyoxyl-OCH
2CH
3, methoxyl group-OCH
3, dimethylamino-N[(CH
3)
2], lignocaine-N[(CH
2CH
3)
2] or methylamino-NH (CH
3) in a kind of.
2. the preparation method of the described water soluble taxad alcohol derivative of claim 1 is characterized in that, may further comprise the steps:
(1) the high molecular preparation of water-soluble paclitaxel bonding poly phosphate: under anhydrous and oxygen-free and inert gas shielding, being solvent with the mixture of o-dichlorohenzene and oxolane, is reaction substrate with phosphate ester monomer and paclitaxel, with stannous octoate Sn (Oct)
2Be catalyst, in 40 ~ 50 ℃ temperature, carried out ring-opening polymerization 5 ~ 7 hours; Wherein, described phosphate ester monomer is
, R
1Be selected from ethyoxyl-OCH
2CH
3, methoxyl group-OCH
3, dimethylamino-N[(CH
3)
2], lignocaine-N[(CH
2CH
3)
2] or methylamino-NH (CH
3) in a kind of;
(2) the high molecular preparation of water-soluble paclitaxel-poly phosphate-folic acid bonding, may further comprise the steps: (i) in the presence of triethylamine, with folic acid abundant stirring and dissolving under the lucifuge in anhydrous dimethyl sulfoxide, add dicyclohexylcarbodiimide and N-hydroxyl succinum imines, stir 12 ~ 24 h, obtain folic acid solution; (ii) the macromolecule with the poly phosphate bonding paclitaxel is dissolved in the dimethylsulfoxide solvent, join again in the folic acid solution of step (i), at room temperature continue the lucifuge stirring reaction 24 ~ 36 hours, and namely obtained the macromolecule of paclitaxel-poly phosphate-folic acid bonding structure.
3. the preparation method of the described water soluble taxad alcohol derivative of claim 2 is characterized in that, in the step (1), the mol ratio of phosphate ester monomer and paclitaxel is 40 ~ 80: 1; The consumption of stannous octoate is 0.5 ~ 1 times of the mole of hydroxyl in the paclitaxel molecule that participate in to cause; The volume ratio of o-dichlorohenzene and oxolane is 2: 1 ~ 1: 2.
4. antitumor drug, the main active ingredient of described antitumor drug is the described paclitaxel-poly phosphate of claim 1-folic acid macromolecule or the acceptable salt of its medical science.
5. the application of the described paclitaxel-poly phosphate of claim 1-folic acid macromolecule in the preparation antitumor drug.
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| CN100431610C (en) * | 2006-01-24 | 2008-11-12 | 中国科学院长春应用化学研究所 | Amphiphilic tri-block copolymer-paclitaxel bonded drug and preparation method thereof |
| CN1961962B (en) * | 2006-11-30 | 2010-05-12 | 中国科学院长春应用化学研究所 | Amphiphilic tri-block copolymer taxol bonding medicament and synthesis method thereof |
| JP2010516675A (en) * | 2007-01-17 | 2010-05-20 | イミューノメディクス、インコーポレイテッド | Recognition moieties for polymer carriers of therapeutic agents and antibody-based targeting of disease sites |
| JP2010126533A (en) * | 2008-11-28 | 2010-06-10 | Bio Verde:Kk | Highly-functionalized anticancer agent |
| CN101766817A (en) * | 2008-12-26 | 2010-07-07 | 中国科学技术大学 | Medicine carrier and application thereof |
| CN102120756A (en) * | 2010-12-07 | 2011-07-13 | 南开大学 | Taxol-based small molecule hydrogel-nanosphere transmission system and preparation method thereof |
| CN102188382B (en) * | 2011-05-04 | 2014-01-15 | 李红霞 | DSPE-PEG-FA-modified nanometer paclitaxel liposome and preparation method thereof |
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