CN102475891A - PH-responsive polyethylene glycol-anticarcinogen conjugate, and synthetic method and application thereof - Google Patents
PH-responsive polyethylene glycol-anticarcinogen conjugate, and synthetic method and application thereof Download PDFInfo
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Abstract
The invention discloses a pH-responsive polyethylene glycol-anticarcinogen conjugate, and a synthetic method and application thereof. After anticarcinogen molecules and polyethylene glycol are covalently linked through pH-sensitive phenylimide linkage, the conjugate is formed, wherein, anticarcinogen can be doxorubicin, epirubicin, daunorubicin, demethoxydaunorubicin or hydrochlorides of the above-mentioned anticarcinogens. The phenylimide linkage is stable under the condition of a normal physiological pH value but undergoes hydrolysis under the condition of a slightly acidic pH value, e.g., a solid tumor cell external pH value and a cell endosome and lysosome pH value; that is, the phenylimide linkage is sensitive to changes of pH values in a range of 7.4 to 4.5 or to below 4.5. The polyethylene glycol-anticarcinogen conjugate has amphiphilic nature and can form nanometer-scale micelle in a saline solution through self-assembly; the micelle can be used as a drug carrier to carry hydrophobic drugs and form a nanometer micelle preparation cladded with drugs, thereby realizing synergy therapy of a plurality of drugs.
Description
Technical field
The invention belongs to the biological medicine technology field, be specifically related to a kind of Polyethylene Glycol with pH response-anticarcinogen key compound and synthetic method thereof that connects based on the benzene imine linkage, and this Polyethylene Glycol-anticarcinogen key compound is as the application of pharmaceutical carrier.
Background technology
Human life and health in the cancer serious harm.According to World Health Organization (WHO) statistics, the whole world had 7,600,000 people to die from cancer in 2005, estimated will reach 9,000,000 in 2015, and the year two thousand thirty reaches 11,500,000.Cancer oneself classified as face of mankind " No. second killer " (being only second to the cardiovascular diseases) (China Cancer, 2009,18,88-89).Owing to be difficult to early discovery, its treatment is the difficult point of medical domain always.Can carry out to implement after chemotherapy before the art, the radiotherapy tumor patient less than 10% of complete resection operation at present; Though about 90% patient can accept radiotherapy, comprises radio frequency or ethanol ablation and give amycin, 5-fluorouracil etc. to carry out system or chemotherapeutic treatment such as arterial infusion, thromboembolism, these methods or medicine also can have certain inhibition or killing effect to tumor tissues or cell really, yet; Because when using conventional formulation chemotherapeutic treatment tumor; Medicine-carried system can not be distinguished normal structure and tumor tissues, normal cell and tumor cell, makes medicine in kill cancer cell, has also brought serious damage for the human normal cell; This is the serious problems (Ann.Surg. that limits medicament dosage, therapeutic effect and patients ' life quality at present; 1999,229,790-800).On the other hand, many treatment of cancer new drugs of developing have well tumor cell in experiment in vitro to be killed/inhibitory action, but most drug complex structure, poor stability; Dissolubility low (about 40% medicine is water-insoluble) (Drug Discovery in the water; 2003,2,337 and references therein); Need new preparation system to adapt to it, otherwise can big limitations their clinical effectiveness.This presses for novel intelligentized pharmaceutical carrier and overcomes, and makes the raising that matter can be arranged the effect of tumor middle and advanced stage treatment.Pharmaceutical carrier is meant that can change medicine gets into intravital mode and distribution in vivo, controls release rate of drugs and conduct drugs to certain organs or the system of tissue.In recent years; Development to novel intelligent chemical medicine thing carrier attracts great attention, and wherein the functionalized macromolecular pharmaceutical carrier is considered to one of intelligent antitumor drug bearer type that is hopeful to make a breakthrough most (Nature Reviews Cancer, 2006; 6,688-701).
The polymer drug carrier can be divided into nanometer medicine-carried system (nanoparticulate drug-delivery systems) and polymer-medicine key compound (drug-polymer conjugates) (Angew.Chem.Int.Ed., 2006,45,1198-1215).Nanometer medicine-carried system Chinese medicine molecule is coated on structures such as micelle, liposome, tree-shaped polymer through physical action.Polymer-medicine key compound Chinese medicine molecule then is connected macromolecule end group or side chain through variable covalent bond, like protein, polysaccharide, synthetic high polymer etc.; This theory comes from the universal model (J.Polym.Sci.Polym.Symp.1975 of Ringsdorf at the macromolecule prodrug of proposition in 1975 at first; 51; 135-153), this model structure is made up of four parts: a kind of natural or synthetic water-soluble polymer carrier, a kind of Biodegradable polymeric-medicine spacer groups, a kind ofly have the active medicine of specific pharmacology, an a kind of specific localization homing device.Wherein, spacer groups is being brought into play very important effect.On the one hand; Spacer groups makes low-molecule drug and polymer chain form stable or temporary transient combining, and can in blood circulation, keep certain stability, and under the effect of enzyme or environmental stimulus, through hydrolysis, ion exchange or enzymatic reaction pharmaceutical group is ruptured down again; Promptly have certain stability and hydrolyzable, enzymolysis property (Prog Polym Sci.; 1995,20,211-257); On the other hand, spacer groups can reduce the solid space steric hindrance discharges medicine to enzyme catalysis restriction.Along with the further investigation of the development of macromolecule synthesising technology and life science to the oncology; Chemists can modify brief group through appropriate molecular design on multiple polymers, but so that its can with medicine via specific break chemical bonds bonding; Make up the different structure of molecule kenel; Thereby rely on the physiological responses property of this chemical bond, on molecular level, control speed and drug release position that medicine discharges intelligently from polymer, improve drug effect.The spacer groups of being studied at present mainly comprises following two types: the linking group of acid-sensitive sense, like hydrazone, acetal, amide, imines etc.; Can by the peptide group of lysosomal enzyme hydrolysis (Angew.Chem.Int.Ed.2004,43,278-282).And the notable difference that the sour environment of tumor locus and normal structure exist (pH value of normal structure is generally 7.4, and mesenchyma stroma of tumors pH is at 5.7-7.8, and average is 7.06 (Cancer Res; 1994,54,5670-5674)); And interior lysosome of cell and lower pH value (4.0-6.0) (the J Cell Sci of endosome; 1992,103,211-232) with the existence of lysosomal enzyme; For the fracture of the variable chemical bond of pH response provides the mechanism of inspiring, and about this machine-processed application with expand research and become the science focus gradually.This type of pH response mechanism can make the enrichment of carrier micelle at tumor locus and specific cells device; Promote cell endocytic, targeting to discharge medicine; Increase the concentration in drug effect position such as Cytoplasm and the nucleus greatly; The multiple drug resistance mechanism cell of saturated cancerous cell overcomes the drug resistance of tumor, reduces the toxic and side effects of chemotherapy.Like Bae (Angew.Chem.Int.Ed.; 2003,42,4640-4643) the hydrazone key of quick hydrolysis such as ability such as usefulness such as grade is hydrophobic amycin (adriamycin; ADR or doxorubicin; DOX) be connected on the block copolymer of hydrophilic polyethylene glycol-aspartic acid, form key compound, make the poly-aspartic-acid segment become hydrophobic segment.Parents' block copolymer forms micelle under neutrallty condition.But in the acid solution of pH about 5.0, the hydrazone bond fission, polymer becomes hydrophilic and causes micelle to disintegrate, and discharges medicine.At present existing many polymer-anticarcinogen key compound is used for clinical experiment; Like PK1 (doxorubicin-(HPMA copolymer)); Prothecan (camptothecin-PEG conjugate), CT-2103 (Angew.Chem.Int.Ed., 2006 such as (taxol-polyglutamate conjugate); 45,1198-1215).But the pH sensitivity of existing polymer-anticarcinogen key compound still need improve, but therefore how to design break chemical bonds is present scientists problem demanding prompt solution to respond small environmental difference between suitable polymers-anticarcinogen key compound.
Summary of the invention
One of the object of the invention provides a kind of Polyethylene Glycol with pH response-anticarcinogen key compound that connects based on the benzene imine linkage.
Two of the object of the invention provides a kind of synthetic method of the Polyethylene Glycol with the pH response-anticarcinogen key compound that connects based on the benzene imine linkage.
Three of the object of the invention provides the application of the above-mentioned Polyethylene Glycol with the pH response-anticarcinogen key compound that connects based on the benzene imine linkage as pharmaceutical carrier, obtains the application of the carrier micelle of nanoscale through its self assembly and one or more medicines of load.
The invention discloses a kind of Polyethylene Glycol-anticarcinogen key compound of the pH of having response, is through responsive covalently bound the forming of benzene imine linkage of pH by cancer therapy drug molecule and Polyethylene Glycol; Wherein, Described cancer therapy drug molecule comprises amycin, epirubicin, daunorubicin, DMDR; Or their hydrochlorate, described benzene imine linkage is more stable under the normal physiological pH value, but under the faintly acid pH value; Like the outer pH value of solid-state tumor cell, cellular inclusion, lysosome pH value; Hydrolysis can take place, promptly pH value from 7.4 to 6.5 or lower small pH value variation are had sensitivity, this can improve the Polyethylene Glycol-cellular uptake amount of anticarcinogen key compound Chinese medicine composition under tumor pH value condition.The invention also discloses the application of this key compound.This Polyethylene Glycol-anticarcinogen key compound has amphiphilic, can self assembly in saline solution forms the micelle of nano-scale; This micelle can be used as pharmaceutical carrier; Be used for extremely one or more of derivant, paclitaxel, methotrexate, curcumin, irinotecan, matrine, salvianolic acid etc. of load micromolecule cancer therapy drug such as amycin, camptothecine; Form the nano-micelle preparations of coating medicine, can realize the Synergistic treatment of multiple medicine.This preparation has the pH value response, and the ingredient in the preparation has higher cellular uptake amount under tumor pH value condition.
The present invention is intended to through schiff base reaction amino and aldehyde radical; Be that aldehyde radical reaction on the functional polyethylene glycol of benzaldehyde generates the benzene imine linkage with pH response promptly by amino on the amycin molecular saccharides ring and end group; Mode through introducing phenyl ring overcomes imine linkage this defective of unstability under physiological environment, obtains afterwards with polymer chain as hydrophilic segment and with the parents polymer-anticarcinogen key compound of amycin as hydrophobic part.The hydrolysis and rupturing under solid tumor etc. and the discrepant weak acid pH value of normal structure acidity physiological environment of sensitive chemical key in this key compound---benzene imine linkage.
The Polyethylene Glycol with the pH response-anticarcinogen key compound that connects based on the benzene imine linkage of the present invention can be formed by the functional polyethylene glycol covalent bond of functional group end-blocking, other end band benzaldehyde base by an amycin molecule and an end; Also can form by the functional polyethylene glycol covalent bond of two amycin molecules and two ends band benzaldehyde base.Being used for the end capped described functional group of Polyethylene Glycol (R of following structure) can be the cancer target part, thereby makes the Polyethylene Glycol-anticarcinogen key compound of the described pH of having response have the active targeting ability to tumor.
The Polyethylene Glycol of the pH of having response of the present invention-anticarcinogen key compound has as shown in the formula (I) or formula (II) structure:
(I)
(II)
In said structure formula (I) and the formula (II): R ' is :-CH
2OH or-CH
3, R " be :-OCH
3Or-H, and R ' is-CH
2R during OH " can not be-H;
Like R ' be-CH
2OH, R " be-OCH
3, this moment, structure was the Polyethylene Glycol-adriamycin bonding thing with pH response; R ' is-CH
3, R " be-OCH
3, this moment, structure was the Polyethylene Glycol-daunorubicin key compound with pH response; R ' is-CH
3, R " and be-H that this moment, structure was the Polyethylene Glycol-DMDR key compound with pH response.
R
1For: ester group (OC=O), amide groups (HNC=O) or ether (OCH
2);
R is: methoxyl group, amino, sulfydryl, carboxyl,
(folic acid (Folate) residue)
(RGD residue)
(galactose residue)
n＝9～135。
The Polyethylene Glycol of the pH of having response of the present invention-anticarcinogen key compound has amphiphilic, and it can self assembly in saline solution forms the micelle of nano-scale.Utilize this area dialysis commonly used, direct dissolution method, solvent evaporation method, ultrasonic method etc. can obtain the micelle of nano-scale.
Described nano-scale micelle can be used as pharmaceutical carrier; Can be used in load cancer therapy drug such as amycin, epirubicin, daunorubicin, DMDR, camptothecine and derivant thereof, paclitaxel, methotrexate, curcumin, irinotecan, matrine, the salvianolic acid etc. one or more; To form the Polyethylene Glycol-anticarcinogen key compound nano-carrier that coats multiple medicine; And the pH response of the benzene imine linkage in dependence Polyethylene Glycol-anticarcinogen key compound; Speed and drug release position that the control medicine discharges from Polyethylene Glycol-anticarcinogen key compound nano-carrier, the Synergistic treatment of realization medicine.The method of carrying medicament can interact through supermolecule, like hydrophobic-hydrophobic interaction, electrostatic interaction, the π-π effect of piling up, interaction of hydrogen bond etc.
The preparation of the Polyethylene Glycol of the pH of having response of the present invention-anticarcinogen key compound obtains through one of following method:
Method one: with material medicine is that a kind of in doxorubicin hydrochloride, Farmorubine Hydrochloride, daunorubicin hydrochloride and the hydrochloric acid DMDR or any several kinds are dissolved in the solvent; Adding acid binding agent stirs; Preferred mixing time is not more than 24 hours, obtains the acidifying drug solution of desalination; Join in the acidifying drug solution of above-mentioned desalination after strand one end and/or strand two ends are had the Polyethylene Glycol of benzaldehyde base or be dissolved in it in solvent; In reaction temperature is to react under 4～100 ℃; Reaction product solution that obtains or dispersion liquid promptly obtain the Polyethylene Glycol with the pH response-anticarcinogen key compound of above-mentioned formula (I) or formula (II) structure after desolvating through separation, purification, drying;
Wherein: the mol ratio of material medicine and acid binding agent is 1: 1～1: 4; Strand one end and/or strand two ends have the Polyethylene Glycol of benzaldehyde base and the mol ratio of material medicine is 1: 1～1: 8.
Method two: with material medicine is that a kind of in doxorubicin hydrochloride, Farmorubine Hydrochloride, daunorubicin hydrochloride and the hydrochloric acid DMDR or any several kinds are dissolved in the solvent; Adding acid binding agent stirs; Preferred mixing time is not more than 24 hours, obtains the acidifying medicine of desalination after preferably adopting extraction (extractant can adopt isopyknic dichloromethane/water), the way of distillation, the sedimentation method or their combination in any to remove solvent; The Polyethylene Glycol that the acidifying medicine of the desalination that is obtained, strand one end and/or strand two ends are had a benzaldehyde base is dissolved in the solvent simultaneously or is dissolved in the solvent back respectively and mixes; In reaction temperature is to react under 4～100 ℃; Reaction product solution that obtains or dispersion liquid promptly obtain the Polyethylene Glycol with the pH response-anticarcinogen key compound of above-mentioned formula (I) or formula (II) structure after desolvating through separation, purification, drying;
Wherein: the mol ratio of material medicine and acid binding agent is 1: 1～1: 4; Strand one end and/or strand two ends have the Polyethylene Glycol of benzaldehyde base and the mol ratio of material medicine is 1: 1～1: 8.
Method three: with material medicine be Polyethylene Glycol that a kind of or any several kinds of mixture and strand one end and/or strand two ends in amycin, epirubicin, daunorubicin and the DMDR have a benzaldehyde base be dissolved in the solvent simultaneously or be dissolved in the solvent respectively after mix; In reaction temperature is to react under 4～100 ℃; Reaction product solution that obtains or dispersion liquid promptly obtain the Polyethylene Glycol with the pH response-anticarcinogen key compound of above-mentioned formula (I) or formula (II) structure after desolvating through separation, purification, drying;
Wherein: strand one end and/or strand two ends have the Polyethylene Glycol of benzaldehyde base and the mol ratio of material medicine is 1: 1～1: 8.
Described solvent is selected from water, formic acid, acetic acid, hydrochloric acid solution, N, at least a in the group that N '-dimethyl formamide, dimethyl sulfoxide, methanol, ethylene glycol, ethanol and acetonitrile etc. are formed.
The solvent that described strand one end and/or strand two ends have in the solution of Polyethylene Glycol of benzaldehyde base is selected from water, formic acid, acetic acid, hydrochloric acid solution, N, at least a in the group that N '-dimethyl formamide, dimethyl sulfoxide, methanol, ethylene glycol, ethanol and acetonitrile etc. are formed.
Described acid binding agent is selected from least a in the group that potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, pyridine, triethylamine (TEA) and diisopropylethylamine trimethylamines such as (DIEA) form, preferred TEA.
Described is that the response time of reacting under 4～100 ℃ is 0.5～96 hour in reaction temperature, and the preferred time is 24～48 hours.
Described separation, purification, dry run can adopt solvent precipitation (solvent for use can be ether, normal hexane, cyclohexane extraction etc.), recrystallization method (as using isopropyl alcohol, thionyl chloride, dimethyl formamide etc.), chromatographic column partition method (chromatographic column can be silica gel, polydextran gel etc.), preparation liquid phase separation method (eluent is acetonitrile/water (volume ratio is 1: 1), methanol (volume ratio is 1: 1) etc.), dialysis; Freeze-drying, boulton process, natural seasoning, or the combination in any of said method.
Described strand one end has Polyethylene Glycol (commercially available prod or employing document Biomacromolecules 2010,11, the 1043-1051 of benzaldehyde base; Biomacromolecules 2008,9, the disclosed method of 255-262. synthesize obtain) structural formula be:
Wherein, R is: methoxyl group, amino, sulfydryl, carboxyl,
(folic acid (Folate) residue)
(RGD residue)
(galactose residue)
R ' is: ester group (OC=O), amide groups (HNC=O) or ether (OCH
2).
n＝9～135。
Described strand two ends have Polyethylene Glycol (commercially available prod or employing document Biomacromolecules 2010,11, the 1043-1051 of benzaldehyde base; Biomacromolecules 2008,9, the disclosed method of 255-262. synthesize obtain) structural formula be:
R is: ester group (OC=O), amide groups (HNC=O) or ether (OCH
2).
n＝9～135。
Polyethylene Glycol-anticarcinogen key compound with pH response of the present invention at saline solution (like HPBS buffer or NaHCO
3Aqueous solution) can form micelle through self assembly in, and as pharmaceutical preparation.Its preparation method can adopt this area dialysis commonly used, direct dissolution method, solvent evaporation method, ultrasonic method or their combination in any.
Polyethylene Glycol-anticarcinogen key compound with pH response of the present invention and micromolecule cancer therapy drug in saline solution (like HPBS buffer or NaHCO
3Aqueous solution) can form carrier micelle through self assembly, and as pharmaceutical preparation.Its preparation method can adopt this area dialysis, solvent evaporated method, emulsion process or their combination in any commonly used.Described micromolecule cancer therapy drug is amycin, epirubicin, daunorubicin, DMDR, camptothecine and derivant thereof, paclitaxel, methotrexate, curcumin, irinotecan, matrine, salvianolic acid or their any mixture etc.
The present invention has following characteristics:
1, in dewatering medicament, to introduce hydrophilic segment preparation through the benzene imine linkage be the Polyethylene Glycol-medicine key compound of construction unit with the drug molecule in the present invention; This key compound has parents' lipoid plastid or type surfactant structure, and hydrophilic segment and hydrophobic part can be self-assembled into the micelle of nanoscale at certain condition.The micelle of this type of nano-scale has biocompatibility, and can assemble at tumor locus effectively through the ultra penetrating and accumulating effect (EPR Effect) of tumor tissues, promptly impels medicine passive target and tumor tissues.
2, stable under normal physiological conditions as the benzene imine linkage of spacer groups; But it can and rupture via the weakly acidic condition of tumor tissues and low the inducing of pH value of corresponding organelle; Thereby initiatively targeting is in pathological tissues and corresponding born of the same parents' device, the speed of control drug release intelligently on molecular level.The benzene imine linkage is significant to making up the pharmaceutical carrier system that can respond small pH fluctuation in the physiological environment sensitively.
3, the nano-scale micelle among the present invention can be used as pharmaceutical carrier; Be used for one or more of load cancer therapy drug such as amycin, daunorubicin, DMDR, camptothecine and derivant thereof, paclitaxel, methotrexate, curcumin, irinotecan, matrine, salvianolic acid etc.; To form the nano-carrier that coats multiple medicine; Afterwards combine initiatively targeting and passive target, realize the Synergistic treatment of medicine.Interact owing to existing chemical bonding between medicine and polymer support has physics again simultaneously, stablized inner core to a certain extent, strengthen the nuclear adhesion strength, make the blood circulation half-life of pharmaceutical carrier prolong.
4, the method for preparing of Polyethylene Glycol of the present invention-anticarcinogen key compound is simple, easy to operate, adopts the conventional method in this area to get final product.
Description of drawings
Fig. 1 is the nuclear-magnetism figure based on the Polyethylene Glycol with the pH response-anticarcinogen key compound of methoxy poly (ethylene glycol) benzaldehyde monoesters of preparation in the embodiment of the invention 1.
Fig. 2 is the nuclear-magnetism figure based on the targeting Polyethylene Glycol-anticarcinogen key compound with pH response of folic acid polyethyleneglycol of end group benzaldehyde amide of preparation in the embodiment of the invention 2.
Fig. 3 is the synthetic nuclear-magnetism figure based on the Polyethylene Glycol with pH response-anticarcinogen key compound of holding the benzaldehyde Polyethylene Glycol of preparation in the embodiment of the invention 3.
Fig. 4 is the Polyethylene Glycol-micellar transmission electron microscope picture of anticarcinogen key compound of preparation in the application implementation example 1.
The specific embodiment
Embodiment 1 is synthetic based on the Polyethylene Glycol with the pH response-anticarcinogen key compound of methoxy poly (ethylene glycol) benzaldehyde monoesters
The synthesis path of reaction is following:
(1) with 4g (0.002mol) mono methoxy polyethylene glycol, 2.4g (0.016mol) terephthalaldehydic acid; 0.1222g (0.001mol) 4-dimethylaminopyridine (DMAP) joins in the round-bottomed flask of 100ml, adds the exsiccant dichloromethane of 60ml and makes the reactant mix homogeneously.In 37 ℃ of water-baths, also under agitation, drip 10ml and be dissolved with 3.3g (0.016mol) N, the dichloromethane solution of N '-dicyclohexylcarbodiimide (DCC) is to round-bottomed flask, to remove the water that produces in the dereaction.Constant temperature stirs after 24 hours, with reacting liquid filtering, to remove byproduct of reaction N, N '-1,3-Dicyclohexylurea (DCU); Filtrating concentrates the back and carries out recrystallization with isopropyl alcohol, and the crude product priority that obtains is with isopropyl alcohol and ice ether washing three times; After vacuum drying desolventizes, to remove excessive DCC, obtain white powder product-methoxy poly (ethylene glycol) benzaldehyde monoesters after the lyophilization with method for washing.
(2) taking by weighing each 40mg of doxorubicin hydrochloride and Farmorubine Hydrochloride (0.138mmol altogether) is dissolved in the exsiccant methanol of 40ml; Add 20 μ l (0.138mmol; With the mol ratio of doxorubicin hydrochloride and Farmorubine Hydrochloride medicine 1: 1) triethylamine is as acid binding agent; Stirred 4 hours, and obtained the acidifying drug solution of desalination.With 147mg (0.069mmol; With the mol ratio of doxorubicin hydrochloride and Farmorubine Hydrochloride medicine 1: 2) the synthetic methoxy poly (ethylene glycol) benzaldehyde of step (1) monoesters is dissolved in the 10ml methanol; Dropwise join in the acidifying drug solution of above-mentioned desalination, reaction is 100 hours in the ice-water bath (4 ℃).The reaction product solution that obtains dilute with water behind membrane filtration utilizes dialysis to carry out the separation and purification postlyophilization and obtains dark red solid, is the Polyethylene Glycol-anticarcinogen key compound with pH response.Its structure has
1H NMR characterizes, and is as shown in Figure 1.
(1) Polyethylene Glycol and the 0.99g (0.004mol of 3.4g (0.001mol) end is amino, an end folic acid base; The mol ratio of the Polyethylene Glycol of, an end folic acid base amino with an end 1: 4) N-succinimido-p-formoxyl benzoate (SFB) is dissolved in the exsiccant dichloromethane of 60ml, in 50 ℃ of water-baths and under agitation reacted 24 hours.After reaction finishes, with reacting liquid filtering, to remove unreacted SFB; Filtrating concentrates the back and carries out recrystallization with isopropyl alcohol, and the crude product priority that obtains is with isopropyl alcohol and ice ether washing three times, obtains pale yellow powder shape product-folic acid polyethyleneglycol of end group benzaldehyde amide after vacuum drying desolventizes.
(2) taking by weighing 77.8mg (0.138mmol) daunorubicin hydrochloride medicine is dissolved in the 40ml secondary water; Add 22mg (0.552mmol; With the mol ratio of daunorubicin hydrochloride medicine 1: 4) sodium hydroxide is as acid binding agent; The room temperature lucifuge stirred 15 hours, used and the isopyknic dichloromethane extraction of above-mentioned mixed liquor, and dichloromethane obtains the acidifying daunorubicin of desalination through revolving to steam to desolventize.Acidifying daunorubicin of resulting desalination and the synthetic folic acid polyethyleneglycol of end group of 490mg (mol ratio 1: 1) step (1) benzaldehyde amide are dissolved in 10ml dimethyl sulfoxide and the 0.1ml acetic acid, are 100 ℃ in temperature and reacted 0.5 hour down.The reaction product solution that obtains is behind membrane filtration; Utilize Sephadex LH-20 sephadex column that concentrated solution is carried out separation and purification; With a certain proportion of hplc grade methanol/water is eluent (volume ratio is 1: 1); Collect first section product and revolve driedly, obtain dark red solid, be targeting Polyethylene Glycol-anticarcinogen key compound with pH response.Its structure has
1H NMR characterizes, and is as shown in Figure 2.
(1) is that 4600 Polyethylene Glycol, 1.236g (0.008mol) are dissolved in the exsiccant chloroform of 60ml the aldehyde radical benzyl chloride with 4.6g (0.001mol) molecular weight, adds 0.6g K
2CO
3, be 80 ℃ of condition refluxed after 8 hours in temperature, with reacting liquid filtering, filtrating concentrates the back and carries out recrystallization with isopropyl alcohol, and the crude product that obtains is successively with isopropyl alcohol and the washing of ice ether three times; Obtain the white powder product behind the vacuum drying, be end benzaldehyde Polyethylene Glycol (Polyethylene Glycol that has the benzaldehyde base with the two ends of ehter bond connection).
(2) take by weighing 214mg (0.4mmol) DMDR, with 242mg (0.05mmol; With the mol ratio of DMDR 1: 8) the synthetic end benzaldehyde of step (1) Polyethylene Glycol is dissolved in the exsiccant ethanol of 100ml; The room temperature lucifuge stirred 4 hours, then was 40 ℃ in temperature and continued reaction 24 hours down.The reaction product solution that obtains is behind membrane filtration, and filtrating is contracted through revolving inspissation; Utilizing the SephadexLH-20 sephadex column that concentrated solution is carried out separation and purification, is eluent with the hplc grade methanol, collects first section product and revolves driedly, obtains dark red solid, is the Polyethylene Glycol-anticarcinogen key compound with pH response.Its structure has
1H NMR characterizes, and is as shown in Figure 3.
Embodiment 4
Polyethylene Glycol with the pH response-anticarcinogen key compound of 5g embodiment 1 preparation is dissolved in the PBS buffer of 5ml and pH=7.4 or the NaHCO of pH＞7.4
3In the aqueous solution, under the room temperature ultrasonic 5 minutes, ultrasonic power 100w; The gained dark red solution places that jolting is after 4 hours on the shaking table, and self assembly obtains having the Polyethylene Glycol-anticarcinogen key compound micelle of pH response.Fig. 4 is that the Polyethylene Glycol-anticarcinogen key compound self assembly with pH response forms micellar transmission electron microscope picture.
Embodiment 5
Polyethylene Glycol with the pH response-anticarcinogen key compound of 5g embodiment 1 preparation and the targeting Polyethylene Glycol-anticarcinogen key compound with pH response of embodiment 2 preparations were dissolved in the PBS buffer of 5ml and pH=7.4 or the NaHCO of pH＞7.4 by weight 5: 1
3In the aqueous solution, under the room temperature ultrasonic 5 minutes, ultrasonic power 100w; The gained dark red solution places that jolting promptly obtained having the Polyethylene Glycol with the pH response-anticarcinogen key compound micelle of target function after 4 hours on the shaking table.
Embodiment 6
The 2mg paclitaxel is dissolved in the 0.5ml dichloromethane; The Polyethylene Glycol with the pH response-anticarcinogen key compound that takes by weighing 10mg embodiment 3 preparations is dissolved in the 2ml oxolane; Drip above-mentioned taxol drug solution while stirring, dropwise continued and stirred 30 minutes.Taxol drug and the Polyethylene Glycol-anticarcinogen key compound mixed liquor with pH response are dropwise joined the PBS buffer of 10ml and pH=7.4 or the NaHCO of pH＞7.4
3In the aqueous solution, fully stir and volatilized fully to oxolane in 6 hours.With the mixed liquor molecular cut off of packing into is in 2000 the bag filter, the NaHCO in pH＞7.4
3Dialysis is 24 hours in the aqueous solution, with the taxol drug molecule of removing DMSO and not coated, and the Polyethylene Glycol with pH response of the paclitaxel-anticarcinogen key compound carrier micelle that obtained load.
Claims (10)
1. Polyethylene Glycol-anticarcinogen the key compound with pH response is characterized in that, the Polyethylene Glycol of the described pH of having response-anticarcinogen key compound has formula (I) or formula (II) structure:
(I)
(II)
Wherein: in structural formula (I) and the formula (II): R ' is :-CH
2OH or-CH
3, R " be :-OCH
3Or-H, and R ' is-CH
2R during OH " can not be-H;
R
1For: ester group, amide groups or ether;
R is: methoxyl group, amino, sulfydryl, carboxyl,
n＝9～135。
2. method for preparing with Polyethylene Glycol-anticarcinogen key compound of pH response according to claim 1, it is characterized in that: described method is:
With material medicine is that a kind of in doxorubicin hydrochloride, Farmorubine Hydrochloride, daunorubicin hydrochloride and the hydrochloric acid DMDR or any several kinds are dissolved in the solvent, adds acid binding agent and stirs, and obtains the acidifying drug solution of desalination; Join in the acidifying drug solution of above-mentioned desalination after strand one end and/or strand two ends are had the Polyethylene Glycol of benzaldehyde base or be dissolved in it in solvent; In reaction temperature is to react under 4～100 ℃; Reaction product solution that obtains or dispersion liquid obtain the Polyethylene Glycol with the pH response-anticarcinogen key compound of formula described in the claim 1 (I) or formula (II) structure after desolvating through separation, purification, drying;
Wherein: the mol ratio of material medicine and acid binding agent is 1: 1～1: 4; Strand one end and/or strand two ends have the Polyethylene Glycol of benzaldehyde base and the mol ratio of material medicine is 1: 1～1: 8;
Or
With material medicine is that a kind of in doxorubicin hydrochloride, Farmorubine Hydrochloride, daunorubicin hydrochloride and the hydrochloric acid DMDR or any several kinds are dissolved in the solvent, adds acid binding agent and stirs, and obtains the acidifying medicine of desalination after removing solvent; The Polyethylene Glycol that the acidifying medicine of the desalination that is obtained, strand one end and/or strand two ends are had a benzaldehyde base is dissolved in the solvent simultaneously or is dissolved in the solvent back respectively and mixes; In reaction temperature is to react under 4～100 ℃; Reaction product solution that obtains or dispersion liquid obtain the Polyethylene Glycol with the pH response-anticarcinogen key compound of formula described in the claim 1 (I) or formula (II) structure after desolvating through separation, purification, drying;
Wherein: the mol ratio of material medicine and acid binding agent is 1: 1～1: 4; Strand one end and/or strand two ends have the Polyethylene Glycol of benzaldehyde base and the mol ratio of material medicine is 1: 1～1: 8;
Or
With material medicine be Polyethylene Glycol that a kind of or any several kinds of mixture and strand one end and/or strand two ends in amycin, epirubicin, daunorubicin and the DMDR have a benzaldehyde base be dissolved in the solvent simultaneously or be dissolved in the solvent respectively after mix; In reaction temperature is to react under 4～100 ℃; Reaction product solution that obtains or dispersion liquid obtain the Polyethylene Glycol with the pH response-anticarcinogen key compound of formula described in the claim 1 (I) or formula (II) structure after desolvating through separation, purification, drying;
Wherein: strand one end and/or strand two ends have the Polyethylene Glycol of benzaldehyde base and the mol ratio of material medicine is 1: 1～1: 8.
3. method for preparing according to claim 2; It is characterized in that: described separation, purification, dry run are to adopt solvent precipitation, recrystallization method, chromatographic column partition method, preparation liquid phase separation method, dialysis, freeze-drying, boulton process, natural seasoning, or the combination in any of said method.
4. method for preparing according to claim 2; It is characterized in that: described solvent is selected from water, formic acid, acetic acid, hydrochloric acid solution, N, at least a in the group that N '-dimethyl formamide, dimethyl sulfoxide, methanol, ethylene glycol, ethanol and acetonitrile are formed;
The solvent that described strand one end and/or strand two ends have in the solution of Polyethylene Glycol of benzaldehyde base is selected from water, formic acid, acetic acid, hydrochloric acid solution, N, at least a in the group that N '-dimethyl formamide, dimethyl sulfoxide, methanol, ethylene glycol, ethanol and acetonitrile are formed.
5. method for preparing according to claim 2 is characterized in that: described acid binding agent is selected from least a in the group that potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, pyridine, triethylamine and diisopropylethylamine form.
6. method for preparing according to claim 2 is characterized in that: described is that the response time of reacting under 4～100 ℃ is 0.5～96 hour in reaction temperature.
7. according to claim 2 or 4 described method for preparinies, it is characterized in that:
The structural formula that described strand one end has the Polyethylene Glycol of benzaldehyde base is:
Wherein, R is: methoxyl group, amino, sulfydryl, carboxyl,
R ' is: ester group, amide groups or ether;
n＝9～135；
The structural formula that described strand two ends have the Polyethylene Glycol of benzaldehyde base is:
R is: ester group, amide groups or ether;
n＝9～135。
8. purposes with Polyethylene Glycol-anticarcinogen key compound of pH response according to claim 1; It is characterized in that: the Polyethylene Glycol of the described pH of having response-anticarcinogen key compound is through dialysis, direct dissolution method, solvent evaporation method, ultrasonic method or their combination in any; Self assembly forms micelle in saline solution, and as pharmaceutical preparation.
9. purposes with Polyethylene Glycol-anticarcinogen key compound of pH response according to claim 1; It is characterized in that: the Polyethylene Glycol of the described pH of having response-anticarcinogen key compound and micromolecule cancer therapy drug form carrier micelle through dialysis, solvent evaporated method, emulsion process or their combination in any in saline solution.
10. purposes according to claim 9 is characterized in that: described micromolecule cancer therapy drug is amycin, epirubicin, daunorubicin, DMDR, camptothecine and derivant thereof, paclitaxel, methotrexate, curcumin, irinotecan, matrine, salvianolic acid or their any mixture.
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