CN103421195B - Acid-sensitive cationic segmented copolymer and preparation method thereof and application - Google Patents

Acid-sensitive cationic segmented copolymer and preparation method thereof and application Download PDF

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CN103421195B
CN103421195B CN201310362819.8A CN201310362819A CN103421195B CN 103421195 B CN103421195 B CN 103421195B CN 201310362819 A CN201310362819 A CN 201310362819A CN 103421195 B CN103421195 B CN 103421195B
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acid
segmented copolymer
radical polymerization
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CN103421195A (en
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倪沛红
郝莹
张明祖
何金林
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Suzhou University
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Suzhou University
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Abstract

The invention discloses a kind of Acid-sensitive cationic segmented copolymer and preparation method thereof and application.The present invention in conjunction with ring-opening polymerization, atom transfer radical polymerization and " click " chemical reaction, has prepared the Acid-sensitive cationic segmented copolymer of fluorescence-pH double-response first.The novel Acid-sensitive cationic segmented copolymer of the present invention's exploitation, there is fluorescence, pH response, sensitivity to acid and good biocompatibility, self-assembly can form micella in aqueous, biodegradable polyester segment may be used for bag and carries hydrophobic anticancer drug, simultaneously, the cationic segment of pH response with electronegative DNA by electrostatic interaction, can play the effect of compression DNA, as genophore; Therefore, it simultaneously as genophore and pharmaceutical carrier, can have a good application prospect in biomedicine.

Description

Acid-sensitive cationic segmented copolymer and preparation method thereof and application
Technical field
The invention belongs to field of biomedical polymer materials, be specifically related to a kind of Acid-sensitive cationic segmented copolymer, its preparation method and its application as genophore and pharmaceutical carrier.
Background technology
Cancer therapy is the biggest problem that the mankind face in medical science.Common chemotherapy is that cancer therapy drug is delivered to whole body by vein, carrys out the growth of anticancer by blocking fissional mechanism, therefore also can kill and carry out fissional normal cell, the health tissues of injury normal function and cell.Compared with common chemotherapy, functional nano pharmaceutical carrier has prolong drug action time, increases curative effect, reduces the advantages such as toxic side effects, can control the rate of release of medicine and conduct drugs to lesions position, reducing the toxic side effect to human body.
A kind of methods for the treatment of of simple employing is difficult to reach desirable effect, adopts multiple method synthesis to treat, and collaborative work mutually, such as: pharmacology combines with genomics, can reach more preferably effect.Pharmacogenomics for target, studies various transgenation and drug effect with drug effect and security.
In recent years, gene therapy has become one of most active research field, can be used for clinically treating various diseases, comprises Therapeutic cancer disease.Gene therapy refers to by medicative gene by certain way transfered cell, to correct genetic flaw or to play therapeutic action, thus disease therapy.At present, portion gene treatment plan enters clinical experimental stage, but also encounters a lot of difficulty, as: the problems such as poor stability, transfection efficiency are lower.Build a good biocompatibility, security is high, transfection efficiency is high and expression level is high carrier, goal gene is obtained in target cell important research direction that safe, controlled, efficient, stable expression is gene therapy.
At present, conventional genophore is non-viral cationic carrier, with electronegative DNA by electrostatic interaction, and can effective condensation DNA.But too much positive charge easily causes toxicity to increase, and, stronger electrostatic interaction also can restriction gene enter nucleus after discharge from mixture, thus the expression of restriction gene; Meanwhile, too much positive charge can increase the toxicity of carrier.In order to overcome the defect of cationic polymers, researchist can consider to introduce some hydrophilic segment, for shielding positive charge when designing cation carrier.The scopiform segmented copolymer with high-density side-chain radical can change the microenvironment around polycation backbone, the specific inductivity around main chain can be reduced, and energy shielded packaged food, reduce the self aggregation of mixture, reduce carrier toxicity, extend carrier cycling time in vivo, and there is anti-albumen non-specific adsorption performance.
In addition, research finds, the pathological tissues such as tumour and inflammation pH value that is inner and surrounding microenvironment is lower than the pH value of healthy tissues and organ, presents slightly acidic.Therefore, at design block polymer as the acid sensitive group introducing some facile hydrolysiss in acid condition during carrier, as: acetal radical, hydrazone key, ortho-formiate, when carrier enters tumour cell, under mildly acidic conditions, acid sensitive group or segment can rupture, and micella is dissociated, thus the medicine that its inner bag carries can be discharged fast.During design vector, carrier multiple stimulation responsiveness can be given as required, play the synergetic property of " intelligence " carrier, thus improve the effect of gene therapy tumour.
In the prior art, some are used as pharmaceutical carrier and genophore simultaneously report about segmented copolymer is had.But, as gene-pharmaceutical carrier, good biocompatibility and biodegradability should be had, and, as the carrier of antitumor drug, also should have following features: can form stable polymer micelle in aqueous, its hydrophobic cores can load hydrophobic anticancer drug, and wetting ability shell plays the effect of stable micella, raising micella blood circulation time; When carrier micelle arrives tumour or pathological tissues, the feature that the pH value of local organization is lower can be utilized, micella is dissociated, discharges cancer therapy drug rapidly; More " intelligence " responsiveness should be had simultaneously, avoid carrier adsorpting aggregation in working cycle in vivo, reach the effect of fixed point release medicine, promotion genetic expression.
Therefore, need to research and develop novel acid-sensitive cationic block copolymers.
Summary of the invention
The object of the invention is, a kind of Acid-sensitive cationic segmented copolymer and preparation method thereof is provided, this multipolymer should have fluorescence-pH dual responsiveness, sensitivity to acid, anti-protein adsorption and good biocompatibility, can be used as genophore and pharmaceutical carrier simultaneously.
For achieving the above object, general plotting of the present invention is: in conjunction with atom transfer radical polymerization (ATRP), ring-opening polymerization (ROP) and " click " (Click) chemical reaction, prepare the Acid-sensitive cationic segmented copolymer of fluorescence-pH double-response.First utilize the micromolecular hydroxyl of coumarins with fluorescence response to carry out ROP reaction to cyclic ester monomer, after modifying further, obtain the polyester that end is respectively coumarin group and acetal-azido group; Utilize the ATRP initiator containing alkynyl, the monomer and the hydrophilic monomer polyethylene glycol methacrylate-styrene polymer that cause pH sensitivity carry out ATRP copolymerization, obtain the polymer chain of pH sensitivity containing alkynyl and the multipolymer of scopiform polymer chain; The polyester finally above-mentioned end being contained respectively coumarin group and acetal-azido group carries out " Click " with the polymer chain of pH sensitivity and the multipolymer of scopiform polymer chain that contain alkynyl and reacts, and obtains the Acid-sensitive cationic segmented copolymer of fluorescence-pH double-response.
The concrete technical scheme of the present invention is: a kind of Acid-sensitive cationic segmented copolymer, is expressed by the following chemical structure formula:
；
In formula, R 1be selected from , or in one; R 2be selected from , , or in one; X is bromine or chlorine; M is 30 ~ 90, n be 30 ~ 60, r is 10 ~ 30.
In technique scheme, the group with sensitivity to acid selects acetal radical, and its chemical structural formula is: ; This amphipathic cationic segmented copolymer of biodegradable with sensitivity to acid, structurally both containing hydrophobic polyester block, can be used for loading hydrophobic anticancer drug; Again containing the acetal radical that can occur in acid condition to be hydrolyzed, under certain pH conditions, acetal radical is hydrolyzed, and micella is destroyed, thus discharges the hydrophobic anticancer drug being wrapped in micella inside rapidly.
Tonka bean camphor is the fluorescence molecule that a class is distributed widely in vegitabilia's secondary metabolite, has the performances such as excellent antitumor, antiviral, anticoagulant property and photodimerization, is widely used in biology, medicine and other fields.Tonka bean camphor is colourless or Light yellow crystals under visible light, can show blueness or purple fluorescence under ultraviolet light.Therefore, introduced by fluorescence molecule in polymkeric substance, the polymkeric substance obtained can send fluorescence under rayed effect, can be used for location and the detection of carrier.So polymkeric substance disclosed by the invention has fluorescence-pH double-response characteristic.
The preparation method of above-mentioned Acid-sensitive cationic segmented copolymer, comprises the following steps:
(1) in argon gas atmosphere, with coumarin fluorescent molecule for initiator, cyclic ester monomer is reactant, under the catalysis of stannous octoate, carry out ring-opening polymerization in polar solvent, and obtaining molecular chain one end containing coumarin fluorescent group, the other end is the functionalized polyester of hydroxyl; Described coumarin fluorescent molecule is 7-(2 '-hydroxyl-3 '-chlorine) propane-4-methylcoumarin; Cyclic ester monomer is e-caprolactone; Wherein, the mol ratio of cyclic ester monomer and initiator is 30: 1 ~ 90: 1; The mol ratio of catalyzer and initiator is 1: 5 ~ 1: 10; The chemical structural formula of functionalized polyester is as follows:
(2) in argon gas atmosphere, the functionalized polyester utilizing step (1) to obtain and 2-chloroethyl-vinyl ether are reactant, and tosic acid pyridine is catalyzer, are obtained by reacting the functionalized polyester that chlorine replaces in polar solvent; Wherein, the mol ratio of catalyzer and functionalized polyester is 1: 5 ~ 1: 15; The mol ratio of 2-chloroethyl-vinyl ether and functionalized polyester is 1: 1 ~ 8: 1;
Then, the functionalized polyester that sodiumazide and above-mentioned chlorine replace is reacted in polar solvent, the polyester that the azide that acquisition one end is fluorophor, the other end is acetal-azido-is modified; Wherein, the mol ratio of functionalized polyester that sodiumazide and chlorine replace is 8: 1 ~ 12: 1;
The chemical structural formula of the polyester that azide is modified is as follows:
(3) in argon gas atmosphere, utilize the atom transfer radical polymerization initiator containing alkynyl, under the existence of atom transfer radical polymerization catalyzer and atom transfer radical polymerization catalyst ligand, in alcohol organic solvent, atom transition free radical polymerization reaction is carried out with the monomer of polyethylene glycol methacrylate-styrene polymer and pH sensitivity, obtaining end group is the pH sensitive polymer chain of alkynyl and the segmented copolymer of poly-(polyethylene glycol methacrylate-styrene polymer), is called the segmented copolymer containing alkynyl;
Wherein, polyethylene glycol methacrylate-styrene polymer is 10: 1 ~ 30: 1 with the mol ratio of the atom transfer radical polymerization initiator containing alkynyl; The monomer of pH sensitivity is 30: 1 ~ 60: 1 with the mol ratio of the atom transfer radical polymerization initiator containing alkynyl; The mol ratio of atom transfer radical polymerization catalyzer and catalyst ligand is 1: 1 ~ 1: 4; Be 1: 0.5 ~ 1: 2 containing the atom transfer radical polymerization initiator of alkynyl and the mol ratio of atom transfer radical polymerization catalyzer; The monomer of described pH sensitivity is selected from: methacrylic acid-2-( n,N-dimethylamino) ethyl ester, methacrylic acid-2-( n,N-diethylin) ethyl ester, methacrylic acid-2-( n,N-diisopropylaminoethyl) ethyl ester, methacrylic acid-2-( n-tert-butylamino) one in ethyl ester;
Chemical structural formula containing the segmented copolymer of alkynyl is as follows:
(4) in argon gas atmosphere, under the existence of " click " chemical reaction catalyst with " click " chemical reaction catalyst part, the polyester that the azide obtained with step (2) is modified and the segmented copolymer containing alkynyl that step (3) obtains are that reactant carries out " click " chemical reaction, obtain described Acid-sensitive cationic segmented copolymer; Its chemical structural formula is as follows:
Wherein, " click " chemical reaction catalyst is 1: 1 ~ 1: 4 with the mol ratio of " click " chemical reaction catalyst part; Macromolecular reaction thing is 1: 0.5 ~ 1: 2 with the mol ratio of " click " chemical reaction catalyst; The polyester that azide is modified is 0.8: 1 ~ 1.2: 1 with the segmented copolymer mol ratio containing alkynyl.
In technique scheme, described polar solvent is toluene or methylene dichloride.
In technique scheme, in step (2), solvent when preparing the functionalized polyester of chlorine replacement is methylene dichloride; Solvent when preparing the polyester of sodiumazide modification is DMF.
In technique scheme, in step (3), the atom transfer radical polymerization initiator containing alkynyl is bromo acid propynyl ester; Atom transfer radical polymerization catalyzer is cuprous chloride or cuprous bromide; Atom transfer radical polymerization catalyst ligand is selected from: the one in dipyridyl, five methyl diethylentriamine, Tetramethyl Ethylene Diamine or hexamethyl Triethylenetetramine (TETA); Described alcohol organic solvent is Virahol.
In technique scheme, in step (4), " click " chemical reaction catalyst is cuprous chloride or cuprous bromide; Click " chemical reaction catalyst part is selected from: the one in dipyridyl, five methyl diethylentriamine, Tetramethyl Ethylene Diamine or hexamethyl Triethylenetetramine (TETA).
Further technical scheme, after step (1) ~ (4) complete, carry out purification processes respectively to product, described purge process comprises the following steps:
I the purification processes of () polyester: after completion of the reaction, cools reaction solution, rotary evaporation is except desolventizing, and precipitate in ice methyl alcohol, volume ratio is 1: 5 ~ 1: 15.Occur pressed powder, liquid is after suction filtration, dry under 25 DEG C of conditions in vacuum drying oven, obtains white powder product;
(ii) purification processes of the polyester of azide modification: after completion of the reaction, the unreacted raw material solid of elimination, reaction soln pumps most of solvent.Add methylene chloride dilution, use solution washing organic phase, collect organic phase, dry, filtrate is through rotary evaporation except desolventizing, and precipitate in normal hexane/ether (volume ratio is 1: 0.5 ~ 1: 2), liquid is after suction filtration, dry under 25 DEG C of conditions in vacuum drying oven, obtain white powder product;
(iii) containing the purification processes of the segmented copolymer of alkynyl: after the completion of reaction, add alcohol organic solvent and reaction product is diluted, and contact with air under the condition stirred, make reaction terminating, after solution turned blue green, make it pass through neutral Al is housed 2o 3pillar, then rotary evaporation makes solution concentrate, and is instilled by concentrated solution in hexane solution, and volume ratio is to precipitate at 1: 5 ~ 1: 15, finally that obtained throw out is dry under 25 DEG C of conditions in vacuum drying oven, obtains flaxen sticky shape solid product;
(iv) purification processes of Acid-sensitive cationic segmented copolymer: after the completion of reaction, add methylene chloride reaction product is diluted, and contact with air under agitation, make reaction terminating, after solution turned blue green, it is made to pass through neutral Al is housed 2o 3pillar, then rotary evaporation makes solution concentrate, and is instilled by concentrated solution in hexane solution, and volume ratio is to precipitate at 1: 5 ~ 1: 15, finally that obtained throw out is dry under 25 DEG C of conditions in vacuum drying oven.Desciccate is soluble in water, put into dialysis tubing, use water as further as medium dialysis, remove unreacted raw material, after lyophilize, obtain sticky shape solid product, be i.e. described Acid-sensitive cationic segmented copolymer.
In above-mentioned steps (iii), described alcohol organic solvent is Virahol.
The present invention asks to protect above-mentioned Acid-sensitive cationic segmented copolymer simultaneously as the application of genophore and pharmaceutical carrier simultaneously.
Wherein, coumarin fluorescent group gives carrier fluorescence response performance; Hydrophobic polyester segment containing biodegradability in polymkeric substance, can be used for loading hydrophobic anticancer drug, as pharmaceutical carrier; Cationic block containing pH sensitivity, under certain pH conditions can generating portion protonated, positively charged, with electronegative DNA by electrostatic interaction, thus compression DNA, as genophore; Further, based on scopiform polymer poly (polyethylene glycol methacrylate-styrene polymer) segment of PEG, make carrier have anti-protein adsorption and extend the function of blood circulation time; Can there is hydrolytic cleavage under acidic conditions in the acetal groups of acid-sensitive, thus destroy the micella of polymer self assembles formation in cell, discharges the medicine wrapping and be loaded in micella core rapidly, as stimulating responsive pharmaceutical carrier.
Due to the enforcement of such scheme, the present invention compared with prior art, has the following advantages:
1, the present invention is first in conjunction with atom transfer radical polymerization, ring-opening polymerization method and " click " chemical reaction, has prepared the segmented copolymer of the fluorescence-pH stimuli-responsive with good biocompatibility; The coumarins fluorescence molecule introduced, it also has the excellent performance such as antitumor, antiviral, makes the polymkeric substance obtained can send fluorescence under rayed effect, can be used for location and the detection of carrier;
2, the Acid-sensitive cationic segmented copolymer of the present invention's acquisition, in aqueous after self-assembly, the micella skin obtained is wetting ability brush, maskable electric charge in vivo, reduces the self aggregation of mixture, reduces the effect with cell tissue, reduce the toxicity of carrier, improve carrier distribution in vivo, extend carrier cycling time in vivo, there is anti-protein non-specific adsorption performance;
3, the Acid-sensitive cationic segmented copolymer that the present invention obtains self-assembly can form micella in aqueous, biodegradable polyester segment may be used for bag and carries hydrophobic anticancer drug, simultaneously, the cationic segment of pH response can pass through electrostatic interaction with electronegative DNA, play the effect of compression DNA, as genophore.Therefore, the Acid-sensitive cationic segmented copolymer of fluorescence-pH double-response disclosed by the invention can bag medicine carrying thing and DNA simultaneously, in cancer therapy, has good using value.
Accompanying drawing explanation
Fig. 1 is Hymecromone and 7-(2 '-hydroxyl-3 in embodiment one '-chlorine) the hydrogen nuclear magnetic resonance spectrogram of propane-4-methylcoumarin;
Fig. 2 is CE-PCL and CE-PCL in embodiment two 61- a-N 3hydrogen nuclear magnetic resonance spectrogram;
Fig. 3 is alkynyl-(PDMAEMA in embodiment four 32- co-PPEGMA 16) hydrogen nuclear magnetic resonance spectrogram;
Fig. 4 is Acid-sensitive cationic block copolymer C E-PCL in embodiment five 61- a-(PDMAEMA 32- co-PPEGMA 16) hydrogen nuclear magnetic resonance spectrogram;
Fig. 5 is Hymecromone, CE, CE-PCL, CE-PCL in embodiment 61- a-N 3and CE-PCL 61- a-(PDMAEMA 32- co-PPEGMA 16) infrared spectra (FT IR) figure;
Fig. 6 is polymkeric substance CE-PCL in embodiment three 68-N 3, segmented copolymer alkynyl-(PDMAEMA in embodiment four 32- co-PPEGMA 16) and embodiment six in Acid-sensitive cationic block copolymer C E-PCL 68- a-(PDMAEMA 32- co-PPEGMA 16) gel permeation chromatography elution curve figure;
Fig. 7 is Acid-sensitive cationic block copolymer C E-PCL in embodiment five 61- a-(PDMAEMA 32- co-PPEGMA 16) critical aggregation concentration test result in aqueous phase;
Fig. 8 is Acid-sensitive cationic block copolymer C E-PCL in embodiment six 68- a-(PDMAEMA 32- co-PPEGMA 16) critical aggregation concentration test result in aqueous phase;
Fig. 9 is CE-PCL in embodiment seven 61- a-(PDMAEMA 32- co-PPEGMA 16) and CE-PCL 68- a-(PDMAEMA 32- co-PPEGMA 16) gel blocking electrophoresis test result; In 1 ~ 14 swimming lane, multipolymer is respectively 0,0.1,0.5,1.0,1.5,2.0,2.5,3.0,5.0,7.0,10,15,20 and 25 with the N/P ratio of DNA;
Figure 10 is Acid-sensitive cationic block copolymer C E-PCL 61- a-(PDMAEMA 32- co-PPEGMA 16) and CE-PCL 68- a-(PDMAEMA 32- co-PPEGMA 16) transmission electron microscope photo of self-assembly form in aqueous;
Figure 11 is Acid-sensitive cationic block copolymer C E-PCL in embodiment six 61- a-(PDMAEMA 32- co-PPEGMA 16) and CE-PCL 68- a-(PDMAEMA 32- co-PPEGMA 16) Toxic test results to cervical cancer cell (HeLa cell).
Embodiment
Below in conjunction with embodiment and accompanying drawing, the invention will be further described:
Embodiment one: initiator 7-(2 '-hydroxyl-3 '-chlorine) synthesis of propane-4-methylcoumarin (CE)
By Hymecromone (5 g, 28.5 mmol), in 120 DEG C of oven dryings, use after cooling in exsiccator again, epoxy chloropropane (11.55 g, 125 mmol) and catalyzer triphenylphosphine (0.13 g, 0.5 mmol) are joined in 150 mL three-necked bottles, reflux temperature 85 DEG C is slowly heated under agitation condition, treat that solution is yellow all phase times, stop heating, and keep this temperature, magnetic agitation, reacts 12 hours.After reaction terminates, reaction solution is poured in separating funnel, add appropriate trichloromethane (CHCl 3), use saturated K 2cO 3solution repeatedly extracts on a small quantity, and to remove unreacted raw material Hymecromone, until during water layer clear, separatory takes off a layer solution, rotary evaporation removing solvent C HCl 3and epoxy chloropropane, finally, after twice, dehydrated alcohol recrystallization, obtain yellow compound, be dried to constant weight at the vacuum drying oven of 25 DEG C, obtain product and CE, recording productive rate is 53.4%, keeps in Dark Place.
Accompanying drawing 1 is the hydrogen nuclear magnetic resonance spectrogram of above-mentioned Hymecromone and CE, and wherein (A) is Hymecromone, and solvent is deuterated dimethyl sulfoxide (DMSO- d 6); (B) be 7-(2 '-hydroxyl-3 '-chlorine) propane-4-methylcoumarin, solvent is deuterochloroform (CDCl 3).(A), (B) in accompanying drawing 5 is respectively the infrared spectra spectrogram of above-mentioned Hymecromone and CE.
In conjunction with above test result, prove to successfully synthesize CE.
Embodiment two: the polyester CE-PCL that azide is modified 61- a-N 3synthesis
Arm round-bottomed flask is put into 120 DEG C of baking ovens dry, ground glass stopper beyond the Great Wall after taking-up, takes out cold with pump until reach room temperature, continues to be full of argon gas by bottle after charge and discharge argon gas three times.Initiator 7-(2 '-hydroxyl-3 '-chlorine) propane-4-methylcoumarin (CE) (0.3 g, 1.18mmol) adds in side tube flask, injects 15 mL dry toluenes and is stirred to dissolving, adds the sub-tin [Sn (Oct) of octoate catalyst 2] (0.08 g, 0.2 mmol), continue to be full of argon gas by bottle after charge and discharge argon gas three times.Syringe injects monomer e-caprolactone (e-CL) (4 g, 35.4 mmol).And under remaining on 90 DEG C of temperature, magnetic agitation, reacts 20 hours.After completion of the reaction, cooled by reaction solution, rotary evaporation remove portion solvent, precipitated, occurs pressed powder, after suction filtration, obtain white powder in ice methyl alcohol, in 25 DEG C of vacuum drying ovens dryings 12 hours.Final product is white powder, and namely the polyester CE-PCL of coumarin fluorescent group functionalization, records productive rate 86.0%.
Carry out acetal-azide to CE-PCL to modify, arm round-bottomed flask is put into 120 DEG C of baking ovens dry, ground glass stopper beyond the Great Wall after taking-up, takes out cold with pump until reach room temperature, continues to be full of argon gas by bottle after charge and discharge argon gas three times.Take CE-PCL(2.25 g, 0.267 mmol, =8430 g mol -1), tosic acid pyridine (PPTS, 0.0267 mmol, 6.7 mg), at arm round-bottomed flask, adds extremely clarification in 20mL toluene, slightly heats dissolution.Heating, air distillation steams toluene, i.e. methylbenzene azeotropic removing moisture content.Add in dropping funnel and be dissolved with 2-chloroethyl-vinyl ether (CEVE; 140 μ L; 1.35 mmol) 10 mL methylene dichloride in; arm round-bottomed flask is slowly added drop-wise under ice bath 0 DEG C of condition; reaction process argon shield; dropwise after about 20 minutes, react 2 hours under 20 DEG C of room temperatures.After completion of the reaction, 10 mL sodium carbonate solutions (5 wt% Na are added 2cO 3), stopped reaction, adds 20 mL CH 2cl 2-dilution, with 10 mL NaCl salt water washings, extraction, get organic phase, aqueous phase uses 30 mL CH again 2cl 2washing, collect organic phase, add anhydrous magnesium sulfate drying 6 hours, after elimination magnesium sulfate solid, filtrate removes most of solvent through rotary evaporation, product after concentrated, precipitate in the normal hexane of 200 mL, obtain pressed powder, after suction filtration, obtain white powder, in 25 DEG C of vacuum drying ovens dryings 12 hours.Obtain product and CE-PCL 61- a-Cl is that white powder records productive rate 64%.
Then, by above-mentioned obtained CE-PCL 61- a-Cl adds in 50 mL round-bottomed flasks, adds 10 mL DMF and is stirred to polymer dissolution, then add NaN 3(2.1mmol, 130mg), in 60 DEG C of oil baths, reacts 40 hours under magnetic agitation condition.After completion of the reaction, the unreacted NaN of elimination 3solid, reaction soln pumps most of solvent DMF through oil pump.Add 20 mL CH 2cl 2dilution, by the solution washing organic phase of pH 10.0, collects organic phase, add anhydrous magnesium sulfate drying 6 hours, after elimination magnesium sulfate solid, filtrate removes most of solvent through rotary evaporation, the product after concentrated, precipitation in the normal hexane/ether (volume ratio is 1:1) of 200 mL, obtain pressed powder, after suction filtration, obtain white powder, in 25 DEG C of vacuum drying ovens dryings 12 hours, final acquisition white powder product, i.e. CE-PCL 61- a-N 3, record productive rate 75%, GPC survey its number-average molecular weight ( ) be 7430 g mol -1.
Accompanying drawing 2 is the hydrogen nuclear magnetic resonance spectrogram of above-mentioned product, and solvent is deuterochloroform (CDCl 3), wherein (A) is CE-PCL, (B) be CE-PCL 61- a-N 3; (C), (D) in accompanying drawing 5 is respectively above-mentioned CE-PCL and CE-PCL 61- a-N 3infrared spectra spectrogram.
In conjunction with above test result, prove to successfully synthesize product.
Embodiment three: CE-PCL 68- a-N 3synthesis
Arm round-bottomed flask is put into 120 DEG C of baking ovens dry, ground glass stopper beyond the Great Wall after taking-up, takes out cold with pump until reach room temperature, continues to be full of argon gas by bottle after charge and discharge argon gas three times.Initiator 7-(2 '-hydroxyl-3 '-chlorine) propane-4-methylcoumarin (CE) (0.3 g, 1.18mmol) adds in side tube flask, injects 15 mL dry toluenes and is stirred to dissolving, adds the sub-tin [Sn (Oct) of octoate catalyst 2] (0.08 g, 0.2 mmol), continue to be full of argon gas by bottle after charge and discharge argon gas three times.Syringe injects monomer e-caprolactone (e-CL) (5.3 g, 47.2 mmol).And under remaining on 90 DEG C of temperature, magnetic agitation, reacts 20 hours.After completion of the reaction, cooled by reaction solution, rotary evaporation remove portion solvent, precipitate in ice methyl alcohol, occur pressed powder, liquid obtained white powder after suction filtration, in 25 DEG C of vacuum drying ovens dryings 12 hours.Product is finally white powder, i.e. CE-PCL, record productive rate 86%, GPC survey its number-average molecular weight ( ) be 9740 g mol -1.
Carry out acetal-azide to CE-PCL to modify, arm round-bottomed flask is put into 120 DEG C of baking ovens dry, ground glass stopper beyond the Great Wall after taking-up, takes out cold with pump until reach room temperature, continues to be full of argon gas by bottle after charge and discharge argon gas three times.Take CE-PCL(2.6 g, 0.267 mmol, =9740 g mol -1), tosic acid pyridine (PPTS, 0.0267 mmol, 6.7 mg), at arm round-bottomed flask, adds extremely clarification in 20mL toluene, slightly heats dissolution.Heating, air distillation steams toluene, i.e. methylbenzene azeotropic removing moisture content.Add in dropping funnel and be dissolved with 2-chloroethyl-vinyl ether (CEVE; 140 μ L; 1.35 mmol) 10 mL methylene dichloride in; arm round-bottomed flask is slowly added drop-wise under ice bath 0 DEG C of condition; reaction process argon shield; dropwise after about 20 minutes, react 2 hours under 20 DEG C of room temperatures.After completion of the reaction, 10 mL sodium carbonate solutions (5 wt% Na are added 2cO 3), stopped reaction, adds 20 mL CH 2cl 2-dilution, with 10 mL NaCl salt water washings, extraction, be separated organic phase, aqueous phase uses 30 mL CH again 2cl 2washing, collect organic phase, add anhydrous magnesium sulfate drying 6 hours, after elimination magnesium sulfate solid, filtrate removes most of solvent through rotary evaporation, product after concentrated, precipitate in 200 mL normal hexanes, obtain pressed powder, after suction filtration, obtain white powder, in 25 DEG C of vacuum drying ovens dryings 12 hours.Obtain product and CE-PCL 68- a-Cl is white powder, records productive rate 78%.
Then, by above-mentioned obtained CE-PCL 68- a-Cl adds in 50 mL round-bottomed flasks, adds 10 mL DMF and is stirred to polymer dissolution, then add NaN 3(2.1mmol, 130mg), in 60 DEG C of oil baths, reacts 40 hours under magnetic agitation condition.After completion of the reaction, the unreacted NaN of elimination 3solid, reaction soln pumps most of solvent DMF through oil pump.Add 20 mL CH 2cl 2dilution, by the solution washing organic phase of pH 10.0, collects organic phase, add anhydrous magnesium sulfate drying 6 hours, after elimination magnesium sulfate solid, filtrate removes most of solvent through rotary evaporation, the product after concentrated, precipitation in 200 mL normal hexane/ether (volume ratio is 1:1), obtain pressed powder, after suction filtration, obtain white powder, in 25 DEG C of vacuum drying ovens dryings 12 hours, obtain white powder product, i.e. CE-PCL 68- a-N 3, record productive rate 78%.
Above-mentioned CE-PCL 68-N 3gel permeation chromatography (GPC) elution curve figure see accompanying drawing 6(A); GPC survey its number-average molecular weight ( ) be 8190 g mol -1.
Embodiment four: containing the segmented copolymer alkynyl-(PDMAEMA of alkynyl 32- co-PPEGMA 16) synthesis
50 mL arm round-bottomed flasks are put into 120 DEG C of baking ovens dry, ground glass stopper beyond the Great Wall after taking-up, takes out cold with pump until reach room temperature, continues to be full of argon gas by bottle after charge and discharge argon gas three times.Number-average molecular weight be 300 g mol -1monomer polyethylene glycol methacrylate-styrene polymer (PEGMA) (2.9 g, 9.6 mmol) and monomer methacrylic acid-2-( n,N-dimethylamino) ethyl ester (DMAEMA) (3.0 g; 19.2 mmol) in side tube flask; be dissolved in 12 mL Virahols, add initiator bromo acid propynyl ester (PBIB, 132.0 mg; 0.64 mmol); part PMDETA (PMDETA) (266 μ L, 1.28 mmol), catalyzer cuprous chloride (CuCl) (64.0 mg; 0.64 mmol) join in above-mentioned mixed system, pass into argon shield.Be warming up to 45 DEG C, and keep this temperature, magnetic agitation, react 12 hours.
After completion of the reaction, add Virahol and reaction product is diluted, and contact with air under agitation, make reaction terminating.After solution virescence, make it by being equipped with neutral Al 2o 3pillar to remove the mantoquita in solution, rotary evaporation makes solution concentrate, then instills in normal hexane by concentrated solution, through the unreacted raw material of precipitation removing, in triplicate.Finally that gained light yellow precipitate is dry at vacuum drying oven, obtain flaxen emplastic, i.e. segmented copolymer alkynyl-(PDMAEMA 32- co-PPEGMA 16), productive rate 93.8%.
Above-mentioned alkynyl-(PDMAEMA 32- co-PPEGMA 16) gel permeation chromatography (GPC) elution curve figure see accompanying drawing 6(B), GPC survey its number-average molecular weight ( ) be 9660 g mol -1; Accompanying drawing 3 is above-mentioned product alkynyl-(PDMAEMA 32- co-PPEGMA 16) proton nmr spectra, solvent is deuterochloroform (CDCl 3).In conjunction with above test result, prove to successfully synthesize product.
Embodiment five: CE-PCL 61- a-(PDMAEMA 32- co-PPEGMA 16) synthesis
50 mL arm round-bottomed flasks are put into 120 DEG C of baking ovens dry, ground glass stopper beyond the Great Wall after taking-up, takes out cold with pump until reach room temperature, continues to be full of argon gas by bottle after charge and discharge argon gas three times.CE-PCL 61- a-N 3(0.19 g, 0.025 mmol) and alkynyl-(PDMAEMA 32- co-PPEGMA 16) (0.27 g; 0.0275 mmol) be dissolved in the anhydrous THF of 10 mL; by part PMDETA (PMDETA) (0.27 g; 0.0275 mmol); catalyzer cuprous bromide (CuBr) (0.0036 g; 0.025 mmol) join in above-mentioned mixed system, pass into argon shield.Be warming up to 25 DEG C, and keep this temperature, magnetic agitation, react 48 hours.After completion of the reaction, rotary evaporation makes solution concentrate, and adds CH 2cl 2reaction product being diluted, making it by being equipped with neutral Al 2o 3pillar to remove the mantoquita in solution, rotary evaporation makes solution concentrate, then instills in normal hexane by concentrated solution, through the unreacted raw material of precipitation remove portion, in triplicate.Be 8000-14000 g mol with molecular weight cut-off -1the unreacted macromolecular reaction thing of dialysis tubing dialysis removing, lyophilize obtains sticky solid sample, i.e. the Acid-sensitive cationic block copolymer C E-PCL of fluorescence-pH double-response 61- a-(PDMAEMA 32- co-PPEGMA 16).
Accompanying drawing 4 is above-mentioned product C E-PCL 61- a-(PDMAEMA 32- co-PPEGMA 16) proton nmr spectra, solvent is deuterochloroform (CDCl 3); In accompanying drawing 5, (E) is the infrared spectrogram of above-mentioned product.In conjunction with above test result, prove to successfully synthesize product.
The Acid-sensitive cationic block copolymer C E-PCL of above-mentioned fluorescence-pH double-response is characterized by fluorescence probe method 61- a-(PDMAEMA 32- co-PPEGMA 16) self-assembly property in aqueous.Accompanying drawing 7 is critical aggregation concentration (CAC) test result of above-mentioned multipolymer, and the critical aggregation concentration of multipolymer is about 0.021 g L -1.
Embodiment six: CE-PCL 68- a-(PDMAEMA 32- co-PPEGMA 16) synthesis
50 mL arm round-bottomed flasks are put into 120 DEG C of baking ovens dry, ground glass stopper beyond the Great Wall after taking-up, takes out cold with pump until reach room temperature, continues to be full of argon gas by bottle after charge and discharge argon gas three times.CE-PCL 68- a-N 3(0.2 g, 0.025 mmol) and alkynyl-(PDMAEMA 32- co-PPEGMA 16) (0.27 g; 0.0275 mmol) be dissolved in the anhydrous THF of 10 mL; by part PMDETA (PMDETA) (0.27 g; 0.0275 mmol); catalyzer cuprous bromide (CuBr) (0.0036 g; 0.025 mmol) join in above-mentioned mixed system, pass into argon shield.Be warming up to 25 DEG C, and keep this temperature, magnetic agitation, react about 48 hours.After completion of the reaction, rotary evaporation makes solution concentrate, and adds CH 2cl 2reaction product being diluted, making it by being equipped with neutral Al 2o 3pillar to remove the mantoquita in solution, rotary evaporation makes solution concentrate, then instills in normal hexane by concentrated solution, through the unreacted raw material of precipitation remove portion, in triplicate.Utilize molecular weight cut-off for 8000-14000 g mol -1dialysis tubing dialyse 48 hours, remove unreacted alkynyl-(PDMAEMA 32- co-PPEGMA 16), lyophilize obtains sticky solid sample, i.e. the Acid-sensitive cationic block copolymer C E-PCL of fluorescence-pH double-response 68- a-(PDMAEMA 32- co-PPEGMA 16).
Above-mentioned CE-PCL 68- a-(PDMAEMA 32- co-PPEGMA 16) gel permeation chromatography elution curve figure see accompanying drawing 6 (C), as can be seen from the figure, compared to polymkeric substance CE-PCL 68- a-n 3with alkynyl-(PDMAEMA 32- co-PPEGMA 16) GPC elution curve, CE-PCL 68- a-(PDMAEMA 32- co-PPEGMA 16) the GPC elution curve time be moved to the left, flow out very fast, illustrate that, after click reaction, the molecular weight of segmented copolymer increases, thus prove that Click reaction is successful.
The Acid-sensitive cationic block copolymer C E-PCL of above-mentioned fluorescence-pH double-response is characterized by fluorescence probe method 68- a-(PDMAEMA 32- co-PPEGMA 16) self-assembly property in aqueous.Accompanying drawing 8 is critical aggregation concentration (CAC) test result of above-mentioned multipolymer, and the critical aggregation concentration of multipolymer is about 0.016 g L -1.
Embodiment seven: utilize sepharose to block the cationic segmented copolymer of Electrophoretic study to the compressed capability of DNA
By polymer samples CE-PCL 61- a-(PDMAEMA 32- co-PPEGMA 16), CE-PCL 68- a-(PDMAEMA 32- co-PPEGMA 16) with DNA be dissolved in 0.5 × TBE(Tris-borate buffer respectively) in, ultrasonic and stir make it dissolve completely, the concentration of described polymers soln and DNA solution is 1 mg mL -1.
According to different N/P ratio, in a certain amount of DNA solution, add polymers soln, whirlpool concussion makes to mix completely, compresses DNA by electrostatic interaction, forms the mixture of polymkeric substance and DNA.Mixed with the loading buffer (85% glycerol and 15% tetrabromophenol sulfonphthalein) of 2 μ L by complex solution (8 μ L), point sample adds containing 0.5 μ g mL -1ethidium bromide 0.8% sepharose in.Electrophoretic voltage is 70 V, and the time is 30 minutes, and buffered soln is 0.5 × TBE.
Above-mentioned N/P is than being polymkeric substance CE-PCL- a-(PDMAEMA- co-PPEGMA) in the mol ratio of phosphorus atom in nitrogen-atoms and DNA.
Accompanying drawing 9 is above-mentioned polymkeric substance sepharose retardance electrophoresis test result, and in 1 ~ 14 swimming lane, multipolymer is respectively 0,0.1,0.5,1.0,1.5,2.0,2.5,3.0,5.0,7.0,10,15,20,25 with the N/P ratio of DNA; (A) be CE-PCL 61- a-(PDMAEMA 32- co-PPEGMA 16), (B) be CE-PCL 68- a-(PDMAEMA 32- co-PPEGMA 16); As can be seen from Figure 9, when N/P ratio is greater than 7, polymkeric substance can be completely fixed DNA, the migration of retardance DNA.
Accompanying drawing 10 is the photo of the Acid-sensitive cationic Self-Assembling of Block Copolymer form by transmission electron microscope observation fluorescence-pH double-response, and wherein (A) is CE-PCL 61- a-(PDMAEMA 32- co-PPEGMA 16), (B) be CE-PCL 68- a-(PDMAEMA 32- co-PPEGMA 16), can find out two kinds of segmented copolymers in aqueous self-assembly form particle diameter and be less than the spherical micelle of 200 nanometers.
Accompanying drawing 11 is that the Acid-sensitive cationic segmented copolymer of above-mentioned fluorescence-pH double-response tested by tetramethyl-azo azoles salt trace enzyme reaction colorimetry (MTT) is to the toxotest of cervical cancer cell (HeLa cell).Result shows, cell survival rate is relatively high, illustrates that the cationic segmented copolymer of this type of fluorescence-pH double-response has hypotoxicity.

Claims (10)

1. an Acid-sensitive cationic segmented copolymer, is characterized in that, is expressed by the following chemical structure formula:
；
In formula, R 1be selected from , or in one; R 2be selected from , , or in one; X is bromine or chlorine; M is 30 ~ 90, n be 30 ~ 60, r is 10 ~ 30.
2. prepare a method for Acid-sensitive cationic segmented copolymer described in claim 1, it is characterized in that, comprise the following steps:
(1) in argon gas atmosphere, with coumarin fluorescent molecule for initiator, cyclic ester monomer is reactant, under the catalysis of stannous octoate, carry out ring-opening polymerization in polar solvent, and obtaining molecular chain one end containing coumarin fluorescent group, the other end is the functionalized polyester of hydroxyl; Described coumarin fluorescent molecule is 7-(2 '-hydroxyl-3 '-chlorine) propane-4-methylcoumarin; Cyclic ester monomer is e-caprolactone; Wherein, the mol ratio of cyclic ester monomer and initiator is 30: 1 ~ 90: 1; The mol ratio of catalyzer and initiator is 1: 5 ~ 1: 10;
(2) in argon gas atmosphere, the functionalized polyester utilizing step (1) to obtain and 2-chloroethyl-vinyl ether are reactant, and tosic acid pyridine is catalyzer, are obtained by reacting the functionalized polyester that chlorine replaces in polar solvent; Wherein, the mol ratio of catalyzer and functionalized polyester is 1: 5 ~ 1: 15; The mol ratio of 2-chloroethyl-vinyl ether and functionalized polyester is 1: 1 ~ 8: 1;
Then, the functionalized polyester that sodiumazide and above-mentioned chlorine replace is reacted in polar solvent, the polyester that the azide that acquisition one end is fluorophor, the other end is acetal-azido-is modified; Wherein, the mol ratio of functionalized polyester that sodiumazide and chlorine replace is 8: 1 ~ 12: 1;
(3) in argon gas atmosphere, utilize the atom transfer radical polymerization initiator containing alkynyl, under the existence of atom transfer radical polymerization catalyzer and atom transfer radical polymerization catalyst ligand, in alcohol organic solvent, atom transition free radical polymerization reaction is carried out with the monomer of polyethylene glycol methacrylate-styrene polymer and pH sensitivity, obtaining end group is the pH sensitive polymer chain of alkynyl and the segmented copolymer of poly-(polyethylene glycol methacrylate-styrene polymer), is called the segmented copolymer containing alkynyl;
Wherein, polyethylene glycol methacrylate-styrene polymer is 10: 1 ~ 30: 1 with the mol ratio of the atom transfer radical polymerization initiator containing alkynyl; The monomer of pH sensitivity is 30: 1 ~ 60: 1 with the mol ratio of the atom transfer radical polymerization initiator containing alkynyl; The mol ratio of atom transfer radical polymerization catalyzer and catalyst ligand is 1: 1 ~ 1: 4; Be 1: 0.5 ~ 1: 2 containing the atom transfer radical polymerization initiator of alkynyl and the mol ratio of atom transfer radical polymerization catalyzer; The monomer of described pH sensitivity is selected from: methacrylic acid-2-( n,N-dimethylamino) ethyl ester, methacrylic acid-2-( n,N-diethylin) ethyl ester, methacrylic acid-2-( n,N-diisopropylaminoethyl) ethyl ester, methacrylic acid-2-( n-tert-butylamino) one in ethyl ester;
(4) in argon gas atmosphere, under the existence of " click " chemical reaction catalyst with " click " chemical reaction catalyst part, the polyester that the azide obtained with step (2) is modified and the segmented copolymer containing alkynyl that step (3) obtains are that reactant carries out " click " chemical reaction, obtain described Acid-sensitive cationic segmented copolymer;
Wherein, " click " chemical reaction catalyst is 1: 1 ~ 1: 4 with the mol ratio of " click " chemical reaction catalyst part; Reactant is 1: 0.5 ~ 1: 2 with the mol ratio of " click " chemical reaction catalyst; The polyester that azide is modified is 0.8: 1 ~ 1.2: 1 with the segmented copolymer mol ratio containing alkynyl.
3. preparation method according to claim 2, is characterized in that: described polar solvent is toluene or methylene dichloride.
4. preparation method according to claim 2, is characterized in that: in step (2), and solvent when preparing the functionalized polyester of chlorine replacement is methylene dichloride; Solvent when preparing the polyester of sodiumazide modification is DMF.
5. preparation method according to claim 2, is characterized in that: in step (3), and the atom transfer radical polymerization initiator containing alkynyl is bromo acid propynyl ester; Atom transfer radical polymerization catalyzer is cuprous chloride or cuprous bromide; Atom transfer radical polymerization catalyst ligand is selected from: the one in dipyridyl, five methyl diethylentriamine, Tetramethyl Ethylene Diamine or hexamethyl Triethylenetetramine (TETA).
6. preparation method according to claim 2, is characterized in that: in step (3), and described alcohol organic solvent is Virahol.
7. preparation method according to claim 2, is characterized in that: in step (4), and " click " chemical reaction catalyst is cuprous chloride or cuprous bromide; " click " chemical reaction catalyst part is selected from: the one in dipyridyl, five methyl diethylentriamine, Tetramethyl Ethylene Diamine or hexamethyl Triethylenetetramine (TETA).
8. preparation method according to claim 2, is characterized in that: after step (1) ~ (4) complete, carry out purification processes respectively to product, described purge process comprises the following steps:
I the purification processes of () functionalized polyester: after completion of the reaction, cools reaction solution, rotary evaporation is except desolventizing, and precipitate in ice methyl alcohol, volume ratio is 1: 5 ~ 1: 15; Occur pressed powder, liquid is after suction filtration, dry under 25 DEG C of conditions in vacuum drying oven, obtains white powder product;
(ii) purification processes of the polyester of azide modification: after completion of the reaction, the unreacted raw material solid of elimination, reaction soln pumps most of solvent; Add methylene chloride dilution, use solution washing organic phase, collect organic phase, dry, filtrate, is precipitated in normal hexane/ether except desolventizing through rotary evaporation, and liquid is after suction filtration, dry under 25 DEG C of conditions in vacuum drying oven, obtains white powder product; The volume ratio of described normal hexane and ether is 1: 0.5 ~ 1: 2;
(iii) containing the purification processes of the segmented copolymer of alkynyl: after the completion of reaction, add alcohol organic solvent and reaction product is diluted, and contact with air under agitation, make reaction terminating, after solution turned blue green, make it pass through neutral Al is housed 2o 3pillar, then rotary evaporation makes solution concentrate, and is instilled by concentrated solution in hexane solution, and volume ratio is to precipitate at 1: 5 ~ 1: 15, finally that obtained throw out is dry under 25 DEG C of conditions in vacuum drying oven, obtains flaxen sticky shape solid product;
(iv) purification processes of Acid-sensitive cationic segmented copolymer: after the completion of reaction, add methylene chloride reaction product is diluted, and contact with air under the condition stirred, make reaction terminating, after solution turned blue green, it is made to pass through neutral Al is housed 2o 3pillar, then rotary evaporation makes solution concentrate, and is instilled by concentrated solution in hexane solution, and volume ratio is to precipitate at 1: 5 ~ 1: 15, finally that obtained throw out is dry under 25 DEG C of conditions in vacuum drying oven; Desciccate is soluble in water, put into dialysis tubing, use water as further as medium dialysis, remove unreacted raw material, after lyophilize, obtain sticky shape solid product, be i.e. described Acid-sensitive cationic segmented copolymer.
9. preparation method according to claim 8, is characterized in that: in step (iii), and described alcohol organic solvent is Virahol.
10. there is the cationic segmented copolymer of sensitivity to acid simultaneously as the application of genophore and pharmaceutical carrier described in claim 1.
CN201310362819.8A 2013-08-19 2013-08-19 Acid-sensitive cationic segmented copolymer and preparation method thereof and application Expired - Fee Related CN103421195B (en)

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