CN102702454A - PH response four-arm star block copolymer and preparation method and application thereof - Google Patents
PH response four-arm star block copolymer and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses pH response four-arm star block copolymer and a preparation method and application thereof. According to the copolymer, pentaerythritol is used as an inner core, each arm is connected with a hydrophobic group, a pH response group and a hydrophilic group; and the preparation method comprises the following steps of: performing ring opening polymerization on pentaerythritol to obtain hydrophobic group copolymer, performing acylation on the tail end of the hydrophobic group copolymer, and sequentially initiating pH response monomer and the hydrophilic group to perform electron transfer activating agent regeneration-atom transfer radical polymerization by using hydrophobic group copolymer of which the tail end is subjected to acylation and which is used as macroinitiator to obtain the pH response four-arm star block copolymer. The copolymer is self-assembled into nano micelle in an aqueous solution, so that insoluble medicines can be effectively solubilized; the copolymer is used for preparing a micelle medicine carrying system for insoluble anti-cancer medicines, and the medicines can be kept to be slowly released when pH of normal tissues is 7.4, and can be quickly released in a controllable way under the faintly acid condition that pH of cancer cells is 5 to 6; and the proportion of foundational groups of the copolymer is easy to control, and the copolymer is simple in synthesis process and high in yield.
Description
Technical field
The invention belongs to biological medicine and use the macromolecule polymer material field, relate to a kind of macromolecule polymer material and preparation method thereof and application, be specifically related to a kind of pH and respond 4 arm star segmented copolymers.
Background technology
Star-type polymer is the base polymer that a fulcrum or nuclear are drawn several or a plurality of polymer chains; Owing to be of compact construction, globular form and intramolecular block structure; Show the character different with linear polymer, as: molecular chain not the viscosity of easy entanglement, solution and the body linear polymer, the molecule chain end that are starkly lower than the same molecular amount have functional group that can supply further modification in a large number etc.The singularity of structure makes it have unique microfacies form, and some special property and function.Amphipathic multipolymer is made up of the segment of two kinds of different hydrophilic property, and the outside stimuluss such as variation that one of them segment receives pH value, temperature and the ionic strength of solution can become hydrophobic, and in water, is self-assembled into micella.Amphipathic star-type polymer because a plurality of segments are connected on the polyfunctional group nuclear through covalent linkage, also has its special nature except that the character that possesses general amphipathic linear block copolymers.In dilute solution or the arm number more for a long time, amphipathic star-type polymer can form constitutionally stable unimolecular micelle, does not allow to be subject to the influence of ambient conditionss such as concentration, temperature and changes.In strong solution, perhaps less the or hydrophilic segment of arm number more in short-term, its intermolecular hydrophobic interaction power strengthens, and is prone to form by a plurality of molecular aggregates.Though the stability of polymolecular aggregate is not as unimolecular micelle; Yet because the segment of star-type polymer hydrophobic region twines the formation reticulated structure mutually; Intermolecular Forces is bigger, makes the polymolecular aggregate be difficult to be destroyed, and has better more stable than linear polymer micella.
As: [Weizhong Yuan such as Yuan; Jinying Yuan, Mi Zhou1, Caiyuan Pan. Synthesis; Characterization; And fluorescence of pyrene-containing eight-arm star-shaped dendrimer-like copolymer with pentaerythritol core. Journal of Polymer Science, 2008,46:2788] be nuclear with the tetramethylolmethane; (be called for short: ATRP) (be called for short: ROP) obtain a kind of 8 arm polymkeric substance through ATRP with the caprolactone ring-opening polymerization; Show the character different with linear caprolactone, at fluorescent probe, there is potential application PDT and photoelectric device aspect; Wang Beilei etc. [Wang Beilei is coated with pine, Qiu Yongbing, Chen Yuanwei, Luo Xianglin. star-like amphipathic caprolactone-
b-polymethyl acrylic acid (2-hydroxyl ethyl ester) segmented copolymer synthetic and characterizing. polymer journal, 2011,10:1151] prepared one type of novel segmented copolymer: six arm stars gather (6-caprolactone)-
b-polymethyl acrylic acid (2-hydroxyl ethyl ester) (is called for short: 6sPCL-
b-PHEMA), PCL and HEMA carry out after the copolymerization, and can reduce the crystallinity of PCL and improve the wetting ability of polymkeric substance.
At first, amphipathic star-type polymer mainly is synthetic through active anionic polymerization and active ring-opening polymerization, but it is limited to obtain the kind of polymkeric substance.In recent years; Development along with controlled/" activity " radical polymerization technique; (be called for short: ATRP), living free radical polymerization polymerization, reversible addition-cracking chain transfer polymerization etc., the synthetic of amphipathic star-type polymer is more prone to, kind is also more like ATRP.Wherein ATRP method speed is fast; Temperature of reaction is moderate; Even can in the presence of small amount of oxygen, carry out; Can make all free yl polymerizating monomers that controlled/" activity " polymerization takes place in principle, and can carry out structurally-modifiedly effectively to existing polymkeric substance, therefore in the polymer molecular structure design, have very tempting prospect.Usually, use the synthetic star-type polymer of ATRP technology that nuclear method and three kinds of methods of end of the chain coupling method behind nuclear postbrachium method, the first arm are arranged earlier.
Wherein, Nuclear postbrachium method is the trigger monomer polymerization simultaneously of multifunctional initiator of utilization earlier, generates the method for star-type polymer arm, owing to synthesized multi-functional initiator earlier; Therefore the brachium unanimity of synthetic star-type polymer and arm number are confirmed, accurately the controlled polymerization degree.[Steffen Maier such as Frey; Alexander Sunder; Holger Frey, Rolf M ü lhaupt. Synthesis of poly (glycerol)-block-poly (methyl acrylate) multi-arm star polymers. Macromol. Rapid Commun., 2000; 21:226] hydroxyl of periphery is carried out bromination; Obtaining with hyperbranched poly glycerine is the polyfunctional group ATRP initiator of nuclear, further causes monomers such as methyl acrylate and carries out polymerization, obtains the star-type multi-arm polymkeric substance; [Xiaojie Li, Yinfeng Qian, Tao Liu such as Li; Xianglong Hu, Guoying Zhang, Yezi You; Shiyong Liu. Amphiphilic multiarm star block copolymer-based multifunctional unimolecular micelles for cancer targeted drug delivery and MR imaging. Biomaterials, 2011,32 (27): 6595] be kernel with the hyper-branched polyester; Synthesized a kind of amphipathic star-type polymer through caprolactone ROP and ATRP reaction; Nexine is a hydrophobicity, and the outside is hydrophilic, can be used as the hydrophobic anticancer drug carrier.
Patent WO2003078489-A1 has announced a kind of preparation method who prepares wetting ability two blocks, three blocks and star-type polymer, under protection of inert gas, is got by at least a vinyl monomer, macromole degradability chain-transfer agent and initiator polymerization preparation.Patent 200910024899.X has announced a kind of star type block acid sensitive nano micelle; It is to gather silicious sesquioxane by cage modle eight to cause D; The active ring-opening polymerization of L-rac-Lactide; With N, N-dimethylaminoethyl-methacrylic ester (is called for short: DMAEMA) carry out ATRP reaction institute synthetic, through temperature and pH sensitivity are realized the controlled release to medicine again.Existing these multi-arm star-shaped segmented copolymers are perfect not enough on stability and controlled release properties.
Summary of the invention
The objective of the invention is to deficiency, provide a kind of pH to respond 4 arm star segmented copolymers and preparation method thereof and application to above-mentioned prior art.
The present invention is nuclear with the tetramethylolmethane; Connect hydrophobic group, pH response group and hydrophilic radical on every arm successively and form 4 arm star block polymers; At first be that kernel obtains the hydrophobic group polymkeric substance through ring-opening polymerization with the tetramethylolmethane, with its terminal acidylate, with this as macromole evocating agent; Cause the transfer transport acvator regeneration-ATRP of pH response monomer and hydrophilic radical successively, make pH and respond 4 arm star segmented copolymers.Polymkeric substance of the present invention self-assembly in the aqueous solution is a nano-micelle, effective solubilising poorly water soluble drugs, and the bag that can be used for hydrophobic anticancer drug carries.When the pH 7.4 of healthy tissues, slowly discharge, fast controllable discharges under the pH of tumour cell 5 ~ 6 solutions of weak acidity.PH of the present invention responds 4 arm star block copolymer structures can keep more effective control drug release under the prerequisite of high drug load, thereby improves micellar pH response sensitivity and release efficiency, improves the controlled release properties of micelle medicine carrying system.
In order to achieve the above object, the present invention has adopted following technical scheme:
A kind of pH responds 4 arm star segmented copolymers, has following structure:
Wherein, x=17 ~ 44, y=11 ~ 27, z=4 ~ 8.
The number-average molecular weight that said pH responds 4 arm star segmented copolymers is 28000 ~ 60000 g/mol.
The present invention also provides a kind of pH to respond the preparation method of 4 arm star segmented copolymers, may further comprise the steps:
(1) grafted hydrophobic group: under protection of inert gas and anhydrous condition with hydrophobic monomer, catalyst A, initiator and solvent; React 24 ~ 48h down at 110 ~ 140 ℃; Through rotary evaporation, deposition, filtration, the dry polymkeric substance that gets grafted hydrophobic group, reaction formula is following:
(2) preparation macromole evocating agent: under protection of inert gas and anhydrous condition; Polymkeric substance, acylating agent, acid binding agent and solvent that step (1) is obtained; In ice-water bath, react 2 ~ 5h; At room temperature react 24 ~ 48h then, obtain macromole evocating agent through rotary evaporation, deposition, filtration, drying, reaction formula is following:
(3) preparation pH responds 4 arm star segmented copolymers: under protection of inert gas and anhydrous condition, macromole evocating agent, pH response monomer, part, catalyst B and solvent with step (2) obtains add reductive agent again after stirring; React 5 ~ 10h down at 60 ~ 90 ℃; After adding hydrophilic monomer reaction 5 ~ 10h then,, remove catalyzer with the THF dissolving; Rotary evaporation, deposition, filtration, drying obtain pH and respond 4 arm star segmented copolymers, and reaction formula is following:
The parts by weight of reactant are following in the step (1):
0.75 ~ 1.34 part of initiator,
98.46 ~ 99.15 parts of hydrophobic monomers,
0.05 ~ 0.20 part of catalyst A;
The parts by weight prescription of reactant is following in the step (2):
56.91 ~ 73.11 parts in polymkeric substance,
18.68 ~ 29.92 parts of acylating agents,
8.20 ~ 13.17 parts of acid binding agents;
The parts by weight prescription of reactant is following in the step (3):
27.46 ~ 49.55 parts of macromole evocating agents,
0.02 ~ 0.03 part of catalyst B,
0.16 ~ 0.32 part of part,
0.27 ~ 0.56 part of reductive agent,
24.77 ~ 45.77 parts of pH response monomers,
19.88 ~ 35.12 parts of hydrophilic monomers.
Initiator according to the invention is a tetramethylolmethane; Said hydrophobic monomer is the e-caprolactone; Said pH response monomer is a diethylaminoethyl methacrylate; Said hydrophilic monomer is a methylacrylic acid mono methoxy polyethylene glycol ester.
In the step of the present invention (1), said catalyst A is a stannous octoate, and said solvent is a toluene.
In the step of the present invention (2), said solvent is a THF, and said acid binding agent is a triethylamine, and said acylating agent is a 2-bromine isobutyl acylbromide.
In the step of the present invention (3), said part is the hexamethyl Triethylenetetramine (TETA), and said solvent is a toluene, and said reductive agent is a stannous octoate, and said catalyst B is a cupric bromide.
In the step of the present invention (1), the consumption of said catalyst A be hydrophobic monomer quality 0.05 ~ 0.2%, be preferably 0.1%.
In the step of the present invention (2), the consumption of said acylating agent is 4 ~ 8 times of amount of substance of polymkeric substance; The consumption of said acid binding agent is 4 ~ 8 times of amount of substance of polymkeric substance, is preferably 5 times.
In the step of the present invention (3), the consumption of said part is 5 ~ 10 times of amount of substance of catalyst B, is preferably 10 times; The consumption of said reductive agent is 5 ~ 10 times of amount of substance of catalyst B, is preferably 10 times.
Temperature of reaction in the step (1) is preferably 130 ℃, and the reaction times is preferably 36h.
Temperature of reaction in the step (3) is preferably 70 ℃, and the reaction times is preferably 8h.
In step of the present invention (1) and (2), said deposition may further comprise the steps: the solution behind the rotary evaporation is joined in the mixing solutions of 0 ℃ of cold methanol being equivalent to 10 times of its volumes and water, cold methanol and water volume ratio are 1:1.
In the step of the present invention (3), the said catalyzer of removing comprises following steps: with THF dissolved reaction product, cross the neutral alumina chromatography column, adopt THF as eluent; Said deposition may further comprise the steps: the solution behind the rotary evaporation is joined in the 0 ℃ of cold normal hexane that is equivalent to 10 times of its volumes.
The present invention also provides a kind of pH to respond the application of 4 arm star segmented copolymers in the micelle medicine carrying system of preparation slightly water-soluble cancer therapy drug.
The preparation process of the micelle medicine carrying system of said slightly water-soluble cancer therapy drug is: pH is responded 4 arm star segmented copolymers and the slightly water-soluble cancer therapy drug is dissolved in the organic solvent; With deionized water dialysis 48h postlyophilization, obtain the micelle medicine carrying system of slightly water-soluble cancer therapy drug behind the stirring 4h; Said organic solvent is N or DMSO 99.8MIN.; Said poorly water soluble drugs is the medicine that solubleness is less than or equal to 1g in 1L water.
PH through the present invention's preparation responds micelle medicine carrying system may command hydrophobic drug slowly release under the pH of healthy tissues 7.4 conditions that 4 arm star segmented copolymers prepare, and fast controllable discharges under the pH of tumour cell 5 ~ 6 solutions of weak acidity.
The present invention compared with prior art has the following advantages and beneficial effect:
(1) 4 arm star polymer inner layer of the present invention are made up of hydrophobic superpolymer polycaprolactone, and hydrophobic drug has higher drug loading therein; The middle layer is the responsive polymethyl acrylic acid lignocaine ethyl ester of pH, and the protection medicine does not discharge under the pH neutral of healthy tissues or slowly discharges, and discharges with very fast speed at the sour environment Chinese traditional medicine of tumour; Skin is hydrophilic polymethyl acrylic acid mono methoxy polyethylene glycol ester, and the rate of release that can come regulating medicine through the content of each group in the telomerized polymer molecular material satisfies the release request of different pharmaceutical;
(2) preparation method of the present invention is simple to operate, and reaction conditions is gentle, and the brachium of four arm star polymkeric substance of gained is prone to control, and molecular weight is adjustable in the scope of broad, is a kind of excellent performance, medicine carrying material with pH susceptibility;
(3) the critical aggregate concentration of polymkeric substance of the present invention is merely 2 ~ 3 mg/L far below tensio-active agent and conventional polymer micella, thereby its carrier micelle has advantages of higher stability.
Description of drawings
Fig. 1 is that (be called for short: GPC), moving phase is THF for the gel permeation chromatography figure of the polymkeric substance of grafted hydrophobic group among the embodiment 1.
Fig. 2 be the polymkeric substance of grafted hydrophobic group among the embodiment 1 proton nmr spectra (be called for short:
1H NMR), solvent be deuterochloroform (be called for short:
d-CDCl
3).
Fig. 3 is a macromole evocating agent among the embodiment 1
1H NMR spectrum, solvent does
d-CDCl
3
Fig. 4 responds the GPC elution curve of 4 arm star segmented copolymers for pH among the embodiment 1.
Fig. 5 is that pH responds 4 arm star segmented copolymers among the embodiment 1
1H NMR spectrum, solvent does
d-CDCl
3
Fig. 6 carries Zorubicin micellar release in vitro curve for product pH among the embodiment 3 responds 4 arm star segmented copolymers (polymethyl acrylic acid lignocaine ethyl ester block molecule amount about 9000).
Fig. 7 responds the micelle-forming concentration test curve of 4 arm star segmented copolymers (polymethyl acrylic acid lignocaine ethyl ester block molecule amount about 18000) for product pH among the embodiment 6.
Fig. 8 (is called for short: SEM) figure for the ESEM that pH among the embodiment 6 responds 4 arm star block copolymer micelles.
Fig. 9 carries Zorubicin micellar release in vitro curve for pH among the embodiment 6 responds 4 arm star segmented copolymers (polymethyl acrylic acid lignocaine ethyl ester block molecule amount about 18000).
Figure 10 responds the blank micellar vitro cytotoxicity of 4 arm star segmented copolymers for pH among the embodiment 3 and 6.
Figure 11 carries Zorubicin micellar vitro cytotoxicity for pH among the embodiment 3 and 6 responds 4 arm star segmented copolymers.
Embodiment
Below in conjunction with specific embodiment the present invention is further explained, but the scope that the present invention requires to protect is not limited thereto.The abbreviation contrast of uses such as monomer, catalyzer, initiator is as shown in table 1 in an embodiment.
Use the Chinese and English abbreviation contrast of material among table 1 embodiment
(1) polymkeric substance of synthetic grafted hydrophobic group: stirrer and 0.136g tetramethylolmethane are placed reaction flask, vacuumize after the sealing-Tong argon gas three times, successively with syringe with 20mL solvent toluene, 12g monomer e-CL and 0.012g Sn (Oct)
2Add in the reaction flask, with liquid nitrogen three times freezing-bleed-ramp cycle after, under argon shield in 120 ℃ of oil baths stirring reaction 36h; Reaction is cooled to room temperature, pressure reducing and steaming toluene after accomplishing; Add 50mL THF dilution, use 0 ℃ of methanol of 300mL (1:1 volume ratio) deposition then, at 45 ℃ of following vacuum-drying 24h; Obtain the polymkeric substance 4AS-PCl that white powder is grafted hydrophobic group, productive rate is 91%
M n=13898, PDI=1.35;
(2) synthetic macromolecule initiator: get the exsiccant there-necked flask, add 12g 4AS-PCl and 150mL THF, the logical argon gas 10min in sealing back, 2.02g TEA is injected in the sealing back; Be cooled to 0 ℃ with ice-water bath, add 4.6g 2-bromine isobutyl acylbromide then, behind 0 ℃ of reaction 5h, at room temperature react 24h more earlier; Reaction is cooled to room temperature after accomplishing, and removes by filter quaternary ammonium salt with the neutral alumina pillar; THF makes eluent, and the solution that obtains slowly adds 0 ℃ of methanol of 300mL (1:1 volume ratio) deposition after rotary evaporation concentrates, filter; At 45 ℃ of following vacuum-drying 24h, obtain white powder and be macromole evocating agent 4AS-PCL-Br then, productive rate is 92%;
(3) synthetic pH responds 4 arm star segmented copolymers: with stirrer, 0.011g CuBr
2Place reaction flask with 12g 4AS-PCL-Br; Vacuumize after the sealing-Tong argon gas three times; Add 30mL solvent toluene, 18g pH response monomer DEAEMA, 0.115g part HMTETA with syringe successively, stir 15min catalyst complex is formed, add reductive agent 0.203g Sn (Oct) again
2, change stirring reaction 7h in 70 ℃ of oil baths over to behind the stirring 5min, continue to add 9g hydrophilic monomer PEGMA and carry out successive polymerization reaction 8h; Reaction is cooled to room temperature after accomplishing, and adds the 40mLTHF dilution; Remove by filter catalyzer with the neutral alumina pillar then, THF makes eluent, and the solution that obtains slowly joins in 0 ℃ of normal hexane of 300mL after rotary evaporation concentrates and precipitates; Filter the back at 35 ℃ of following vacuum-drying 24h, obtain white powder and be pH and respond 4 arm star segmented copolymer 4AS-PCL-
b-PDEAEMA-
b-PPEGMA, productive rate are 80%,
M n=33385, PDI=1.45.
Fig. 1 is the GPC elution curve of 4AS-PCL among the embodiment 1, can find out, product is the normal state unimodal distribution,
M n=33385, PDI=1.45.
Fig. 2 is 4AS-PCL among the embodiment 1
1H NMR spectrogram, solvent does
d-CDCl
3, can find out that 4.06ppm is in the tetramethylolmethane structure-CH
2The proton peak of O-, 1.38,1.65 is to link to each other on the PCL main chain-CH with 2.31ppm
2-proton peak, 3.65ppm links to each other-CH with the PCL terminal hydroxyl
2-the characteristic proton peak.
Fig. 3 is 4AS-PCL-Br among the embodiment 1
1H NMR spectrogram, solvent does
d-CDCl
3, can find out that through after the acidylate, the proton peak of the methylene radical that originally links to each other with terminal hydroxyl is transferred to 4.17ppm fully from 3.65ppm, appear at 1.93ppm with the proton peak of stylish two pending methyl groups that connect.
Fig. 4 is 4AS-PCL-among the embodiment 1
b-PDEAEMA-
bThe GPC elution curve of-PPEGMA can find out that curve presents symmetric unimodal form, shows that the controllability of continuous ARGET ATRP is good, and molecular weight of product is evenly distributed.
Fig. 5 is 4AS-PCL-among the embodiment 1
b-PDEAEMA-
b-PPEGMA's
1H NMR spectrum, solvent does
d-CDCl
3, can find out that chemical shift 0.90 and 1.82 ~ 1.92ppm are respectively on the methacrylate backbone-CCH
3With-CH
2-the hydrogen proton peak, 2.71 with 4.01ppm corresponding to-CH
2CH
2-two continuous methene proton peaks, 1.05 correspond respectively in the DEAEMA structure-CH with the chemical shift of 2.59ppm
2CH
3Terminal methyl group and the proton peak of methylene radical.
(1) synthetic 4AS-PCl: stirrer and 0.136g tetramethylolmethane are placed reaction flask, vacuumize after the sealing-Tong argon gas three times, successively with syringe adding 20mL solvent toluene, 10g monomer e-CL and 0.020g Sn (Oct)
2, with liquid nitrogen three times freezing-bleed-ramp cycle after, under argon shield in 140 ℃ of oil baths stirring reaction 24h; Reaction is cooled to room temperature, pressure reducing and steaming toluene after accomplishing; Add 50mL THF dilution, use 0 ℃ of methanol of 300mL (1:1 volume ratio) deposition then, at 45 ℃ of following vacuum-drying 24h; Obtain white powder and be product 4AS-PCl, productive rate is 92%
M n=11036, PDI=1.60;
(2) synthetic 4AS-PCL-Br: get the exsiccant there-necked flask, add 10g 4AS-PCl and 150mL THF, the logical argon gas 10min in sealing back, the sealing back adds 1.62gTEA; Be cooled to 0 ℃ with ice-water bath, add 3.68g 2-bromine isobutyl acylbromide then, behind 0 ℃ of reaction 2h, at room temperature react 36h more earlier; Reaction is cooled to room temperature after accomplishing, and removes by filter quaternary ammonium salt with the neutral alumina pillar; THF makes eluent, and the solution that obtains slowly adds 0 ℃ of methanol of 300mL (1:1 volume ratio) deposition after rotary evaporation concentrates, filter; At 45 ℃ of following vacuum-drying 24h, obtain white powder and be product 4AS-PCL-Br then, productive rate is 87%;
(3) synthetic 4AS-PCL-
b-PDEAEMA-
b-PPEGMA: with stirrer, 0.011g CuBr
2Place reaction flask with 10g 4AS-PCL-Br; Vacuumize after the sealing-Tong argon gas three times; Add 30mL solvent toluene, 12g pH response monomer DEAEMA, 0.058g part HMTETA with syringe successively, stir 15min catalyst complex is formed, add 0.100g reductive agent Sn (Oct) again
2, change stirring reaction 10h in 60 ℃ of oil baths over to behind the stirring 5min, continue to add 12g hydrophilic monomer PEGMA and carry out successive polymerization reaction 10h; Reaction is cooled to room temperature after accomplishing, and adds the 40mLTHF dilution; Remove by filter catalyzer with the neutral alumina pillar then, THF makes eluent, and the solution that obtains slowly joins in 0 ℃ of normal hexane of 300mL after rotary evaporation concentrates and precipitates; Filter the back at 35 ℃ of following vacuum-drying 24h, obtain white powder and be product 4AS-PCL-
b-PDEAEMA-
b-PPEGMA, productive rate are 73%,
M n=32114, PDI=1.50.
(1) synthetic 4AS-PCl: stirrer and 0.136g tetramethylolmethane are placed reaction flask, vacuumize after the sealing-Tong argon gas three times, successively with syringe adding 20mL solvent toluene, 18g monomer e-CL and 0.018g Sn (Oct)
2, with liquid nitrogen three times freezing-bleed-ramp cycle after, under argon shield in 130 ℃ of oil baths stirring reaction 36h; Reaction is cooled to room temperature, pressure reducing and steaming toluene after accomplishing; Add 50mL THF dilution, use 0 ℃ of methanol of 300mL (1:1 volume ratio) deposition then, at 45 ℃ of following vacuum-drying 24h; Obtain white powder and be product 4AS-PCl, productive rate is 86%
M n=18025, PDI=1.59;
(2) synthetic 4AS-PCL-Br: get exsiccant 250mL there-necked flask, add 18g 4AS-PCl and 150mL THF, the logical argon gas 10min in sealing back, the sealing back adds 2.02g TEA; Be cooled to 0 ℃ with ice-water bath, add 4.6g 2-bromine isobutyl acylbromide then, behind 0 ℃ of reaction 5h, at room temperature react 24h more earlier; Reaction is cooled to room temperature after accomplishing, and removes by filter quaternary ammonium salt with the neutral alumina pillar; THF makes eluent, and the solution that obtains slowly adds 0 ℃ of methanol of 300mL (1:1 volume ratio) deposition after rotary evaporation concentrates, filter; At 45 ℃ of following vacuum-drying 24h, obtain white powder and be product 4AS-PCL-Br then, productive rate is 88%;
(3) synthetic 4AS-PCL-
b-PDEAEMA-
b-PPEGMA: with stirrer, 0.011g CuBr
2Place reaction flask with 18g 4AS-PCL-Br; Vacuumize after the sealing-Tong argon gas three times; Add 30mL solvent toluene, 9g pH response monomer DEAEMA, 0.115g part HMTETA with syringe successively, stir 15min catalyst complex is formed, add 0.203g reductive agent Sn (Oct) again
2, change stirring reaction 8h in 80 ℃ of oil baths over to behind the stirring 5min, continue to add 9g hydrophilic monomer PEGMA and carry out successive polymerization reaction 7h; Reaction is cooled to room temperature after accomplishing, and adds the 40mLTHF dilution; Remove by filter catalyzer with the neutral alumina pillar then, THF makes eluent, and the solution that obtains slowly joins in 0 ℃ of normal hexane of 300mL after rotary evaporation concentrates and precipitates; Filter the back at 35 ℃ of following vacuum-drying 24h, obtain white powder and be product 4AS-PCL-
b-PDEAEMA-
b-PPEGMA, productive rate are 76%,
M n=31305, PDI=1.47.
Adopt dialysis method to prepare carrier micelle, concrete steps are: accurately take by weighing the 20mg Zorubicin and be dissolved among the 20mL DMF, add the TEA 20 μ L of 2 times of molar weights, stirred overnight takes by weighing 40mg 4AS-PCL-simultaneously
b-PDEAEMA-
b-PPEGMA is dissolved among the 20mL DMF, both is mixed continue to dialyse behind the stirring 4h, and the every 4h of preceding 12h changes water once, and 6h changes water once subsequently, and freeze-drying promptly obtains DOX carrier micelle powder after the 0.45m filtering head filters.
Extracorporeal releasing experiment: the DOX carrier micelle that takes by weighing the above-mentioned preparation of 5mg respectively is dispersed in the 5mL damping fluid of pH 7.4, pH 6.5, pH 5.0; Place dialysis tubing then, change in the damping fluid of the identical pH value of 35mL and place medicament dissolution instrument, carry out release in vitro under the 110rpm rotating speed at 37 ℃; Timing sampling 2mL analyzes; And add the 2mL fresh buffer, and discharge ibuprofen concentration in the liquid with the determined by ultraviolet spectrophotometry different time, draw its release in vitro curve.
Fig. 6 is the product 4AS-PCL-of embodiment 3
b-PDEAEMA-
bThe release in vitro curve of-PPEGMA (PDEAEMA molecular weight about 9000), under the pH of healthy tissues 7.4 environment, the rate of release of DOX is very slow, and the prominent amount of releasing of DOX is less than 10%, and the cumulative release amount of 24h has only about 22%, and the cumulative release amount of 108h is 33%; During near condition pH is reduced to tumor tissues (pH=6.5), the rate of release of DOX is accelerated, and the cumulative release amount of 24h and 108h is compared with pH 7.4 all have been increased about 10%; And under the pH of tumour cell endosome 5.0 environment, the rate of release of DOX is obviously accelerated, and prominent release phenomenon do not increase thereupon (<10%), 24h cumulative release amount is increased to 48%, and 60h reaches 62%, and 108h has discharged 81%.
(1) synthetic 4AS-PCl: stirrer and 0.136g tetramethylolmethane are placed reaction flask, vacuumize after the sealing-Tong argon gas three times, successively with syringe adding 20mL solvent toluene, 16g monomer e-CL and 0.008g Sn (Oct)
2, with liquid nitrogen three times freezing-bleed-ramp cycle after, under argon shield in 110 ℃ of oil baths stirring reaction 48h; Reaction is cooled to room temperature, pressure reducing and steaming toluene after accomplishing; Add 50mL THF dilution, use 0 ℃ of methanol of 300mL (1:1 volume ratio) deposition then, at 45 ℃ of following vacuum-drying 24h; Obtain white powder and be product 4AS-PCl, productive rate is 85%
M n=17325, PDI=1.63;
(2) synthetic 4AS-PCL-Br: get exsiccant 250mL there-necked flask, add 16g4AS-PCl and 150mL THF, the logical argon gas 10min in sealing back, the sealing back adds 3.24g TEA; Be cooled to 0 ℃ with ice-water bath, add 7.36g 2-bromine isobutyl acylbromide then, behind 0 ℃ of reaction 4h, at room temperature react 48h more earlier; Reaction is cooled to room temperature after accomplishing, and removes by filter quaternary ammonium salt with the neutral alumina pillar; THF makes eluent, and the solution that obtains slowly adds 0 ℃ of methanol of 300mL (1:1 volume ratio) deposition after rotary evaporation concentrates, filter; At 45 ℃ of following vacuum-drying 24h, obtain white powder and be product 4AS-PCL-Br then, productive rate is 88%;
(3) synthetic 4AS-PCL-
b-PDEAEMA-
b-PPEGMA: with stirrer, 0.011g CuBr
2Place reaction flask with 16g 4AS-PCL-Br; Vacuumize after the sealing-Tong argon gas three times; Add 30mL solvent toluene, 24g pH response monomer DEAEMA, 0.092g part HMTETA with syringe successively, stir 15min catalyst complex is formed, add 0.16g reductive agent Sn (Oct) again
2, change stirring reaction 5h in 90 ℃ of oil baths over to behind the stirring 5min, continue to add 18g hydrophilic monomer PEGMA and carry out successive polymerization reaction 5h; Reaction is cooled to room temperature after accomplishing, and adds the 40mLTHF dilution; Remove by filter catalyzer with the neutral alumina pillar then, THF makes eluent, and the solution that obtains slowly joins in 0 ℃ of normal hexane of 300mL after rotary evaporation concentrates and precipitates; Filter the back at 35 ℃ of following vacuum-drying 24h, obtain white powder and be product 4AS-PCL-
b-PDEAEMA-
b-PPEGMA, productive rate are 70%,
M n=52367, PDI=1.56.
(1) synthetic 4AS-PCl: stirrer and 0.136g tetramethylolmethane are placed reaction flask, vacuumize after the sealing-Tong argon gas three times, successively with syringe adding 20mL solvent toluene, 14g monomer e-CL and 0.007g Sn (Oct)
2, with liquid nitrogen three times freezing-bleed-ramp cycle after, under argon shield in 130 ℃ of oil baths stirring reaction 36h; Reaction is cooled to room temperature, pressure reducing and steaming toluene after accomplishing; Add 50mL THF dilution, use 0 ℃ of methanol of 300mL (1:1 volume ratio) deposition then, at 45 ℃ of following vacuum-drying 24h; Obtain white powder and be product 4AS-PCl, productive rate is 87%
M n=15193, PDI=1.54;
(2) synthetic 4AS-PCL-Br: get exsiccant 250mL there-necked flask, add 14g 4AS-PCl and 150mL THF, the logical argon gas 10min in sealing back, the sealing back adds 3.24g TEA; Be cooled to 0 ℃ with ice-water bath, add 7.36g 2-bromine isobutyl acylbromide then, behind 0 ℃ of reaction 4h, at room temperature react 36h more earlier; Reaction is cooled to room temperature after accomplishing, and removes by filter quaternary ammonium salt with the neutral alumina pillar; THF makes eluent, and the solution that obtains slowly adds 0 ℃ of methanol of 300mL (1:1 volume ratio) deposition after rotary evaporation concentrates, filter; At 45 ℃ of following vacuum-drying 24h, obtain white powder and be product 4AS-PCL-Br then, productive rate is 86%;
(3) synthetic 4AS-PCL-
b-PDEAEMA-
b-PPEGMA: with stirrer, 0.011g CuBr
2Place reaction flask with 14g 4AS-PCL-Br; Vacuumize after the sealing-Tong argon gas three times; Add 30mL solvent toluene, 14g pH response monomer DEAEMA, 0.115g part HMTETA with syringe successively, stir 15min catalyst complex is formed, add 0.203g reductive agent Sn (Oct) again
2, change stirring reaction 7h in 80 ℃ of oil baths over to behind the stirring 5min, continue to add 14g hydrophilic monomer PEGMA and carry out successive polymerization reaction 8h; Reaction is cooled to room temperature after accomplishing, and adds the 40mLTHF dilution; Remove by filter catalyzer with the neutral alumina pillar then, THF makes eluent, and the solution that obtains slowly joins in 0 ℃ of normal hexane of 300mL after rotary evaporation concentrates and precipitates; Filter the back at 35 ℃ of following vacuum-drying 24h, obtain white powder and be product 4AS-PCL-
b-PDEAEMA-
b-PPEGMA, productive rate are 75%,
M n=45913, PDI=1.48.
(1) synthetic 4AS-PCl: stirrer and 0.136g tetramethylolmethane are placed reaction flask, vacuumize after the sealing-Tong argon gas three times, successively with syringe adding 20mL solvent toluene, 18g monomer e-CL and 0.018g Sn (Oct)
2, with liquid nitrogen three times freezing-bleed-ramp cycle after, under argon shield in 130 ℃ of oil baths stirring reaction 36h; Reaction is cooled to room temperature, pressure reducing and steaming toluene after accomplishing; Add 50mL THF dilution, use 0 ℃ of methanol of 300mL (1:1 volume ratio) deposition then, at 45 ℃ of following vacuum-drying 24h; Obtain white powder and be product 4AS-PCl, productive rate is 86%
M n=18025, PDI=1.59;
(2) synthetic 4AS-PCL-Br: get exsiccant 250mL there-necked flask, add 18g 4AS-PCl and 150mL THF, the logical argon gas 10min in sealing back, the sealing back adds 2.02g TEA; Be cooled to 0 ℃ with ice-water bath, add 4.6g 2-bromine isobutyl acylbromide then, behind 0 ℃ of reaction 5h, at room temperature react 24h more earlier; Reaction is cooled to room temperature after accomplishing, and removes by filter quaternary ammonium salt with the neutral alumina pillar; THF makes eluent, and the solution that obtains slowly adds 0 ℃ of methanol of 300mL (1:1 volume ratio) deposition after rotary evaporation concentrates, filter; At 45 ℃ of following vacuum-drying 24h, obtain white powder and be product 4AS-PCL-Br then, productive rate is 88%;
(3) synthetic 4AS-PCL-
b-PDEAEMA-
b-PPEGMA: with stirrer, 0.011g CuBr
2Place reaction flask with 18g 4AS-PCL-Br; Vacuumize after the sealing-Tong argon gas three times; Add 30mL solvent toluene, 18g pH response monomer DEAEMA, 0.092g part HMTETA with syringe successively, stir 15min catalyst complex is formed, add 0.16g reductive agent Sn (Oct) again
2, change stirring reaction 8h in 70 ℃ of oil baths over to behind the stirring 5min, continue to add 9g hydrophilic monomer PEGMA and carry out successive polymerization reaction 7h; Reaction is cooled to room temperature after accomplishing, and adds the 40mLTHF dilution; Remove by filter catalyzer with the neutral alumina pillar then, THF makes eluent, and the solution that obtains slowly joins in 0 ℃ of normal hexane of 300mL after rotary evaporation concentrates and precipitates; Filter the back at 35 ℃ of following vacuum-drying 24h, obtain white powder and be product 4AS-PCL-
b-PDEAEMA-
b-PPEGMA, productive rate are 82%,
M n=43321, PDI=1.36.
Utilize the fluorescent probe method to measure the product 4AS-PCL-of embodiment 6 preparations
b-PDEAEMA-
bThe micelle-forming concentration of-PPEGMA, concrete steps are following:
(1) preparation pyrene solution: pyrene is mixed with 12 ' 10 with acetone
-5The solution of mol/L;
(2) join sample solution: take by weighing 10mg 4AS-PCL-
b-PDEAEMA-
b-PPEGMA is dissolved in 5mL acetone; Dropwise join in the 100mL deionized water, obtain 0.1mg/mL solution behind the volatilization acetone, be diluted to the series concentration of 0.0001 ~ 0.1mg/ml subsequently; Get 20 10mL volumetric flasks; Every adds 0.1mL pyrene solution, and the polymers soln that adds above-mentioned different concns then respectively is made into sample liquid, and the concentration of pyrene is 6 ' 10 in the sample liquid
-7Mol/L;
(3) fluorescence spectrum test: as emission wavelength, specimen liquid is got at the excitation spectrum of 300 ~ 350nm with 373nm
I 339/
I 336Ratio is to concentration logarithm log
CMapping, as shown in Figure 7, curve break is the micelle-forming concentration value, records 4AS-PCL-
b-PDEAEMA-
bThe micelle-forming concentration of-PPEGMA is 2.2mg/L.
Adopt dialysis method to prepare embodiment 6 product 4AS-PCL-
b-PDEAEMA-
bThe carrier micelle of-PPEGMA, and characterize pattern, Fig. 8 shows that its pattern is spherical for evenly.
Extracorporeal releasing experiment: utilize the DOX carrier micelle of the above-mentioned preparation of determined by ultraviolet spectrophotometry to discharge the ibuprofen concentration in the liquid, draw its release in vitro curve at different time, as shown in Figure 9.
Fig. 9 is embodiment 6 product 4AS-PCL-
b-PDEAEMA-
bThe release in vitro curve of-PPEGMA (PDEAEMA molecular weight about 18000).Under the pH of healthy tissues 7.4 environment, the rate of release of DOX is slower, and the prominent amount of releasing of DOX is less than 10%, and the cumulative release amount of 24h has only 31%, and the cumulative release amount of 108h is 46%; During near condition pH is reduced to tumor tissues (6.5), the rate of release of DOX is accelerated, and the cumulative release amount of 24h and 108h is compared with pH 7.4 all have been increased about 12%; And under the pH of tumour cell endosome 5.0 environment, the rate of release of DOX is obviously accelerated, and 12h promptly discharges 50%, and 36h cumulative release amount is increased to 75%, and 96h promptly all discharges.
Vitro cytotoxicity test: the product 4AS-PCL-of difference test implementation example 3 and 6
b-PDEAEMA-
bThe cytotoxicity of-PPEGMA, concrete steps are following: get the flat tissue culturing plate in 96 holes, add 200mL DMEM cell culture medium respectively as blank control group in the orifice plate all around, every hole is with 1x10 in middle 60 holes
4The cell concn inoculation HepG2 cell of cells/well (200mL), wherein the 2nd row are placed into 37 ℃ with 96 orifice plates, saturated humidity, 5%CO as contrast
2Cultivate 24h in the incubator; To dissociate subsequently Zorubicin, freeze dried blank or carrier micelle is diluted to different polymer concentration (blank micella 1 ~ 400mg/L) or drug level (free Zorubicin or carry the Zorubicin micella with cell culture medium; 0.1 ~ 20mg/L); In removing 96 orifice plates from the 2nd be listed as the 11st row behind the cell culture medium porose; In the 2nd row, add fresh developing medium,, be listed as the 10th row from the 3rd as contrast; The sample solution that in all holes, adds 200mL respectively, the sample of each concentration join in 6 holes and carry out repetition; After cultivating 24h, siphon away the supernatant in all holes of containing cell, add the PBS rinse cell of 200mL; Siphon away PBS then, be listed as the 11st from the 2nd and be listed as, in each hole, add the MTT solution of 20mL and the developing medium of 180mL respectively; Then 96 orifice plates are positioned over and cultivate 4h in the incubator, siphon away unreduced MTT solution and developing medium subsequently, each hole is washed one time with the PBS of 200mL; And siphon away PBS, and in each hole, adding the DMSO dissolving MTT crystallization of 200mL, whole 96 orifice plates are placed on the 10min that vibrates in 37 ℃ of shaking tables; Utilize ELIASA to measure the absorbancy in each hole, 490nm place then, and then calculate cell survival rate.
Figure 10 is blank 4AS-PCL-
b-PDEAEMA-
b-PPEGMA micellar toxicity result can know 4AS-PCL-from figure
b-PDEAEMA-
b-PPEGMA is nontoxic basically to the HepG2 cell, and cell survival rate is still up to 90% under the high density of 400mg/L.
Figure 11 is free Zorubicin and Zorubicin 4AS-PCL-
b-PDEAEMA-
b-PPEGMA micellar cytotoxicity result; From figure, can know,, carry the also corresponding increase of Zorubicin micellar toxicity along with the PDEAEMA molecular weight 9000 is increased to 18000 among the embodiment 6 from embodiment 3 products; This mainly is because PDEAEMA has the pH response property; After micella gets into cell, the protonated micella swelling that makes of PDEAEMA, thereby the release of promotion Zorubicin.Year Zorubicin micella and the free Zorubicin of embodiment 6 products have had close cytotoxicity, explain that Zorubicin can effectively keep its antitumour activity through Bao Zaihou.
Claims (10)
1. a pH responds 4 arm star segmented copolymers, it is characterized in that having following structure:
Wherein, x=17 ~ 44, y=11 ~ 27, z=4 ~ 8.
2. pH according to claim 1 responds 4 arm star segmented copolymers, it is characterized in that, the number-average molecular weight that said pH responds 4 arm star segmented copolymers is 28000 ~ 60000g/mol.
3. claim 1 or 2 described pH respond the preparation method of 4 arm star segmented copolymers, it is characterized in that, may further comprise the steps:
(1) grafted hydrophobic group: under protection of inert gas and anhydrous condition,, react 24 ~ 48h down, through rotary evaporation, deposition, filtration, the dry polymkeric substance that gets grafted hydrophobic group at 110 ~ 140 ℃ with hydrophobic monomer, catalyst A, initiator and solvent;
(2) preparation macromole evocating agent B: under protection of inert gas and anhydrous condition; Polymkeric substance, acylating agent, acid binding agent and solvent that step (1) is obtained; In ice-water bath, react 2 ~ 5h; At room temperature react 24 ~ 48h then, obtain macromole evocating agent through rotary evaporation, deposition, filtration, drying;
(3) preparation pH responds 4 arm star segmented copolymers: under protection of inert gas and anhydrous condition; Macromole evocating agent, pH response monomer, part, catalyst B and solvent with step (2) obtains add reductive agent again after stirring, react 5 ~ 10h down at 60 ~ 90 ℃; After adding hydrophilic monomer reaction 5 ~ 10h then; With the THF dissolving, remove catalyzer, rotary evaporation, deposition, filtration, drying obtain pH and respond 4 arm star segmented copolymers;
The parts by weight of reactant are following in the step (1):
0.75 ~ 1.34 part of initiator,
98.46 ~ 99.15 parts of hydrophobic monomers,
0.05 ~ 0.20 part of catalyst A;
The parts by weight prescription of reactant is following in the step (2):
56.91 ~ 73.11 parts in polymkeric substance,
18.68 ~ 29.92 parts of acylating agents,
8.20 ~ 13.17 parts of acid binding agents;
The parts by weight prescription of reactant is following in the step (3):
27.46 ~ 49.55 parts of macromole evocating agents,
0.02 ~ 0.03 part of catalyst B,
0.16 ~ 0.32 part of part,
0.27 ~ 0.56 part of reductive agent,
24.77 ~ 45.77 parts of pH response monomers,
19.88 ~ 35.12 parts of hydrophilic monomers.
4. preparation method according to claim 3 is characterized in that, said initiator is a tetramethylolmethane; Said hydrophobic monomer is the e-caprolactone; Said pH response monomer is a diethylaminoethyl methacrylate; Said hydrophilic monomer is a methylacrylic acid mono methoxy polyethylene glycol ester.
5. preparation method according to claim 4 is characterized in that,
In the step (1), said catalyst A is a stannous octoate, and said solvent is a toluene;
In the step (2), said solvent is a THF, and said acid binding agent is a triethylamine, and said acylating agent is a 2-bromine isobutyl acylbromide;
In the step (3), said part is the hexamethyl Triethylenetetramine (TETA), and said solvent is a toluene, and said reductive agent is a stannous octoate, and said catalyst B is a cupric bromide.
6. preparation method according to claim 5 is characterized in that,
In the step (1), the consumption of said catalyst A be hydrophobic monomer quality 0.05 ~ 0.2%;
In the step (2), the consumption of said acylating agent is 4 ~ 8 times of amount of substance of polymkeric substance; The consumption of said acid binding agent is 4 ~ 8 times of amount of substance of polymkeric substance;
In the step (3), the consumption of said part is 5 ~ 10 times of amount of substance of catalyst B; The consumption of said reductive agent is 5 ~ 10 times of amount of substance of catalyst B.
7. preparation method according to claim 6; It is characterized in that; In step (1) and (2), said deposition may further comprise the steps: the solution behind the rotary evaporation is joined in the mixing solutions of 0 ℃ of cold methanol being equivalent to 10 times of its volumes and water, cold methanol and water volume ratio are 1:1;
In the step (3), the said catalyzer of removing comprises following steps: with THF dissolved reaction product, cross the neutral alumina chromatography column, adopt THF as eluent; Said deposition may further comprise the steps: the solution behind the rotary evaporation is joined in the 0 ℃ of cold normal hexane that is equivalent to 10 times of its volumes.
8. claim 1 or 2 described pH respond the application of 4 arm star segmented copolymers in the micelle medicine carrying system of preparation slightly water-soluble cancer therapy drug.
9. application according to claim 8; It is characterized in that; The preparation process of the micelle medicine carrying system of said slightly water-soluble cancer therapy drug is: pH is responded 4 arm star segmented copolymers and the slightly water-soluble cancer therapy drug is dissolved in the organic solvent; Stir behind the 4h with the deionized water 48h that dialyses, lyophilize obtains the micelle medicine carrying system of slightly water-soluble cancer therapy drug.
10. application according to claim 9 is characterized in that, said organic solvent is N or DMSO 99.8MIN.; Said poorly water soluble drugs is less than or equal to the medicine of 1g for solubleness in 1L water.
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