CN105175656B - A kind of temperature and oxidant stimuli-responsive Micelle-like Nano-structure of Two preparation method and application - Google Patents
A kind of temperature and oxidant stimuli-responsive Micelle-like Nano-structure of Two preparation method and application Download PDFInfo
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Abstract
A kind of temperature and oxidant stimuli-responsive Micelle-like Nano-structure of Two preparation method and application, the invention discloses the temperature-sensitive that the redox by using beta cyclodextrin (β CD) and ferrocene (Fc) includes principle and polymer Capillary electrophoresis (PNIPAM), the PNIPAM β CD that β CD main groups are contained in end are connected by the non-covalent bond effect of Host-guest Recognition in aqueous with another for the hydrophilic polyglycol (mPEG Fc) of end modified Fc guest moieties, form supramolecular complex mPEG Fc/PNIPAM β CD.When temperature is higher than PNIPAM LCST, the macromo-lecular adducts can further be collected as micellar structure in water.By adjusting the temperature of solution and the addition of oxidant, it is possible to achieve the formation of micella is with disintegrating.Cytotoxic evaluation experiment finds that the supramolecular complex has good biocompatibility.Wrapping up the supermolecule micella of anti-cancer drug doxorubicin has the effect for suppressing A549 growth of tumour cell well.The present invention has that preparation method is simple and environmentally-friendly, economy, possesses larger application value in biomedicine field.
Description
Technical field
The invention belongs to field of nanometer technology, it is related to a kind of temperature and oxidant stimuli-responsive Micelle-like Nano-structure of Two system
Preparation Method and application.
Background technology
Stimulating responsive polymer micella can be outer to pH, temperature, illumination, oxidant, enzyme and ultrasound wave irradiation etc.
Corresponding (Kang Y, Guo K, Li B-J, the Zhang S.Chemical of feedback is made in the stimulation of the environment on boundary
Communications 2014；50:11083-92.), it has been widely used in pharmaceutical carrier (Hu J, Liu
S.Macromolecules 2010；43:8315-30.), sensor (Nunes SP, Behzad AR, Hooghan B,
Sougrat R,Karunakaran M,Pradeep N,Vainio U,Peinemann KV.ACS Nano 2011；5:3516-
22.), nanometer apparatus (Feng D, Lv Y, Wu Z, Dou Y, Han L, Sun Z, Xia Y, Zheng G, Zhao D.Journal
of the American Chemical Society 2011；133:15148-56.) etc. numerous areas.But, traditional thorn
Sharp responsive polymer has response single, it is impossible to the defect such as real-time monitoring, limits its further development and application.Together
When, single stimulating responsive can not meet the architectural study complicated increasingly to be fine.In the last few years, designed and made
The standby polymeric system with double/multiple stimulation response has been subjected to the favor of more and more researchers.
The most common method for preparing multiple stimulation response micella is introduced simultaneously in amphipathic block copolymer
Two kinds or the two or more chemical bonds with different response characteristics.For example, Thayumanavan etc. is by the acetal of acid-sensitive
Change hydroxy-ethyl acrylate with temperature sensing polymer NIPA (NIPAMm) by the two of a glutathione sensitivity
Sulfide linkage link, obtain with triple stimulating responsives first-stage polymerization thing molecule (Klaikherd A, Nagamani C,
Thayumanavan S.Journal of the American Chemical Society 2009；131:4830-8.), and
Drug release studies are successfully applied it to.Zhao Yue seminars are successfully prepared with isotope of redox-sensitive characteristic and photaesthesia
Stimuli-responsive block copolymer (Xuan J, Han D, Xia H, the Zhao Y.Langmuir 2013 of characteristic；30:
410-7.), the copolymer molecule can be self-assembly of the micellar structure of nano-scale in aqueous, it is possible to realize medicine
Parcel accurately discharged with response.
Traditional stimulating responsive polymer is all the covalent chemical bond by environmental sensitivity by series of chemical
(such as imine linkage, hydrazone key, disulfide bond) introduces polymer segment, but is difficult in the presence of cumbersome, purification difficult, molecular weight is prepared
Many defects (Pollino JM, Weck M.Chemical Society Reviews 2005 such as control, costly；34:
193-207；Chen G,Jiang M.Chemical Society Reviews 2011；40:2254-66.).Therefore, it is how simple
Single stimulating responsive polymer that efficiently prepares is pendulum problem urgently to be resolved hurrily in face of chemist.In the last few years, molecule is utilized
Between host-guest identification non-covalent bond effect caused extensively instead of traditional covalent bond to construct responsive polymer
General concern.Due to the stimuli responsive invertibity of host-guest recognition reaction, such as illumination, temperature, oxidant can be made can
The feedback of inverse property, compared with the preparation method of traditional stimulating responsive polymer, is recognized using the host-guest of non-covalent bond and made
Unrivaled superiority (Jing J, Szarpak- are shown for preparing the method for stimulating responsive polymer
Jankowska A,Guillot R,Pignot-Paintrand I,Picart C,Auzély-Velty R.Chemistry of
Materials 2013；25:3867-73.).The non-covalent bond recognized based on cyclodextrin host-guest is made from the bright seminar in the Congjiang
With being incorporated into polymer (Wang J, Jiang M.Journal of the American Chemical since preparing micella
Society 2006；128:3703-8.), based on non-covalent bond polymer micelle (noncovalently connected
Micelles, NCCM) developmental research achieve significant progress (Liu Y, Yu C, Jin H, Jiang B, Zhu X, Zhou
Y,Lu Z,Yan D.Journal of the American Chemical Society 2013；135:4765-70.).Zhu Xin
The remote oxidant sensitivity characteristic using cyclodextrin and ferrocene, has constructed the novel cation supermolecule genophore of a class formation
(Dong R J,Su Y,Yu S Y,Zhou Y F,Lu Y F,Zhu X Y.Chemical Communications 2013；
49:9845-7.).After the genophore for wrapping up plasmid molecule is swallowed by cancer cell, due to the H of higher concentration in cancer cell2O2,
So that Fc molecules are oxidized to Fc+, so that the host-guest inclusion structure that itself and cyclodextrin are formed is disintegrated, and result in whole
Individual genophore is disintegrated as β-CD2And Fc+-TEPA-Fc+, now it is wrapped in the plasmid molecule inside micella and is released,
And further integrate with intracellular original DNA molecular, expression, reach the effect for transfecting and carrying out gene therapy.But, how
Accurately regulate and control stimulating responsive non-covalent bond polymer micelle and the control of medicine how is realized using this micella
Release still annoyings researchers.
The content of the invention
We utilize method (the Homopolymer Orthogonal Self- of the orthogonal self assembly of homopolymer in the present invention
Assembly, HOSA), the poly- second two for being modified ferrocene using the invertibity host-guest recognition reaction of cyclodextrin and ferrocene
Alcohol monomethyl ether (mPEG-Fc) passes through reversible non-covalent bond chain with beta-schardinger dextrin NIPA (PNIPAM- β-CD)
Fetch and construct supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD, and study the dual environment thorn of its oxidant and temperature
Swash corresponding sexual behaviour.In aqueous, when temperature is higher than PNIPAM critical transitions concentration (lower critical
Solution temperature, LCST) when, the supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD of total hydrophilic will
Amphipathic molecule can be changed into, and further self assembly is the parcel (such as Fig. 1) that micellar structure carries out medicine in water.It is double when adding
When oxygen water is as oxidant, due to the ionic state Fc that hydrogen peroxide Oxidation of Ferrocene is positively charged+, Fc+Bag can not be produced with cyclodextrin
Close so that original inclusion structure is disintegrated, and discharged along with the part of medicine, supermolecule block copolymer is changed into mPEG-Fc+
With PNIPAM- β-CD.And because now temperature is still on PNIPAM LCST, PNIPAM- β-CD can be with secondary assembling shape
Into using PNIPAM segments as hydrophobic cores, using β-CD as the secondary micellar structure of hydrophily shell, and some drugs are wrapped up
Herein among secondary micellar structure.When under the further temperature for reducing system to PNIPAM LCST, PNIPAM segments are complete
It is changed into entirely hydrophilic so that secondary micellar structure is disintegrated, along with the complete release of medicine.
Therefore, the present invention provides the preparation side of a kind of temperature and oxidant stimuli-responsive supermolecule block copolymer
Method and application.
Preferably, supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD of the present invention are by a ferrocene
The poly glycol monomethyl ether (mPEG-Fc) of modification leads to the NIPA (PNIPAM- β-CD) of beta-cyclodextrin modified
Cross obtained by reversible host-guest identification non-covalent bond chain fetches and construct.
It is highly preferred that the poly glycol monomethyl ether (mPEG-Fc) of ferrocene modification of the present invention has following structure
Formulas I or II：
Structural formula I
Formula II
It is highly preferred that the NIPA (PNIPAM- β-CD) of beta-cyclodextrin modified of the present invention has
Following formula II I：
Formula II I
Present invention also offers a kind of method for preparing above-mentioned homopolymer mPEG-Fc, in organic solvent, by with DMAP
For catalyst, using DCC as coupling agent, by the simple of poly glycol monomethyl ether (mPEG) and ferrocenecarboxylic acid (Fc-COOH)
Esterification is made；Or in organic solvent by using NHS as catalyst, using EDC as coupling agent, by polyethyleneglycol first
Ether carboxylic acid (mPEG-COOH) and ferrocene amine (Fc-NH2) simple amidation process be made.
Present invention also offers a kind of method for preparing above-mentioned homopolymer PNIPAM- β-CD, in organic solvent, by with
AIBN initiators, it is single for polymerization with NIPA (NIPAM) with mercapto-cyclodextrin (β-CD-SH) for chain-transferring agent
Body, is made by Raolical polymerizable.
Present invention also offers a kind of method for preparing above-mentioned supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD,
This method includes described supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD by homopolymer mPEG-Fc and homopolymer
PNIPAM- β-CD are in the case of equimolar ratio, in blend solvent such as DMSO, DMF, THF, H2Fully dissolve, stir in O etc.,
Assembling, finally removes blend solvent and obtains supermolecule block copolymer.
Present invention also offers a kind of nano-scale micella or vesica, wherein the nano-scale micella or vesica are by this
The described above-mentioned supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD of invention are prepared.
Prepared present invention also offers one kind above-mentioned by above-mentioned supermolecule block copolymer mPEG-Fc/ of the present invention
Nano-scale micella or the method for vesica that PNIPAM- β-CD are prepared, this method include supermolecule block copolymer
MPEG-Fc/PNIPAM- β-CD are dissolved in after certain water, temperature be more than 32 DEG C at formed needed for nano-scale micella or
Vesica, and it is more than the micella or capsule that there is the secondary nano-scale needed for being formed under conditions of oxidant at 32 DEG C in temperature
Bubble.
Present invention also offers one kind is above-mentioned by above-mentioned supermolecule block copolymer mPEG-Fc/ of the present invention
Application of the nano-scale micella or vesica that PNIPAM- β-CD are prepared in as pharmaceutical carrier.
Heretofore described supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD can be in aqueous using this
The methods such as the conventional dialysis in field obtain the micella of nano-scale.Described nano-scale micella can be used as pharmaceutical carrier
In load other cancer therapy drugs such as hydrophobicity such as Doxorubicin, taxol, camptothecin analogues, vincaleukoblastinum and its derivative
One or more in cancer therapy drug, form the Nano medication for carrying multi-medicament, to reach the collaboration between cancer therapy drug
Effect.The method of carrying medicament mainly passes through hydrophobic interaction.
The homopolymer mPEG-Fc and PNIPAM- β-CD of the present invention can select the conventional chemical synthesis process in this area to close
Into supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD can be obtained by self-assembling method.
The present invention has a series of following advantages：
The present invention simply and easily obtains supermolecule embedding by using cyclodextrin and the host-guest recognition reaction of ferrocene
Section copolymer.
The present invention is by using the oxidant sensitiveness and PNIPAM of cyclodextrin and the host-guest recognition reaction of ferrocene
Temperature sensitivity, has obtained the supermolecule block copolymer with doubling sensitivity.
The supermolecule block copolymer of the present invention has a variety of functions：The supermolecule block copolymer can be more than in temperature
The micella of nano-scale is formed by way of self assembly in 32 DEG C of aqueous solution and cancer therapy drug is wrapped up, the glue of this nano-scale
Beam can be accumulated in tumor tissues by the high-permeability of tumor tissues and high retention (EPR effect), so as to realize quilt
Moving-target to effect, after allowing utilize tumor tissues high concentration H2O2Characteristic so that micella is reassembled as secondary micella, and release portion
Divide medicine, reach therapeutic purposes, then, pass through the method for local cooling so that the secondary micella of formation is disintegrated, and medicine has been obtained
Full release, you can to realize the classification controlled release of medicine.
Brief description of the drawings
Fig. 1 is supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD formation nano-micelles of the present invention and thin in tumour
Release schematic diagram in born of the same parents.
Fig. 2 is the supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD prepared in application examples 1 of the present invention transmission electricity
Mirror (TEM) and dynamic light scattering (DLS) result figure.
Fig. 3 is the supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD prepared in application examples 1 of the present invention in hydrogen peroxide
The transmission electron microscope (TEM) and dynamic light scattering (DLS) result figure of the secondary micella formed in the presence of under conditions of.
Fig. 4 is the supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD micellas prepared in application examples 1 of the present invention not
Insoluble drug release result figure with the conditions of.
Fig. 5 be the parcel DOX prepared in application examples 1 of the present invention supermolecule block copolymer mPEG-Fc/PNIPAM- β-
CD micellas, supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD micellas and DOX are to A549 lung carcinoma cell exercising result figures.
Embodiment
In following case study on implementation, specific invention case study on implementation not limited to this, embodiment can be according to invention
Content design is into other forms.
In following case study on implementation, Solution percentages concentration is weight percent concentration unless otherwise indicated.
Embodiment 1：
By using DMAP as catalyst, using DCC as coupling agent, by poly glycol monomethyl ether (mPEG) and ferrocenecarboxylic acid
(Fc-COOH) mPEG-Fc synthesis is made in simple esterification.
(1) mPEG-Fc synthesis
The 100mL round-bottomed flasks of clean dried are taken, by 5.05g (2.53mmol) mPEG2000,0.82g (3.57mmol) two
Ferrocenemonocarboxylic acid and 0.066g (0.54mmol) DMAP are dissolved in the anhydrous CH of 40mL2Cl2In, add 0.85g under ice bath stirring
(4.11mmol) DCC, is then stirred at room temperature reaction 24h under argon gas protection.Reaction filters out accessory substance DCU etc. after terminating, and is evaporated
Solvent.Obtained residue is dissolved with chloroform, is extracted three times with 0.5M sodium hydroxide solution, isolated organic layer, and
It is dried overnight in anhydrous sodium sulfate, is evaporated organic liquid, obtained solid is dissolved in a small amount of chloroform, and adds a large amount of ether,
Precipitation is filtrated to get, so dissolves-precipitates repeatedly three times, obtain lurid solid crude product.Then crude product is crossed into silica gel
Post is separated, and eluant, eluent is MeOH:DCM=1:15(v/v).Obtained yellow solid product is dried in vacuo after 24h and is
Required product mPEG-Fc, 4.35g (yield:85.3%).MPEG-Fc reaction equation is following (n=45)：
(2) PNIPAM- β-CD synthesis
By with AIBN initiators, with mercapto-cyclodextrin (β-CD-SH) for chain-transferring agent, with NIPA
(NIPAM) it is polymerized monomer, PNIPAM- β-CD synthesis is made by Raolical polymerizable.
The 25mL round-bottomed flasks of clean dried are taken, by 1.05g (8.86mmol) NIPAM monomers, 0.48g under Ar protections
(0.42mmol) β-CD-SH and 0.031g (0.18mmol) AIBN are dissolved into 10mL anhydrous DMF solutions under conditions of stirring
In, then Ar protections continue stirring reaction 12h at 60 DEG C.After polymerisation terminates, reaction solution is transferred into molecular cut off is
Dialysed three days with deionized water in 3500 bag filter, to remove solvent DMF, fail the less fragment of polymerized monomer, the degree of polymerization
Deng impurity, the liquid in bag filter is then collected, frozen dried is carried out, you can the solid powdery product of white is obtained
PNIPAM- β-CD, 0.78g (yield:52.7%).Reaction equation is following (n=28)：
(3) supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD synthesis
By accurately weighing mPEG-Fc 6.02mg (2.72mmol), it is dissolved in the anhydrous THF of 1mL, then adds equimolar
After the PNIPAM- β-CD samples of amount, fully dissolving, ultrasonic disperse 0.5h causes intermolecular assembling fully to carry out.Solvent evaporated,
Obtain supermolecule block copolymer.
Embodiment 2：
By using NHS as catalyst, using EDC as coupling agent, by poly glycol monomethyl ether carboxylic acid (mPEG-COOH) and two
Luxuriant sideramines (Fc-NH2) simple amidation process be made mPEG-Fc synthesis.
(1) mPEG-Fc synthesis
The 100mL round-bottomed flasks of clean dried are taken, by 5.05g (2.52mmol) mPEG-COOH, 0.72g (3.57mmol)
Ferrocene amine and 0.061g (0.61mmol) NHS are dissolved in the anhydrous CH of 40mL2Cl2In, add 0.77g under ice bath stirring
(3.98mmol) EDCI, is then stirred at room temperature reaction 24h under argon gas protection.Handy 0.5M sodium hydroxide solution extraction three
It is secondary, isolated organic layer, and be dried overnight in anhydrous sodium sulfate, organic liquid is evaporated, obtained solid is dissolved on a small quantity
In chloroform, and a large amount of ether are added, be filtrated to get precipitation, so dissolved-precipitate repeatedly three times, obtain lurid solids crude production
Thing.Then crude product is crossed into silicagel column to be separated, eluant, eluent is MeOH:DCM=1:15(v/v).By obtained yellow solid
Product mPEG-Fc, 4.31g (yield needed for being after product vacuum drying 24h:77.5%).MPEG-Fc reaction equation is as follows
(n=45)：
(2) PNIPAM- β-CD synthesis
By with AIBN initiators, with mercapto-cyclodextrin (β-CD-SH) for chain-transferring agent, with NIPA
(NIPAM) it is polymerized monomer, PNIPAM- β-CD synthesis is made by Raolical polymerizable.
The 25mL round-bottomed flasks of clean dried are taken, by 1.05g (8.86mmol) NIPAM monomers, 0.24g under Ar protections
(0.21mmol) β-CD-SH and 0.016g (0.09mmol) AIBN are dissolved into the anhydrous DMSO solutions of 10mL under conditions of stirring
In, then Ar protections continue stirring reaction 12h at 75 DEG C.After polymerisation terminates, reaction solution is transferred into molecular cut off is
Dialysed three days with deionized water in 3500 bag filter, to remove solvent DMSO, fail the less fragment of polymerized monomer, the degree of polymerization
Deng impurity, the liquid in bag filter is then collected, frozen dried is carried out, you can the solid powdery product of white is obtained
PNIPAM- β-CD, 0.47g (yield:39.2%).Reaction equation is following (n=59)：
(3) supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD synthesis
By accurately weighing mPEG-Fc 6.02mg (2.72mmol), it is dissolved in the anhydrous THF of 1mL, then adds equimolar
After the PNIPAM- β-CD samples of amount, fully dissolving, ultrasonic disperse 0.5h causes intermolecular assembling fully to carry out.Solvent evaporated,
Obtain supermolecule block copolymer.
Application examples 1：
The preparation of supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD nano-micelles.
Supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD preparation：Accurately weigh mPEG-Fc 6.02mg
(2.72mmol), is dissolved in the anhydrous THF of 1mL, then adds the PNIPAM- β-CD samples of equimolar amounts, fully after dissolving, ultrasound
Scattered 0.5h causes intermolecular assembling fully to carry out.Then, under stirring state, (stream is slowly added dropwise in 20.0mL deionized waters
Speed is 0.3mL min-1) into THF dispersion liquids, 24h is then stirred at 25 DEG C with the THF that fully volatilizees, then by system temperature
It is increased to 37 DEG C and continues stirring 3h to be sufficiently formed micella.
Application examples 2：
Wrap up the preparation of the supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD nano-micelles of Doxorubicin (DOX).
Then mPEG-Fc 6.02mg (2.72mmol) are accurately weighed, is dissolved in the anhydrous THF of 1mL, then adds equimolar
After the PNIPAM- β-CD samples of amount, fully dissolving, ultrasonic disperse 0.5h causes intermolecular assembling fully to carry out, then, stirring
In the case of, 2.01mg DOX, which are dissolved in after 1.0mL THF, to be slowly added dropwise into above-mentioned assembles concentration, then by 20.0mL deionized waters
(flow velocity be 0.3mL min-1) is slowly added dropwise into THF dispersion liquids, 24h is then stirred at 25 DEG C with the THF that fully volatilizees, so
System temperature is increased to 37 DEG C afterwards and continues to stir 3h to be sufficiently formed micella.Finally being transferred to molecular cut off at 37 DEG C is
Dialyse to remove not wrapped free Doxorubicin with deionized water in 3500 bag filter.The nano-micelle needed.
Detected by taking prodrug micella made from application examples 1 and application examples 2 as an example, detection method uses this area
Common detection methods.
At 37 DEG C, the supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD nano-micelles of self assembly are formed in water
Average-size be 218nm, its TEM result and DLS results are as shown in Figure 2.
At 37 DEG C, the supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD of the self assembly added after hydrogen peroxide are formed
The average-size that is formed in water of PNIPAM- β-CD level nano-micelles be 148nm, its TEM result and DLS results such as Fig. 3
It is shown.
By the carry out drug release experiment at different conditions of drug micelles made from application examples 2.Effect is as shown in Figure 4.
As can be seen that under single incentive condition during DOX release, when the temperature of delivery systme directly is down into 25 DEG C, preceding 10h it
It is interior, medicine have one it is obvious prominent release process, its burst size is up to 60%, and eventually in 48h by medicine almost
Discharge completely, this is due to that micella can disintegrate quickly, so that substantial amounts of medicine when temperature is less than PNIPAM LCST
Thing discharges.When being discharged under conditions of existing at 37 DEG C without hydrogen peroxide, even across 48h, also only 28.1% medicine
Thing has been released out, is relatively stable when illustrating the micella of packaging medicine in longer time not by environmental stimulus
's.When hydrogen peroxide content is to be discharged under conditions of 0.5% (w/w) is present at 37 DEG C, by 48h, there is 50.9% DOX
It has been released out, although this is due to the presence of hydrogen peroxide so that the host-guest inclusion of cyclodextrin and ferrocene is disintegrated, has entered one
Step causes supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD to disintegrate as mPEG-Fc+Homopolymer and PNIPAM- β-CD are equal
Polymers, can be due to system temperature still on PNIPAM LCST, therefore, it is thin using PNIPAM newly to be formed in system
Aqueous kernel, remaining medicine using β-CD as the secondary micellar structure of hydrophily shell can be continued to wrap up without being released.By two
Incentive condition release profiles are planted to understand, when hydrogen peroxide content is to be discharged under conditions of 0.5%w/w is present at 37 DEG C, warp
24h is crossed, the DOX for having 28.9% has been released out, and the temperature of delivery systme now is down into 25 DEG C, then by 24h, it is useful
61.8% medicine has been released out, and a total of 90.7% DOX has been released out in 48h, this total volume with
It is directly essentially identical in 25 DEG C of total amounts for discharging 48h.But, by being discharged in the presence of present hydrogen peroxide, then the release that cools, hence it is evident that
Ground is avoided directly discharges the burst drug release phenomenon that 48h is present under the conditions of 25 DEG C so that we become the release process to medicine
Obtain more controllable.Therefore, if this medicine-carried system is used for into oncotherapy, due to the presence of EPR effects, the micella for carrying medicine can be with
Tumor tissues are enriched to substantial amounts of after plasma circulation, then at tumor tissues position by the hydrogen peroxide of high concentration
Some drugs are discharged under effect, because phenomenon of burst release is not present in the release of medicine, it is to avoid the acute poison under high concentration medicine
The generation of side effect, after medicament slow release is to a period of time, utilizes fixed point cooling means clinically to tumor locus so that medicine
Thing reaches complete release, and is finally reached raising curative effect, reduces the purpose of toxic side effect.
By drug micelles made from application examples 1 and application examples 2 and homopolymer mPEG-Fc, PNIPAM- β-CD and small molecule
DOX carries out external anti-A549 activity of tumor cells experiment, and effect is as shown in Figure 5.As can be seen that whether homopolymer mPEG-Fc,
PNIPAM- β-CD or the two by the supermolecule block copolymer mPEG-Fc/PNIPAM- β-CD that are self-assembly of, to A549
Being grown in the range of a larger activity for cell suppresses without obvious, even if the concentration of polymer is increased into 500 μ
G/mL, while as can be seen that compared with simple DOX, our carrier micelle maintains the excellent active anticancers of DOX.
Claims (9)
1. a kind of self-assembled supermolecular block copolymer of temperature and the sensitive stimuli-responsive of oxidant, its feature exists
In, described supermolecule block copolymer be the method using the orthogonal self assembly of homopolymer, using cyclodextrin and ferrocene can
The N- of poly glycol monomethyl ether (mPEG-Fc) and beta-cyclodextrin modified that inverse property host-guest recognition reaction modifies ferrocene is different
Propylacrylamide (PNIPAM- β-CD) fetches the supermolecule block copolymer mPEG- constructed by reversible non-covalent bond chain
Fc/PNIPAM-β-CD。
2. self-assembled supermolecular block copolymer as claimed in claim 1, it is characterised in that it is poly- that described ferrocene is modified
Glycol monoethyl ether (mPEG-Fc) has following structural formula A：
N=3-300
Structural formula A.
3. self-assembled supermolecular block copolymer as claimed in claim 1, it is characterised in that it is poly- that described ferrocene is modified
Glycol monoethyl ether (mPEG-Fc) has following structural formula B：
Q=3-300
Structural formula B.
4. self-assembled supermolecular block copolymer as claimed in claim 1, it is characterised in that described beta-cyclodextrin modified
NIPA (PNIPAM- β-CD) has following structural formula C：
P=10-100
Structural formula C.
5. self-assembled supermolecular block copolymer as claimed in claim 1, it is characterised in that the polyethylene glycol of ferrocene modification
The preparation method of monomethyl ether (mPEG-Fc) is included in organic solvent by using DMAP as catalyst, using DCC as coupling agent, warp
The simple esterification for crossing poly glycol monomethyl ether (mPEG) and ferrocenecarboxylic acid (Fc-COOH) is made.
6. self-assembled supermolecular block copolymer as claimed in claim 1, it is characterised in that the polyethylene glycol of ferrocene modification
The preparation method method of monomethyl ether (mPEG-Fc) is included in organic solvent by using NHS as catalyst, using EDC as coupling agent,
By poly glycol monomethyl ether carboxylic acid (mPEG-COOH) and ferrocene amine (Fc-NH2) simple amidation process be made.
7. self-assembled supermolecular block copolymer as claimed in claim 1, it is characterised in that the N- isopropyls of beta-cyclodextrin modified
The preparation method of base acrylamide (PNIPAM- β-CD) is included in organic solvent by with AIBN initiators, being pasted with sulfydryl ring
Smart (β-CD-SH) is chain-transferring agent, with NIPA (NIPAM) for polymerized monomer, by Raolical polymerizable
It is made.
8. the preparation method of a kind of nano-scale micella or vesica, it is characterised in that this method is included institute in claim 1
The supermolecule block copolymer obtained is dissolved in after water, is more than the micella or capsule of the nano-scale needed for being formed at 32 DEG C in temperature
Bubble, the micella or vesica of the secondary nano-scale needed for being formed under conditions of there is oxidant at temperature is more than 32 DEG C.
9. the application of nano-scale micella or vesica in as pharmaceutical carrier described in a kind of claim 8.
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| CN106632850B (en) * | 2016-09-30 | 2018-12-04 | 东莞理工学院 | A kind of redox response type lyotropic liquid crystal material |
| CN106475003B (en) * | 2016-09-30 | 2019-04-02 | 东莞理工学院 | A kind of regulation method of Photocrosslinkable type ferrocenyl surfactant micellar |
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| CN113249109B (en) * | 2021-05-20 | 2022-06-28 | 中国石油大学(华东) | PH value response type ternary composite supermolecule clean fracturing fluid |
| CN114848845B (en) * | 2022-05-11 | 2023-05-16 | 南华大学 | Rhodium complex-based polymer micelle, preparation method thereof and application thereof in cancers |
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