CN108939091A - A kind of crosslinking micella of pH responsiveness and the preparation method and application thereof containing cumarin unit - Google Patents

A kind of crosslinking micella of pH responsiveness and the preparation method and application thereof containing cumarin unit Download PDF

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CN108939091A
CN108939091A CN201810967633.8A CN201810967633A CN108939091A CN 108939091 A CN108939091 A CN 108939091A CN 201810967633 A CN201810967633 A CN 201810967633A CN 108939091 A CN108939091 A CN 108939091A
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micella
crosslinking
responsiveness
crosslinking micella
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李玉玲
卜乐然
张诃娜
许康
杜百祥
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Jiangsu Normal University
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    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
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    • A61K31/365Lactones
    • A61K31/366Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37Coumarins, e.g. psoralen
    • AHUMAN NECESSITIES
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    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/593Polyesters, e.g. PLGA or polylactide-co-glycolide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

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Abstract

A kind of crosslinking micella of the pH responsiveness containing cumarin unit, main chain are the poly- oxazoline of hydrophily pH sensitivity and the amphipathic triblock polymer that hydrophobic polyurethane is constituted, and centre is hydrophobic block, is blocked as the poly- oxazoline of hydrophily.Hydrophobic section is with 5, the hydrophobic polyurethane that bis- (2- the hydroxyl-oxethyl) -4- methylcoumarins (DHEMC) of 7- and diisocyanate polyisocyanate polyaddition obtain, hydrophilic section is the polymer poly oxazoline with pH sensibility, the urethane key connection formed between three block with isocyanate group and hydroxyl condensation.Amphiphilic polymer, which is self-assembled into after micella to be crosslinked under UV photoinduction, obtains the crosslinking micella of stable pH sensitivity.The crosslinking micella is not easy to dissociate in extracellular and blood, and entrapped drug is stablized, and into after tumour cell, quickly dissociates in the acidic environment of lysosome in the cell, discharges drug.The crosslinking micella can improve the deficiency of conventional medicament release system, be expected to become a kind of drug delivery platform of novel target tumor.

Description

A kind of crosslinking micella of pH responsiveness containing cumarin unit and preparation method thereof with Using
Technical field
The invention belongs to chemical synthesis and biomedicine field, a kind of specific nano-micelle of the pH responsiveness of Photocrosslinkable And the preparation method and application thereof.
Background technique
One of biggest threat as human health, global cancer morbidity sustainable growth.Currently, operation excision lesion group Knit be still general clinical treatment malignant tumour main method, but patient is postoperative easy to recur, the shortcomings that cancer cell easily shifts occurs. Therefore, it is necessary to long-term and continuous administration chemotherapeutics to reduce risk of recurrence.But most of anticancer drugs such as taxol, how soft ratio Star and fluorouracil etc. have the shortcomings that high toxicity, stability are poor, dissolubility is poor, are difficult to accumulate in tumor locus, swollen killing Huge damage is caused to normal cell when oncocyte, so as to cause serious toxic side effect.Therefore, chemotherapeutant is improved in water In solubility and stability and their targeting ability be the key that research and develop effective cancer treatment method at present.? In past decades, a variety of nano-carriers for biomedical applications, such as micella, nanoparticle, vesica have been had already appeared And nanogel.In various carrier materials, polyurethane (PU) is readily synthesized with it, high stability and good biocompatibility The advantages that in drug delivery field cause numerous concerns.
The various polymer (Du, X.X, et al.Polym.Chem.2014,5,5300-5309) of amphipathic PU can be very It is easily self-assembled into micella, and drug is integrated into hydrophobic core.Therefore the secondary of conventional medicine can be greatly reduced to make With, and their water solubility can be enhanced, so as to improve their effects in tumor tissues.But amphipathic polymer micella In vivo circulation administration when due to by body fluid Macrodilution and with the interaction of blood so that carrier micelle reach tumour portion It is just destroyed before position, leads to premature release drug, to reduce therapeutic effect and cause a series of side effects.Therefore increase Carrier micelle stability is vital in drug delivery field.And developing chemical crosslinking micella is a kind of increase load medicine glue The available strategy of beam stability.
Summary of the invention
The object of the present invention is to provide a kind of nano-micelles of the pH responsiveness of Photocrosslinkable, to solve amphipathic polymer glue The problem of beam discharges drug too early, causes drug effect low and side effect when recycling administration in vivo.
To achieve the above object, technical scheme is as follows:
A kind of crosslinking micella of the pH responsiveness containing cumarin unit, including hydrophilic outer layer and hydrophobic inner core, it is hydrophobic interior Core hydrophobic polyurethane as obtained by bis- (2- the hydroxyl-oxethyl) -4- methylcoumarins of 5,7- and diisocyanate polyisocyanate polyaddition is crosslinked structure At.
Further, the hydrophilic outer layer is poly- oxazoline, and poly- oxazoline molecular weight is 1000~10000Da.
Further, the diisocyanate is that cystamine diisocyanate, L-lysine ethyl ester diisocyanate or six are sub- Methyl diisocyanate.
Further, the unit number of bis- (2- the hydroxyl-oxethyl) -4- methylcoumarins of 5, the 7- is 5~50.
The present invention also provides the preparation methods of the crosslinking micella of the pH responsiveness of Photocrosslinkable, comprising steps of
S1: using stannous octoate as catalyst, 5,7- bis- (2- hydroxyl-oxethyl) -4- methylcoumarins and diisocyanate contracting It is poly- to obtain hydrophobic polyurethane performed polymer, then base polyurethane prepolymer for use as is blocked with hydrophilic terminal hydroxy group poly- oxazoline, Obtain the amphipathic urethane of bis- (2- hydroxyl-oxethyl) -4- methylcoumarin unit numbers Han different 5,7-;
S2: amphipathic urethane is molten in organic solvent, deionized water is instilled under the conditions of being stirred at room temperature, by from group Dress forms nano-micelle;
S3: being irradiated nano-micelle using the ultraviolet light that wavelength is 365nm or more, forms crosslinking micella.
Further, the time of the ultraviolet light in the step S3 is 2~8 hours.
Application the present invention also provides the crosslinking micella of the pH responsiveness of Photocrosslinkable as pharmaceutical carrier.
Further, the crosslinking micella is one of following condition as the degradation condition of pharmaceutical carrier:
(1) intracellular acidic environment;
(2) the following ultraviolet light of wavelength 300nm;
(3) intracellular acidic environment and the following ultraviolet light of wavelength 300nm.
Further, the drug is the drug for the treatment of cancer.
Compared with prior art, beneficial effects of the present invention:
A kind of crosslinking micella of pH responsiveness containing cumarin unit of the invention, hydrophobic part contain the bis- (2- of 5,7- Hydroxyl-oxethyl) -4- methylcoumarin, the micella that amphipathic polymer can be made to be self-assembly of by ultraviolet light is crosslinked, obtains To the polymer micelle for the pH sensitivity for stablizing crosslinking, which is not easy to dissociate in extracellular and blood, to guarantee micella packet The drug substance stable of envelope;It overcomes drug to be easily compromised in vivo, deliver the deficiencies of low efficiency, can be used as ideal pharmaceutical carrier; After crosslinking micella enters tumour cell, the pH sensibility of carrier micelle dissociates micella quickly, and drug quick release comes out, from And improve the therapeutic effect of drug;A kind of crosslinking micella of pH responsiveness containing cumarin unit of the invention has good PH and optical Response can degrade in 300nm or less ultraviolet light, have potential application prospect in the treatment of cancer; A kind of preparation method of the crosslinking micella of pH responsiveness containing cumarin unit of the invention, preparation process is simple, condition temperature With, it is at low cost, it is suitable for large-scale production.
Specific embodiment:
The synthesis of bis- (2- the hydroxyl-oxethyl) -4- methylcoumarins (DHEMC) of embodiment one: 5,7-
DHEMC is the monomer of hydrophobic synthetic polyurethane, is synthesized by two steps:
(1) 5,7- dihydroxy -4- methylcoumarin (DHMC) is synthesized first, by phloroglucin (NA, 12.6g, 0.1mol) It is added in Isosorbide-5-Nitrae-dioxanes of 60mL with ethyl acetoacetate (ACE, 13.0g, 0.1mol), then slowly adds in the mixture Enter the 3mL concentrated sulfuric acid, heat 1h at 65 DEG C, puts to room temperature.Precipitating in the ice water of reaction solution addition 300mL is obtained yellowish Precipitating, filtering are dried in vacuo crude product, are recrystallized twice with ethyl acetate, finally obtain white crystal DHMC.
(2) under continuous stirring, DHMC (0.86g, 4.47mmol) is dissolved in 10mL DMF, K is added thereto2CO3 (6.30g,0.0456mol).Ethylene bromohyrin (1.67g, 13.4mmol) is dissolved in 5mL DMF, is slowly added dropwise in 15min Into above-mentioned mixed liquor.Make reaction solution under conditions of having nitrogen protection, 18h is reacted in 85 DEG C, is then cooled to room temperature.To mixed It closes and 20mL dehydrated alcohol is added in liquid, and inorganic salts are filtered out, be concentrated to get brown oil liquid.It is pure with silica gel column chromatography Change crude product, obtains white crystal 5, bis- (2- the hydroxyl-oxethyl) -4- methyl -2H-1- chromen-2-ones (DHEMC) of 7-.It produces Rate: 79%.
Embodiment two: the synthesis (Mn=5000Da) of polymer P EtOz-OH
Hydrophilic section polymer blocks the preparation of poly- oxazoline PEtOz-OH, and synthesis is under nitrogen protection, to toluene sulphur Sour methyl esters ring-opening polymerisation 2- ethyl -2- oxazoline.Concrete operations are as follows:
Methyl tosylate (0.34g, 1.83mmol) and 2- ethyl -2- oxazoline are added in dry acetonitrile Mixture is heated to 100 DEG C and is stirred to react for 24 hours by (10.00g, 100.90mmol).It is cooled to room temperature, adds after reaction Enter 0.10mL KOH (1N) and 4h is stirred at room temperature, with ice ether sedimentation separation.By polymer P EOZ-OH deionized water dialysis (MWCO:3500g/mol) it purifies, it is finally freeze-dried to obtain product PEtOz-OH.Yield: 87.6%.
Embodiment three: synthetic polymer (PEtOz-PU (DHEMC-LDI)-PEtOz) (Mn=14.7kDa)
Under argon gas protection, DHEMC (0.14g, 0.50mmol) is dissolved in 10mL DMF, is added to three mouthfuls of burnings of 50mL In bottle, lead under condition of nitrogen gas, successively by LDI (0.12g, 0.53mmol) and Sn (Oct)2(12mg) is added in reaction flask, 65 DEG C oil bath in react 24 hours, be cooled to room temperature after reaction.
The PEtOz-OH being dissolved in 5mL DMF is instilled in the polyurethane solutions upward obtained under the conditions of nitrogen protection (0.25g, 0.05mmol) solution is deposited in cold ether, sediment second after reaction being stirred at room temperature later 48 hours Ether-methanol solution washing is multiple.Vacuum drying 48 hours, yield 63%.Nuclear-magnetism is the result shows that its structure is (PEtOz-PU (DHEMC-LDI)-PEtOz), wherein DHEMC unit number is 14.
Example IV: control group polyethylene glycol urethane-polyethylene glycol PEG-PU (DHEMC-LDI)-PEG synthesis.
The synthetic method and polymer P EtOz-PU of polymer P EG-PU (DHEMC-LDI)-PEG as a control group (DHEMC-LDI)-PEtOz's is identical, but used the terminal hydroxy group polyethylene glycol PEG-OH without pH sensitivity replace PEtOz-OH as Hydrophilic section.
Embodiment five: the preparation of (PEtOz-PU (DHEMC-LDI)-PEtOz) (Mn=14.7kDa) micella
The micella of polymer P EtOz-PU (DHEMC-LDI)-PEtOz is prepared by dialysis process.Detailed process is: will 2mg polymer P EtOz-PU (DHEMC-LDI)-PEtOz is dissolved in 1mL dimethyl sulfoxide, under 25 DEG C of stirring conditions, is dripped thereto Add 1.5mL deionized water.Obtain solution stirring 1h after, be packed into bag filter (SPECTRA/POR, MWCO:3500) in, spend from Sub- water dialysis is for 24 hours.
The preparation of embodiment six: PEG-PU (DHEMC-LDI)-PEG micella
Polymer P EG-PU (DHEMC-LDI)-PEG micella is prepared by dialysis process.Detailed process is: 2mg is polymerize Object PEG-PU (DHEMC-LDI)-PEG is dissolved in 1mL dimethyl sulfoxide, under 25 DEG C of stirring conditions, thereto be added dropwise 1.5mL go from Sub- water.Obtained solution is packed into bag filter (SPECTRA/POR, MWCO:3500), for 24 hours with deionized water dialysis.
The polymer of different hydrophilic section is prepared according to embodiment three and example four, and tests resulting polymers in the nanometer of formation The size and distribution of particle, the results are shown in Table 1:
The urethane micelle characterization containing cumarin unit of 1 different hydrophilic section of table
The crosslinking of embodiment seven: PEtOz-PU (DHEMC-LDI)-PEtOz (Mn=14.7kDa) micella
The polymer micelle being crosslinked in order to obtain, by (0.1 milligram/milli of the polymer nano micelle formed in example IV Rise) it is irradiated 6 hours under the ultraviolet light of 365nm, the nano-micelle being crosslinked.The nano-particles size of crosslinking is 168 nanometers, Particle diameter distribution is 0.16, and to high dilution (simulation is injected intravenously), physiology salinity (150mM), organic solvent (DMSO) has significantly Stability.
The crosslinking of embodiment eight: PEG-PU (DHEMC-LDI)-PEG micella
The polymer micelle being crosslinked in order to obtain exists the polymer nano micelle (0.1mg/mL) formed in embodiment five It is irradiated 6 hours under the ultraviolet light of 365nm.The micella being crosslinked.Having a size of 184.0 nanometers, particle diameter distribution is the micella of crosslinking 0.08, to high dilution (simulation is injected intravenously), physiology salinity (150mM), organic solvent (DMSO) has significant stability.
The crosslinking micella of the polymer of different hydrophilic section is prepared according to embodiment seven, and tests the ruler of the crosslinking micella of formation Very little and distribution, the results are shown in Table 2:
The urethane crosslinks micella containing DHEMC of 2 different hydrophilic section of table
Embodiment nine: the degradation of PEtOz-PU (DHEMC-LDI)-PEtOz micella under acidic environment
Polymer P EtOz-PU (DHEMC-LDI)-PEtOz micella (0.1mg/mL) is divided into two parts, the pH of a copy of it Value acetate buffer solution is adjusted to 5.0, another is as control.Then two parts of micellas are placed in sample cell, in 37 DEG C of constant temperature It is shaken up in shaking table (200rpm), surveys the variation of micellar particle size by DLS at seclected time, 37 DEG C.DLS is the results show that pH Under the conditions of 5.0, PEtOz-PU (DHEMC-LDI)-PEtOz micella partial size after 4h by 168nm increases to 266nm, reaches after 8h 913nm.And partial size is basically unchanged control group micella after 24h, illustrates that this urethane micelle has good pH responsiveness, in pH Under conditions of 5.0, micella is swollen, and partial size is caused to increase.
The solution of lower PEtOz-PU (the DHEMC-LDI)-PEtOz micella of ten: 254nm ultraviolet light of embodiment is crosslinked
PEtOz-PU (DHEMC-LDI)-PEtOz micella (0.1mg/mL) after crosslinking is divided into two parts, a copy of it is used 254nm ultraviolet light 6h, another is as control.Then two parts of micellas are diluted 100 times to be placed in sample cell respectively, is shaken Survey the variation of micellar particle size after even by DLS at 37 DEG C.DLS is the results show that with the PEtOz- of 254nm ultraviolet light 6h PU (DHEMC-LDI)-PEtOz micella after dilution after partial size 319nm increased to by 168nm, and control group partial size is before dilution It is almost unchanged afterwards.Illustrate that this urethane micelle has good optical Response, after 254nm ultraviolet light 6h, micella crosslinking is broken It is bad, it is swollen after dilution, partial size is caused to increase.
After 11: 254nm ultraviolet lighting of embodiment, (DHEMC-LDI-PEtOz micella is under acidic environment by PEtOz-PU Degradation
By PEtOz-PUDHEMC-LDI-PEtOz micella (0.1mg/mL) the 254nm ultraviolet light 6h after crosslinking, it Its pH value acetate buffer solution is adjusted to 5.0 afterwards.Then micella is placed in sample cell, in 37 DEG C of constant-temperature tables (200rpm) In shake up, the variation of micellar particle size is surveyed by DLS at seclected time, 37 DEG C.DLS the results show that under the conditions of pH 5.0, PEtOz-PU (DHEMC-LDI-PEtOz micella partial size after 2h by 168nm increases to 442nm, after 5h partial size not only increase and point It splits for two peaks.Compared with the experimental group in embodiment nine and embodiment ten, the variation of micella under the double action of light and acid Faster also more acutely, illustrate that this urethane micelle has good pH and an optical Response, after 254nm ultraviolet light 6h, micella is handed over Connection destroys, and later under conditions of 5.0 pH, micella occurs to be swollen and crack, and causes partial size to increase and the division at peak occurs.
Embodiment 12: packing model small molecule anticancer drug adriamycin and its pH triggering release
Packing model small molecule anticancer drug adriamycin: 2mg polymer P EtOz-PU (DHEMC-LDI)-PEtOz (Mn= It 14.7kDa) is dissolved in dimethyl sulfoxide with 0.2mg adriamycin, under 25 DEG C of stirring conditions, 1.5mL deionization is added dropwise thereto Water.After obtained solution stirring 1h, it is small with deionized water dialysis 24 that (SPECTRA/POR, MWCO:3500) is fitted into bag filter When.
The determination of encapsulation rate of the DOX in polymer nano-particle: a certain amount of crosslinking and uncrosslinked carrier micelle are taken Solution is freeze-dried, and 0.5mLDMSO dissolution is then added, carries out fluorometric investigation after taking a certain amount of solution to dilute, in conjunction with The standard curve computational envelope rate of adriamycin.
Encapsulation rate=(quality of quality/investment adriamycin of adriamycin in micella) × 100%
The nano-micelle of the two kinds of polymer of different drugloading rates is prepared, and tests the size of gained nano-micelle, distribution And encapsulation rate etc., the results are shown in Table 3:
The nano-micelle of the different drugloading rate of 3 two kinds of polymer of table characterizes
PH triggering release: the nano-micelle for being loaded with DOX is divided into two parts, is fitted into corresponding bag filter, the former immerses In the acetate buffer solution (10mM, pH 5.0) of 40mL, the latter is dipped into the PB (10mM, pH 7.4) of 40mL, is placed in 37 DEG C of perseverances In warm shaking table (200rpm).Dialyzate outside the bag filter that certain time takes setting volume, and supplement the fresh of respective volume Liquid is persistently tested 24 hours.The fluorescence intensity for measuring dialyzate, calculates the cumulative release amount of DOX.
The result shows that being loaded with polymer P EtOz-PU (the DHEMC-LDI)-PEtOz carrier micelle of DOX in PB (10mM, pH 7.4) in for 24 hours in only release 10% drug.And in the acetate buffer solution (10mM, pH 5.0) for simulating intracellular lysosome Under environment, carrier micelle can rapidly release up to 63% DOX.And the non-pH sensitivity PEtOz-PU as control (DHEMC-LDI) it even if-PEtOz carrier micelle (10mM, pH=5.0) in acetate buffer solution, is also only released interior for 24 hours 8% DOX.The experimental results showed that PEtOz-PU (DHEMC-LDI)-PEtOz carrier micelle has responsiveness to intracellular environment, Drug quickly can be discharged in environment in vivo, to improve curative effect of medication.

Claims (9)

1. a kind of crosslinking micella of the pH responsiveness containing cumarin unit, including hydrophilic outer layer and hydrophobic inner core, feature exist In hydrophobic inner core hydrophobicity obtained by bis- (2- the hydroxyl-oxethyl) -4- methylcoumarins of 5,7- and diisocyanate polyisocyanate polyaddition is poly- Urethane crosslinking is constituted.
2. a kind of crosslinking micella of pH responsiveness containing cumarin unit according to claim 1, which is characterized in that institute Stating hydrophilic outer layer is poly- oxazoline, and poly- oxazoline molecular weight is 1000~10000Da.
3. a kind of crosslinking micella of pH responsiveness containing cumarin unit according to claim 1, which is characterized in that institute Stating diisocyanate is cystamine diisocyanate, L-lysine ethyl ester diisocyanate or hexamethylene diisocyanate.
4. a kind of crosslinking micella of pH responsiveness containing cumarin unit according to claim 1, which is characterized in that institute The unit number for stating bis- (2- the hydroxyl-oxethyl) -4- methylcoumarins of 5,7- is 5~50.
5. a kind of preparation method of the crosslinking micella of the pH responsiveness containing cumarin unit described in any of the above claim, Characterized in that it comprises the following steps:
S1: using stannous octoate as catalyst, 5,7- bis- (2- hydroxyl-oxethyl) -4- methylcoumarins and diisocyanate polycondensation are obtained To hydrophobic polyurethane performed polymer, then base polyurethane prepolymer for use as is blocked with hydrophilic terminal hydroxy group poly- oxazoline, is obtained The amphipathic urethane of bis- (2- hydroxyl-oxethyl) -4- methylcoumarin unit numbers containing different 5,7-;
S2: amphipathic urethane is molten in organic solvent, deionized water is instilled under the conditions of being stirred at room temperature, passes through self assembly shape At nano-micelle;
S3: being irradiated nano-micelle using the ultraviolet light that wavelength is 365nm or more, forms crosslinking micella.
6. a kind of preparation method of the crosslinking micella of pH responsiveness containing cumarin unit according to claim 5, It is characterized in that, the time of the ultraviolet light in the step S3 is 2~8 hours.
7. a kind of crosslinking micella for the pH responsiveness for containing cumarin unit described in claim 1,2,3 or 4 is carried as drug The application of body.
8. a kind of crosslinking micella of pH responsiveness for containing cumarin unit according to claim 7 is as pharmaceutical carrier Using, which is characterized in that the crosslinking micella is one of following condition as the degradation condition of pharmaceutical carrier:
(1) intracellular acidic environment;
(2) the following ultraviolet light of wavelength 300nm;
(3) intracellular acidic environment and the following ultraviolet light of wavelength 300nm.
9. a kind of crosslinking micella of pH responsiveness for containing cumarin unit according to claim 7 is as pharmaceutical carrier Using, which is characterized in that the drug is the drug for the treatment of cancer.
CN201810967633.8A 2018-08-23 2018-08-23 A kind of crosslinking micella of pH responsiveness and the preparation method and application thereof containing cumarin unit Pending CN108939091A (en)

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