CN108078924A - A kind of preparation method of polyethyleneglycol modified high drug load nano-micelle or vesica with pH responses - Google Patents
A kind of preparation method of polyethyleneglycol modified high drug load nano-micelle or vesica with pH responses Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
Abstract
The invention belongs to high molecular materials and biomedical engineering field, and in particular to a kind of preparation method of polyethyleneglycol modified high drug load nano-micelle or vesica with pH responses.Specific method is：The Doxorubicin reaction of polyethylene glycol and cis-aconitic acid anhydride modification is generated into amphiphilic block copolymer, is formed using anti-cancer drug doxorubicin as hydrophobic chain segment, using polyethylene glycol as the high drug load nano-micelle or vesica with pH responses of hydrophilic segment.This nano-micelle or vesica are using anticancer drug as hydrophobic segment, thus with higher drugloading rate, simultaneously, cis-aconitic anhydride acid labile, therefore nano-micelle obtained or vesica have pH responses, suitable for therapeutic field of tumor, chemotherapy efficiency can be improved, reduces the toxic side effect of anticancer drug normal tissue.
Description
Technical field
The invention belongs to high molecular materials and biomedical engineering field, and in particular to a kind of polyethyleneglycol modified has
The nano-micelle of the high drug load of pH responses or the preparation method of vesica.
Background technology
Polyethylene glycol (PEG) is a kind of polymer of good biocompatibility, have it is good it is water-soluble, it is nontoxic it is non-stimulated,
The features such as immunogenicity is low can be excreted by kidney, will not be accumulated in vitro, therefore be widely used in biomedical sector.
Due to polyethylene glycol have good blood compatibility, therefore be usually used in drug release carrier, biomaterial surface changes
Property, tissue engineering material etc..Polyethylene glycol as amphipathic nature block polymer prepared by raw material as pharmaceutical carrier when,
Itself forms medicinal composition without pharmacological action during drug can be wrapped up by self assembly into polymer or with covalent key connection.This
Kind block copolymer plays a crucial role in medicine controlled release carrier, and after drug release, macromolecule carrier will not be in body
Interior long time integration, but discharge or absorbed after hydrolyzing.
At present, the amphipathic copolymer of polyethylene glycol groups can be self-assembled into efficient pharmaceutical carrier in several ways,
And be loaded in interior molecule, cover plasmid-DNA, Fluoresceincarboxylic acid, hydrophobic antitumor drug, hydrophilic drug or
Protein and for inorganic nano-particle for diagnosing/treating etc..
Most traditional antitumor drug is non-selective agent, without targeting effect, therefore in most cases to normal
There are larger lethality for cell.To improve curative effect of medication, toxic side effect is reduced, chemotherapeutics is often now placed in polymer latex
In the self-assemblies such as beam, vesica, liposome, with it is expected play to medicament slow release, control action and diseased region is targeted to
Medicine improves the effects that drugloading rate.Meanwhile control slow releasing function, nano vesicle, micella to environment-responsive etc. to improve drug
Research it is more and more extensive, such as sugared response, pH responses, temperature-responsive.
At present, researchers are to further improve nano-particle drugloading rate, reduce toxic side effect of the drug to normal cell,
Often using good biocompatibility, the polymer-modified antitumor drug of nonhazardous, it is expected to further improve the chemotherapy of tumour
It is horizontal.Antitumor drug adriamycin and camptothecine are connected respectively on hydrophilic radical by Marina Shamis etc., and in the other end
Organized enzyme 38C2 is accessed, to improve drugloading rate and bioactivity (J. Am. Chem. Soc. 2004,126,6)；Shen Youqing etc.
The polyethylene glycol of camptothecin drug and low polymerization degree is reacted into generation amphipathic nature block polymer, then by being self-assembly of capsule
Steep simultaneously packaging medicine adriamycin (J. Am. Chem. Soc. 2010,132,4259-4265)；Min Hee Lee etc. by 1,
8- naphthalimides connect camptothecine, other end connection RGD rings as fluoroscopic examination position, and in its one end by disulfide bond
Peptide is successfully realized targets identification, detection and the oncotherapy of oncotherapy in one (J. Am. as targeting unit
Chem. Soc. 2012, 134, 12668−12674)。
In the present invention, we are by the use of the good polyethylene glycol of biocompatibility as hydrophilic section, and drug doxorubicin is as thin
Water section prepares amphiphilic block copolymer, and introduces to the more sensitive cis-aconitic anhydrides of pH, and nanometer is obtained by self assembly
Micella and vesica so as to improve the drugloading rate of Conventional nano particle, and improve the control ability to drug release, reduce to human body
The toxic action of normal structure.
The content of the invention
It is an object of the invention to provide a kind of polyethyleneglycol modified high drug load nano-micelles with pH responses
Or the preparation method of vesica.
The purpose of the present invention is react to form amphiphilic block copolymerization by polyethylene glycol and anti-cancer drug doxorubicin
Then object is self-assembly of nano-micelle and vesica, break through the defects of original nano-particle drugloading rate is low.Present invention employs
Polyethylene glycol is hydrophilic chain, and anti-cancer drug doxorubicin is hydrophobic chain, is prepared for a series of high drug loads with pH responses
Nano-micelle and vesica.
A kind of polyethyleneglycol modified high drug load nano-micelle or vesica with pH responses proposed by the present invention
Preparation method is as follows：
(1) it is 1 in molar ratio by poly glycol monomethyl ether and succinic anhydride：The ratio of (1 ~ 2) is dissolved in tetrahydrofuran, and 75
After when DEG C reflux 12 ~ 48 is small, precipitate 2 ~ 3 times, filter in precipitating reagent A, filter cake is dried under vacuum to constant weight, obtains end carboxyl and modifies
Polyethylene glycol；
(2) it is 1.3 in molar ratio by pentaerythrite, catalyst 4-dimethylaminopyridine and dicyclohexylcarbodiimide：4：0.3
Ratio be dissolved in solvent B, be made into pentaerythrite solution；The polyethylene glycol that the end carboxyl that step (1) is obtained again is modified is molten
Solution is added drop-wise in solvent B, and with extremely slow speed in the pentaerythrite solution, is sufficiently stirred 2 ~ 3 days；In precipitating reagent A
Middle to precipitate 2 ~ 3 times, filtering, filter cake is dried under vacuum to constant weight, obtains the polyethylene glycol of trihydroxy modification；
(3) doxorubicin hydrochloride is dissolved in the doxorubicin hydrochloride aqueous solution that 3.33-6.66g/L is made into deionized water, then will
Cis-aconitic anhydride is dissolved in the solution that 5-10g/L is made into dioxane, and is added drop-wise to dropwise in doxorubicin hydrochloride aqueous solution,
During which stirring adjusts the pH value of solution as 8.4-8.6 using the sodium hydroxide solution of 0.5M；React 24 it is small when, the hydrochloric acid of 1mol/L
It has been acidified to precipitation to generate, ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration is spin-dried for, dry, obtains the how soft of carboxylic acid modification
Compare star；
(4) by Doxorubicin, the catalyst 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne two of carboxylic acid modification obtained by step (3)
Inferior amine salt hydrochlorate and 4-dimethylaminopyridine are dissolved in 10mL anhydrous dimethyl sulphoxides, and stirring forms Doxorubicin solution；Again will
The polyethylene glycol of trihydroxy modification obtained by step (2) is dissolved in 5mL anhydrous dimethyl sulphoxides, and is added drop-wise to dropwise described how soft
Than in star solution, be protected from light 24 it is small when.The Doxorubicin of carboxylic acid modification, the Doxorubicin of trihydroxy modification, catalyst 1- second
Base-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate and 4-dimethylaminopyridine molar ratio are 1：4：3：0.3.With
The bag filter of 3.5KDa is dialysed 2 ~ 3 days, and freeze-drying obtains amphipathic nature block polymer；
(5) amphipathic nature block polymer obtained by step (4) is dissolved in dimethyl sulfoxide (DMSO), is instilled dropwise under ultrasound condition
In deionized water, to get the polyethyleneglycol modified high drug load nano-micelle or capsule with pH responses after dialysing 2 ~ 3 days
Bubble.
In the present invention, the range of number-average molecular weight of poly glycol monomethyl ether described in step (1) is 550 ~ 5000.
In the present invention, precipitating reagent A is any in methanol, ether, n-hexane or petroleum ether described in step (1) and (2)
Kind.
In the present invention, solvent B described in step (2) is dichloromethane, chloroform, tetrahydrofuran, dimethyl sulfoxide (DMSO), two
It is any in methylformamide or dimethyl acetamide.
The beneficial effects of the present invention are：Cis-aconitic anhydride is accessed during preparing amphipathic nature block polymer, it can
Effectively improve release of the chemotherapeutics in tumour cell；And anticancer drug with polymer chemistry is bonded is effectively improved nanometer
The drugloading rate of micella, the efficiency and the selectivity to chemotherapy tissue for improving oncotherapy.
Description of the drawings
Fig. 1：For embodiment 1 prepare polyethylene glycol-Doxorubicin amphipathic nature block polymer structural formula with1H NMR
Spectrogram；
Fig. 2：For the TEM photos of the polyethyleneglycol modified high drug load nano vesicle with pH responses prepared by embodiment 2.
Fig. 3：For the TEM of the polyethyleneglycol modified high drug load nano-micelle with pH responses prepared by embodiment 3
Photo.
Specific embodiment
Said program is described further below in conjunction with specific embodiment.It is to be understood that these embodiments are for illustrating
The present invention and be not limited to limit the scope of the invention.The implementation condition used in embodiment can be done according to the condition of specific producer
Further adjustment, the implementation condition being not specified is usually the condition in routine experiment.
Embodiment 1：
Poly glycol monomethyl ether 0.75g, 0.12 g of succinic anhydride that molecular weight is taken to be 750 are dissolved in 30ml tetrahydrofurans, and 75
When DEG C reflux 12 is small, ether precipitates 3 times, and filtering, filter cake is dried under vacuum to constant weight, obtains the polyethylene glycol of end carboxyl modification；It takes
Pentaerythrite 34.0mg, 4-dimethylaminopyridine 0.13g and dicyclohexylcarbodiimide 0.61g, which are dissolved in 10ml dichloromethane, to be matched somebody with somebody
Into pentaerythrite solution, the polyethylene glycol 0.75g that end carboxyl is modified is dissolved in 10ml dichloromethane, is dripped with extremely slow speed
It is added in pentaerythrite solution, is sufficiently stirred 2 days, ether precipitates 3 times, filtering, and filter cake vacuum drying constant weight obtains trihydroxy and repaiies
The polyethylene glycol of decorations；Doxorubicin hydrochloride 50mg is taken to be dissolved in 10ml deionized waters and is made into aqueous solution, cis-aconitic anhydride 50mg
It is dissolved in 10ml dioxane, and is added drop-wise to dropwise in Doxorubicin aqueous solution, during which adjusted with the sodium hydroxide solution of 0.5M
System pH is 8.5 or so, and when reaction 24 is small, 1mol/L hydrochloric acid has been acidified to precipitation, ethyl acetate extraction, and anhydrous sodium sulfate is done
Dry, filtering, filtrate is spin-dried for, and vacuum drying obtains the Doxorubicin of end carboxylic acid modification；Take the Doxorubicin of end carboxylic acid modification
70.0mg, catalyst 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate 57.4mg and 4-dimethylaminopyridine
12.2mg is dissolved in 10ml anhydrous dimethyl sulphoxides, and stirring forms Doxorubicin solution.Triatomic polyethylene glycol 32.9mg is molten
In 5ml anhydrous dimethyl sulphoxides, instill dropwise in Doxorubicin solution, be protected from light 24 it is small when after, with the bag filter of 3.5KDa
Dialysis 3 days, freeze-drying, obtains amphiphilic polyethylene glycol-Doxorubicin amphipathic nature block polymer；Taking polyethylene glycol-more
It is soft to be dissolved in than star block copolymer 5mg in 1ml dimethyl sulfoxide (DMSO)s, it is added dropwise under ultrasound condition into the deionized water of 5ml, dialysis 3
The high drug load nano vesicle with pH responses is obtained after it.
Through transmission electron microscope observing, the high drug load nano vesicle size obtained with pH responses is homogeneous, is uniformly dispersed.
Embodiment 2：
Poly glycol monomethyl ether 1.0g, 0.16 g of succinic anhydride that molecular weight is taken to be 1000 are dissolved in 30ml tetrahydrofurans, and 75
When DEG C reflux 12 is small, methanol extraction 3 times, filtering, filter cake is dried under vacuum to constant weight, obtains the polyethylene glycol of end carboxyl modification；It takes
Pentaerythrite 34.0mg, 4-dimethylaminopyridine 0.13g and dicyclohexylcarbodiimide 0.61g, which are dissolved in 10ml chloroforms, to be matched somebody with somebody
Into pentaerythrite solution, the polyethylene glycol 1.0g that end carboxyl is modified is dissolved in 10ml chloroforms, is dripped with extremely slow speed
It is added in pentaerythrite solution, is sufficiently stirred 2 days, ether precipitates 3 times, filtering, and filter cake vacuum drying constant weight obtains trihydroxy and repaiies
The polyethylene glycol of decorations；Doxorubicin hydrochloride 50.0mg is taken to be dissolved in 10ml deionized waters and is made into aqueous solution, cis-aconitic anhydride
50.0mg is dissolved in 10ml dioxane, and is added drop-wise to dropwise in Doxorubicin aqueous solution, during which molten with the sodium hydroxide of 0.5M
Liquid regulation system pH is 8.5 or so, and when reaction 24 is small, 1mol/L hydrochloric acid has been acidified to precipitation, ethyl acetate extraction, anhydrous slufuric acid
Sodium is dried, and filtering, filtrate is spin-dried for, and vacuum drying obtains the Doxorubicin of end carboxylic acid modification；Take the Doxorubicin of end carboxylic acid modification
70.0mg, catalyst 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate 57.4mg and 4-dimethylaminopyridine
12.2mg is dissolved in 10ml anhydrous dimethyl sulphoxides, and stirring forms Doxorubicin solution.Triatomic polyethylene glycol 32.9mg is molten
In 5ml anhydrous dimethyl sulphoxides, instill dropwise in Doxorubicin solution, be protected from light 24 it is small when after, with the bag filter of 3.5KDa
Dialysis 3 days, freeze-drying, obtains amphiphilic polyethylene glycol-Doxorubicin amphipathic nature block polymer；Taking polyethylene glycol-more
It is soft to be dissolved in than star block copolymer 5.0mg in 1ml dimethyl sulfoxide (DMSO)s, it is added dropwise into the deionized water of 5ml, dialyses under ultrasound condition
The high drug load nano vesicle with pH responses is obtained after 3 days.
Through transmission electron microscope observing, the high drug load nano vesicle size obtained with pH responses is homogeneous, is uniformly dispersed.
Embodiment 3：
Poly glycol monomethyl ether 2.0g, 0.16 g of succinic anhydride that molecular weight is taken to be 2000 are dissolved in 30ml tetrahydrofurans, and 75
When DEG C reflux 12 is small, n-hexane precipitates 3 times, and filtering, filter cake is dried under vacuum to constant weight, obtains the polyethylene glycol of end carboxyl modification；
Pentaerythrite 34.0mg, 4-dimethylaminopyridine 0.13g and dicyclohexylcarbodiimide 0.61g is taken to be dissolved in 10ml dimethyl formyls
Pentaerythrite solution is made into amine, the polyethylene glycol 0.75g that end carboxyl is modified is dissolved in 10ml dimethylformamides, with extremely slow
Slow speed is added drop-wise in pentaerythrite solution, is sufficiently stirred 2 days, and n-hexane precipitates 3 times, filtering, filter cake vacuum drying constant weight,
Obtain the polyethylene glycol of trihydroxy modification；Doxorubicin hydrochloride 50.0mg is taken to be dissolved in 10ml deionized waters and is made into aqueous solution, it is suitable
Formula aconitic anhydride 50.0mg is dissolved in 10ml dioxane, and is added drop-wise to dropwise in Doxorubicin aqueous solution, during which with 0.5M's
Sodium hydroxide solution regulation system pH is 8.5 or so, and when reaction 24 is small, 1mol/L hydrochloric acid has been acidified to precipitation, ethyl acetate extraction
It takes, anhydrous sodium sulfate drying, filtering, filtrate is spin-dried for, and vacuum drying obtains the Doxorubicin of end carboxylic acid modification；Take end carboxylic acid modification
Doxorubicin 70.0mg, catalyst 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate 57.4mg and 4- bis-
Methylamino pyridine 12.2mg is dissolved in 10ml anhydrous dimethyl sulphoxides, and stirring forms Doxorubicin solution.Triatomic poly- second two
Alcohol 32.9mg is dissolved in 5ml anhydrous dimethyl sulphoxides, dropwise instill Doxorubicin solution in, be protected from light 24 it is small when after, use
The bag filter of 3.5KDa is dialysed 3 days, and freeze-drying obtains amphiphilic polyethylene glycol-Doxorubicin amphipathic nature block polymer；
Taking polyethylene glycol-Doxorubicin block copolymer 5.0mg is dissolved in 1ml dimethyl sulfoxide (DMSO)s, is added dropwise into 5ml and is gone under ultrasound condition
In ionized water, dialysis obtains the high drug load nano-micelle with pH responses after 3 days.
Through transmission electron microscope observing, the high drug load nano-micelle size obtained with pH responses is homogeneous, is uniformly dispersed.
Embodiment 4：
Poly glycol monomethyl ether 3.0g, the succinic anhydride 0.18g that molecular weight is taken to be 3000 are dissolved in 30ml tetrahydrofurans, 75 DEG C
Flow back 12 it is small when, petroleum ether precipitation 3 times, filtering, filter cake is dried under vacuum to constant weight, obtains the polyethylene glycol of end carboxyl modification；It takes
Pentaerythrite 34.0mg, 4-dimethylaminopyridine 0.13g and dicyclohexylcarbodiimide 0.61g, which are dissolved in 10ml dichloromethane, to be matched somebody with somebody
Into pentaerythrite solution, the polyethylene glycol 0.75g that end carboxyl is modified is dissolved in 10ml dichloromethane, is dripped with extremely slow speed
It is added in pentaerythrite solution, is sufficiently stirred 2 days, petroleum ether precipitation 3 times filters, and filter cake vacuum drying constant weight obtains trihydroxy
The polyethylene glycol of modification；Doxorubicin hydrochloride 50.0mg is taken to be dissolved in 10ml deionized waters and is made into aqueous solution, cis-aconitic anhydride
50.0mg is dissolved in 10ml dioxane, and is added drop-wise to dropwise in Doxorubicin aqueous solution, during which molten with the sodium hydroxide of 0.5M
Liquid regulation system pH is 8.5 or so, and when reaction 24 is small, 1mol/L hydrochloric acid has been acidified to precipitation, ethyl acetate extraction, anhydrous slufuric acid
Sodium is dried, and filtering, filtrate is spin-dried for, and vacuum drying obtains the Doxorubicin of end carboxylic acid modification；Take the Doxorubicin of end carboxylic acid modification
70.0mg, catalyst 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate 57.4mg and 4-dimethylaminopyridine
12.2mg is dissolved in 10ml anhydrous dimethyl sulphoxides, and stirring forms Doxorubicin solution.Triatomic polyethylene glycol 32.9mg is molten
In 5ml anhydrous dimethyl sulphoxides, instill dropwise in Doxorubicin solution, be protected from light 24 it is small when after, with the bag filter of 3.5KDa
Dialysis 3 days, freeze-drying, obtains amphiphilic polyethylene glycol-Doxorubicin amphipathic nature block polymer；Taking polyethylene glycol-more
It is soft to be dissolved in than star block copolymer 5.0mg in 1ml dimethyl sulfoxide (DMSO)s, it is added dropwise into the deionized water of 5ml, dialyses under ultrasound condition
The high drug load nano-micelle with pH responses is obtained after 3 days.
Through transmission electron microscope observing, the high drug load nano-micelle size obtained with pH responses is homogeneous, is uniformly dispersed.
Embodiment 5：
Poly glycol monomethyl ether 5.0g, 0.2 g of succinic anhydride that molecular weight is taken to be 5000 are dissolved in 30ml tetrahydrofurans, 75 DEG C
Flow back 12 it is small when, n-hexane precipitates 3 times, and filtering, filter cake is dried under vacuum to constant weight, obtains the polyethylene glycol of end carboxyl modification；It takes
Pentaerythrite 34.0mg, 4-dimethylaminopyridine 0.13g and dicyclohexylcarbodiimide 0.61g are dissolved in 10ml dimethylformamides
In be made into pentaerythrite solution, by end carboxyl modify polyethylene glycol 0.75g be dissolved in 10ml dimethylformamides, with extremely slowly
Speed be added drop-wise in pentaerythrite solution, be sufficiently stirred 2 days, n-hexane precipitate 3 times, filtering, filter cake vacuum drying constant weight, obtain
The polyethylene glycol modified to trihydroxy；Doxorubicin hydrochloride 50.0mg is taken to be dissolved in 10ml deionized waters and is made into aqueous solution, it is cis
Aconitic anhydride 50.0mg is dissolved in 10ml dioxane, and is added drop-wise to dropwise in Doxorubicin aqueous solution, during which with the hydrogen of 0.5M
Sodium hydroxide solution regulation system pH is 8.5 or so, and when reaction 24 is small, 1mol/L hydrochloric acid has been acidified to precipitation, ethyl acetate extraction,
Anhydrous sodium sulfate is dried, and filtering, filtrate is spin-dried for, and vacuum drying obtains the Doxorubicin of end carboxylic acid modification；Take end carboxylic acid modification
Doxorubicin 70.0mg, catalyst 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate 57.4mg and 4- diformazan
Aminopyridine 12.2mg is dissolved in 10ml anhydrous dimethyl sulphoxides, and stirring forms Doxorubicin solution.Triatomic polyethylene glycol
32.9mg is dissolved in 5ml anhydrous dimethyl sulphoxides, dropwise instill Doxorubicin solution in, be protected from light 24 it is small when after, use 3.5KDa
Bag filter dialyse 3 days, freeze-drying, obtain amphiphilic polyethylene glycol-Doxorubicin amphipathic nature block polymer；Take poly- second
Glycol-Doxorubicin block copolymer 5.0mg is dissolved in 1ml dimethyl sulfoxide (DMSO)s, and the deionized water into 5ml is added dropwise under ultrasound condition
In, dialysis obtains the high drug load nano-micelle with pH responses after 3 days.
Through transmission electron microscope observing, the high drug load nano-micelle size obtained with pH responses is homogeneous, is uniformly dispersed.
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow person skilled in the art
It is that can understand present disclosure and implement according to this, it is not intended to limit the scope of the present invention.It is all according to the present invention
The equivalent transformation or modification that Spirit Essence is done, should be covered by the protection scope of the present invention.
Claims (4)
1. a kind of preparation method of polyethyleneglycol modified high drug load nano-micelle or vesica with pH responses, feature
It is to be as follows：
(1) it is 1 in molar ratio by poly glycol monomethyl ether and succinic anhydride：The ratio of (1 ~ 2) is dissolved in tetrahydrofuran, and 75
After when DEG C reflux 12 ~ 48 is small, precipitate 2 ~ 3 times, filter in precipitating reagent A, filter cake is dried under vacuum to constant weight, obtains end carboxyl and modifies
Polyethylene glycol；
(2) it is 1.3 in molar ratio by pentaerythrite, catalyst 4-dimethylaminopyridine and dicyclohexylcarbodiimide：4：0.3
Ratio be dissolved in solvent B, be made into pentaerythrite solution；The polyethylene glycol that the end carboxyl that step (1) is obtained again is modified is molten
Solution is added drop-wise in solvent B, and with extremely slow speed in the pentaerythrite solution, is sufficiently stirred 2 ~ 3 days；In precipitating reagent A
Middle to precipitate 2 ~ 3 times, filtering, filter cake is dried under vacuum to constant weight, obtains the polyethylene glycol of trihydroxy modification；
(3) doxorubicin hydrochloride is dissolved in the doxorubicin hydrochloride aqueous solution that 3.33-6.66g/L is made into deionized water, then will
Cis-aconitic anhydride is dissolved in the solution that 5-10g/L is made into dioxane, and is added drop-wise to dropwise in doxorubicin hydrochloride aqueous solution,
During which stirring adjusts the pH value of solution as 8.4-8.6 using the sodium hydroxide solution of 0.5M；React 24 it is small when, the hydrochloric acid of 1mol/L
It has been acidified to precipitation to generate, ethyl acetate extraction, anhydrous sodium sulfate drying, suction filtration is spin-dried for, dry, obtains the how soft of carboxylic acid modification
Compare star；
(4) by Doxorubicin, the catalyst 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne two of carboxylic acid modification obtained by step (3)
Inferior amine salt hydrochlorate and 4-dimethylaminopyridine are dissolved in 10mL anhydrous dimethyl sulphoxides, and stirring forms Doxorubicin solution；Again will
The polyethylene glycol of trihydroxy modification obtained by step (2) is dissolved in 5mL anhydrous dimethyl sulphoxides, and is added drop-wise to the carboxylic acid dropwise
In the Doxorubicin solution of modification, be protected from light 24 it is small when；Carboxylic acid modification Doxorubicin, trihydroxy modification Doxorubicin,
Catalyst 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate and 4-dimethylaminopyridine molar ratio are 1：4：3：
0.3；It is dialysed 2 ~ 3 days with the bag filter of 3.5KDa, freeze-drying obtains amphipathic nature block polymer；
(5) amphipathic nature block polymer obtained by step (4) is dissolved in dimethyl sulfoxide (DMSO), is instilled dropwise under ultrasound condition
In deionized water, to get the polyethyleneglycol modified high drug load nano-micelle or capsule with pH responses after dialysing 2 ~ 3 days
Bubble.
2. polyethyleneglycol modified high drug load nano-micelle or vesica with pH responses according to claim 1
Preparation method, it is characterised in that the number-average molecular weight of the poly glycol monomethyl ether described in step (1) is 550 ~ 5000.
3. polyethyleneglycol modified high drug load nano-micelle or vesica with pH responses according to claim 1
Preparation method, it is characterised in that the precipitating reagent A described in step (1) and (2) is in methanol, ether, n-hexane or petroleum ether
It is any.
4. polyethyleneglycol modified high drug load nano-micelle or vesica with pH responses according to claim 1
Preparation method, it is characterised in that the solvent B described in step (2) is dichloromethane, chloroform, tetrahydrofuran, dimethyl are sub-
It is any in sulfone, dimethylformamide or dimethyl acetamide.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20050070721A1 (en) * | 2002-05-19 | 2005-03-31 | University Of Utah Research Foundation | PH-sensitive polymeric micelles for drug delivery |
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| CN113912649A (en) * | 2021-09-30 | 2022-01-11 | 苏州大学 | Amphiphilic nano metal complex and preparation method and application thereof |
| CN113912649B (en) * | 2021-09-30 | 2023-02-10 | 苏州大学 | Amphiphilic nano metal complex and preparation method and application thereof |
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