CN105727309B - The preparation and application of sensitive amphiphilic polysaccharide-adriamycin conjugate and its pharmaceutical compositions - Google Patents
The preparation and application of sensitive amphiphilic polysaccharide-adriamycin conjugate and its pharmaceutical compositions Download PDFInfo
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- CN105727309B CN105727309B CN201610205613.8A CN201610205613A CN105727309B CN 105727309 B CN105727309 B CN 105727309B CN 201610205613 A CN201610205613 A CN 201610205613A CN 105727309 B CN105727309 B CN 105727309B
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- polysaccharide
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Classifications
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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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Biophysics (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of sensitive amphiphilic polysaccharide-adriamycin conjugates, this kind of conjugate is to introduce hydrophobic anticancer drug adriamycin by the linking arm containing disulfide bond and hydrazone bond on polysaccharide skeleton, make polysaccharide-adriamycin conjugate that there is amphipathic property, in water can self assembly be nano-micelle, it can be directly used for oncotherapy, also in addition can be used for antineoplaston by physical load anti-tumor drug.It is primarily characterized in that: 1) after nano-micelle reaches lesions position, disulfide bond in linking arm can be by the intracellular high concentration reducing substances selective degradation of lesion, the hydrazone bond in linking arm can degrade in the special pH environment of lesions position simultaneously, to make micella degrade and drug quick release, curative effect is improved；2) anti-tumor drug is loaded by chemical coupling and physically encapsulation two ways, reaches co-therapies effect.The polysaccharide conjugate and pharmaceutical composition can be used for injecting, take orally or topical route administration, can significantly improve anti-tumor activity, provide new approaches for the exploitation of anti-tumor drug.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, it is related to a kind of sensitive amphiphilic polysaccharide-adriamycin conjugate as drug
Carrier, the invention further relates to the preparation method and applications of the carrier.
Background technique
Cancer occupy whole world morbidity and it is dead the main reason for column, World Health Organization's statistical data show 2012 about
There are 14,000,000 new cancer cases and 8,200,000 cancer related mortalities.It is expected that 20 years from now on neopathy number of cases will increase about
70%.
Clinic relies primarily on pharmaceutical chemistry treating cancer at present, but most of anti-tumor drugs are slightly water-soluble now
Object is closed, has the following disadvantages: that oral absorption is poor, bioavilability is lower, and metabolism is fast in vivo, maintains effective blood drug concentration
Time is shorter etc..It is current often by addition surfactant or to be prepared into liposome, inclusion compound or micro-capsule (ball) etc. and increase
The solubility of drug.But due to the critical micelle concentration (CMC) of some low-molecular-weight surfactants is higher by (about 10-2G/L), infuse
Enter in vivo poor through hemodilution rear stability, and exhibiting high surface activating agent generates certain toxic side effect, therefore current research
Emphasis is how to develop long-acting, sustained release but also with the anti-tumor medicinal preparation of targeting.
Macromolecule-antitumor medicine conjugate is come into being, i.e., by water-soluble macromolecule and slightly water-soluble anti-tumor drug
It is coupled to form Polymeric prodrug object by covalent bond.These conjugates can be self-assembly of nucleocapsid knot in an aqueous medium
Structure, wherein dewatering medicament enters inside core, and dewatering medicament is in shell.It is covalently attached and improves drug LOADING RATES, extend body-internal-circulation
Time, increase intracellular absorption, optimal control release promotes therapeutic efficiency.In view of most of synthesis macromolecules exist not
With degree haemolysis, pyrogen reaction and permeability the defects of；Water soluble protein is easily by protease hydrolytic, body in large biological molecule
Interior degradation speed is very fast.Therefore, naturally occurring polysaccharide highlights its unique advantage.
Polysaccharide is the important component of all living organisms, in control cell division, adjusts cell growth and maintains life
Life organism eubolism etc. plays an important role, and from a wealth of sources, cheap and easy to get.Natural polysaccharide is as medicinal macromolecule material
Material has many advantages: 1. having excellent biocompatibility and degradability, biodegradable in vivo is small molecule, finally
It is CO that metabolism, which produces,2、H2O and urea etc.；2. some polysaccharide materials have broad-spectrum tumor targeting；3. containing a large amount of in polysaccharide structures
Active group, such as carboxyl, amino, hydroxyl, aldehyde radical, to provide enough reaction sites to chemically modifying polysaccharides.Cause
This is more and more concerned as macromolecule-antitumor medicine conjugate water-soluble portion using polysaccharide.
It is well known that the release of general polymer micella Intracellular drug be typically due to lack tumor locus differential stimulus and
Limit its drug release.A small amount of medication amount of tumor locus release is not enough to play antitumous effect, thus the higher medicine of demand
Agent amount, but cause stronger toxic side effect therewith.Therefore environment-responsive and Biodegradable polymeric micella are used for phase
It answers tumour specific environment to obtain the quick release of drug, higher antitumous effect is generated under specific behavior.Blood and just
Normal tissue physiology pH about 7.4, but in tumour cell pH about 6.5. and cell endoplasm/endosome pH value from 4.0~6.5.Together
When, GSH concentration can be broken disulfide bond to disconnect polymer architecture in tumour cell, and rapid delivery of pharmaceuticals concentration is higher than cell
Outer 100~1000 times.Sensitive to cell internal stimulus drug delivery system researcher discovery, pH and reduction Lazer's sensitive polymeric with
And related nano-carrier has received significant attention, therefore can enhance tumour to the sensitive characteristic of tumour cell environment specificity
Fraction medicine accumulation promotes curative effect and reduces side effect.
In view of the above problems, this patent is using natural polysaccharide as skeleton, the carboxyl in polysaccharide or carboxyl, the ammonia by derivatization
Base or through derivatization formed amino, hydroxyl or through derivatization formed hydroxyl on, pass through disulfide bond and hydrazone bond linking arm connection
Hydrophobic anticancer drug adriamycin makes it have dual-sensitivity and amphipathic characteristic, in an aqueous medium can self assembly be nanometre glue
Beam, solubilized drug.Novel sensitive amphiphilic polysaccharide-adriamycin conjugate has following characteristics as pharmaceutical carrier: 1. polysaccharide-
Adriamycin conjugate has amphipathic characteristic, is self-assembly of nano-micelle in aqueous solution, avoids using a large amount of organic solvents, table
Face activating agent, crosslinking agent or heating condition；2. physically encapsulation is more such under the hydrophobic forces of hydrophobic anticancer drug
Anti-tumor drug or other insoluble anti-tumor medicaments significantly improve drugloading rate, increase medicine stability；3. polysaccharide and hydrophobic group
Linking arm between group contains disulfide bond, this disulfide bond is more stable in body circulation and extracellular interior environment, but can be by lesion cell
The reducing substances glutathione of interior high concentration is degraded.In addition contain hydrazone bond in linking arm, under the conditions of lesions position special pH
It degrades, rapid delivery of pharmaceuticals avoids the adriamycin being chemically bonded on carrier and is wrapped in antitumor in micella
Drug fails release, does not act on the shortcomings that active component is removed, is remarkably improved bioavilability and drug effect.By containing
Disulfide bond and the linking arm of hydrazone bond introducing hydrophobic grouping are formed by sensitive amphiphilic polysaccharide-adriamycin conjugate and there is no document
And patent report.
Summary of the invention
The object of the present invention is to provide a kind of with anti-tumor activity and biodegradable amphiphilic polysaccharide-adriamycin is even
Join object.The conjugate can be self-assembly of nano-micelle in an aqueous medium, avoid using chemical cross-linking agent, a large amount of organic solvents and
Heating condition, preparation process are simple；The hydrophobic inner core formed through hydrophobic anti-tumor drug can be more such anti-through physically encapsulation
Tumour medicine or other insoluble anti-tumor medicaments, to significantly improve the dissolubility and drugloading rate of anti-tumor drug；In addition, through
Chemical coupling and physically encapsulation hydrophobic anticancer drug, while achieving the effect that treating cancer.Amphiphilic polysaccharide-the adriamycin
Conjugate has many advantages: anti-tumor activity is strong, drugloading rate is high, stability is good, drug effect is promoted, toxic side effect reduces etc..
It is a further object to provide the preparation methods of above-mentioned carrier.
It is a still further object of the present invention to provide application of the above-mentioned carrier in pharmacy.
In order to achieve the above objectives, the present invention also provides a kind of sensitive amphiphilic polysaccharide-adriamycin conjugate carrier,
Structure is as shown in following chemical formula:
Wherein: GLY is polysaccharide molecule chain, and n+m is alkylidene number contained by linking arm, and D is hydrophobic anticancer drug base
Group, R are the number that hydrophobic grouping replaces on polysaccharide molecule.
Sensitive amphiphilic polysaccharide-adriamycin the conjugate, wherein the polysaccharide selected includes the high score containing carboxyl
It is son amount hyaluronic acid, low-molecular-weight hyaluronic acid, unfraction heparin, low molecular weight heparin, desulfated heparin, chondroitin, more
Chondroitin sulphate, alginic acid；Originally the carboxymethyl chitosan, succinyl-chitosan, Portugal for not having carboxyl but introducing carboxyl are poly-
Sugar, fungi polysaccharide；Chitosan, carboxymethyl chitosan, hydroxyethyl chitosan, succinyl-chitosan containing amino and script do not have
Have amino but introduce the high molecular weight hyaluronic acid of amino, low-molecular-weight hyaluronic acid, unfraction heparin, low molecular weight heparin,
Desulfated heparin, chondroitin, poly-sulfated chondroitin, alginic acid, glucan, fungi polysaccharide；High molecular weight containing hydroxyl
Hyaluronic acid, low-molecular-weight hyaluronic acid, unfraction heparin, low molecular weight heparin, desulfated heparin, chondroitin, more sulfuric acid
Cartilage element, alginic acid, chitosan, hydroxyethyl chitosan, succinyl-chitosan, glucan, fungi polysaccharide.
Sensitive amphiphilic polysaccharide-adriamycin the conjugate, wherein linking arm contains lesions position selective degradation
Disulfide bond and hydrazone bond, the integer that alkylidene number contained by linking arm is 2~16.
Sensitive amphiphilic polysaccharide-adriamycin the conjugate, wherein chemical coupling hydrophobic anticancer drug be Ah
Mycin, physically encapsulation anti-tumor drug include taxol, Docetaxel, adriamycin, daunorubicin, Epi-ADM, camptothecine,
Hydroxycamptothecin, all-trans retinoic acid, 9-cis-retinoic acid, methotrexate (MTX), aminopterin, oleanolic acid, ursolic acid, gamboge
Acid, Neo-garcinolic acid, glycyrrhizic acid, enoxolone, vincaleukoblastinum, vincristine.
The sensitive amphiphilic polysaccharide derivative carrier, the number that wherein hydrophobic grouping replaces on polysaccharide molecule chain are
2~600 integer.
Sensitive amphiphilic polysaccharide-adriamycin the conjugate, wherein polysaccharide molecule and linking arm one end pass through amide
Key or ester bond are connected, and the linking arm other end is connected with adriamycin by hydrazone bond.
Sensitive amphiphilic polysaccharide-adriamycin conjugate preparation method includes the following steps: that carboxyl will be contained
The polysaccharide of (amino, hydroxyl) is dissolved in reaction dissolvent containing the polysaccharide derivates of carboxyl (amino, hydroxyl), using containing two sulphur
Key and both ends are all the linking arm of amino (both ends are all carboxyl, Amino End Group one end carboxyl), with EDC and NHS or EDC and HOBt
Or EDC and DMAP is that activator carries out condensation reaction, one end generation esterification of polysaccharide and linking arm or amidation process are contained
There is the polysaccharide product of disulfide bond.Upper step product and methyl acrylate and hydration hydrazine reaction are obtained containing disulfide bond and hydrazides key
Polysaccharide product；Hydrophobic anticancer drug containing carbonyl or the anti-tumor drug derivative containing carbonyl are dissolved in appropriate molten
In agent, pass through the further hydrazine with other end hydrazides key on polysaccharide intermediate linking arm of the carbonyl of hydrophobic anticancer drug group
Solution reaction is to get with sensitive amphiphilic polysaccharide-adriamycin conjugate carrier.
The amphiphilic polysaccharide-adriamycin conjugate preparation method, wherein reaction dissolvent is water, methanol, N, N- diformazan
Base formamide, formamide, tetrahydrofuran, pyridine, ethyl acetate, methylene chloride, chloroform, carbon tetrachloride, acetone, dimethyl
The mixed solvent of sulfoxide, N-Methyl pyrrolidone or in which any two kinds of solvents.
Sensitive amphiphilic polysaccharide-adriamycin conjugate application, conjugate can be directly as formulation application；?
It can be used for antineoplastic pharmaceutical compositions, as other pharmaceutical actives or pharmacological activity molecular vehicle application.Wherein pharmaceutical active or
Pharmacological activity molecule is selected from: taxanes, camptothecin, vinca, tretinoin, Anthraquinones, anthracycline, podophyllotoxin
Any one of plain class, purine antagonist, Pyrimidine antagonists, antifol, gambogic acid antineoplastic.
The polysaccharide-adriamycin conjugate may be used as intravascular injection, intramuscular injection, oral or external application.Wherein infuse
Administration optimizing injection, freeze-dried powder are penetrated, preferred tablet, capsule, pill, syrup, granule, oral administration solution is administered orally
Agent, the preferred patch of topical administration, liniment, lotion, gelling agent, paint, ointment.
The polysaccharide-adriamycin conjugate is prepared into micella or carrier micelle method and step is as follows: amphiphilic polysaccharide-Ah
Mycin and water are 1~50: 1000 ratio dissolution by weight, arrive polysaccharide-adriamycin through ultrasound or high-pressure homogeneous processing
The nano-micelle of conjugate；The indissoluble of therapeutically effective amount or the organic drug for being slightly soluble in water is molten with pharmaceutically acceptable solvent
Xie Hou, after mixing with above-mentioned amphiphilic polysaccharide-adriamycin conjugate aqueous solution, through ultrasound or high-pressure homogeneous processing, solution is used
Dialysis or ultrafiltration or post separation method remove organic solvent and small molecule, and the nanometer that lyophilized preparation partial size is 10~1000nm carries
Medicine micella.
Specific embodiment is as follows:
Polysaccharide carboxyl, amino or hydroxyl by containing disulfide bond and hydrazone bond can selective degradation linking arm introduce it is hydrophobic
Property anti-tumor drug adriamycin makes it have dual-sensitivity and amphipathic, can be self-assembled into nano-micelle in an aqueous medium.It is hydrophobic
Anti-tumor drug be gathered into kernel, polysaccharide molecule hydrophilic chain forms highly hydrophilic shell, has and improves anti-tumor activity, steady
The effect determined micella, effectively hide the capture of monokaryon-mononuclear phagocyte system.Therefore this kind of amphiphilic polysaccharide-adriamycin conjugate
It is a kind of excellent pharmaceutical carrier, particularly with insoluble anti-tumor medicament.The amphiphilic polysaccharide-conjugate micella reaches lesion
Behind position, disulfide bond linking arm can be connected by the intracellular high concentration reducing substances glutathione selective degradation of lesion, hydrazone bond
Connecing arm can be by the intracellular special pH environment degradable of lesion, and the quick separating of adriamycin and hydrophilic radical leads to the fast quick-release of drug
It puts, acts on lesions position, be remarkably improved lesions position free drug concentration, curative effect and bioavilability.The conjugate is also
It can be used as pharmaceutical carrier, partial size is controllable in 10~1000nm, and surface is smooth, good evenness, and redispersibility is good, drugloading rate and encapsulating
Rate is high.The conjugate can be used for intravascular or intramuscular injection, oral or external application.
The synthesis of sensitive amphiphilic polysaccharide-adriamycin conjugate and pharmacy or physiologically active composition preparation method are detailed
It is described as follows:
One, sensitive amphiphilic polysaccharide-adriamycin conjugate synthesis
1, the synthesis of polysaccharide intermediate
(1) polysaccharide is reacted with the linking arm that both ends are amino
A certain amount of carboxylic polysaccharide or carboxylic polysaccharide derivates are dissolved in reaction dissolvent, are added excessive two
End is the linking arm of amino, with 1- ethyl-(3- dimethylaminopropyl) carbodiimide (EDC) and HOSu NHS
(NHS) or 1- ethyl-(3- dimethylaminopropyl) carbodiimide (EDC) and I-hydroxybenzotriazole (HOBt) are that activator is anti-
It answers, polysaccharide precipitation is come out using excessive acetone after reacting 12h~48h, filters and isolates and purifies sediment.Upper step is precipitated
Object is dissolved in reaction dissolvent, with triethylamine (TEA) for catalyst, is gone out polysaccharide precipitation using excessive acetone after reacting 12h~48h
Come, filter and isolate and purify sediment, proper volume hydrazine hydrate is added, is rotated after reacting 12h~48h, obtain polysaccharide intermediate.
Synthetic route is shown below:
(2) polysaccharide is that the linking arm that carboxyl one end is amino reacts with one end
A certain amount of polysaccharide containing carboxyl (amino, hydroxyl) or the polysaccharide derivates containing carboxyl (amino, hydroxyl) are dissolved in
In reaction dissolvent, it is the linking arm that the carboxyl other end is amino that excessive one end, which is added, with 1- ethyl-(3- dimethylamino third
Base) carbodiimide (EDC) and HOSu NHS (NHS) or 1- ethyl-(3- dimethylaminopropyl) carbodiimide (EDC)
With I-hydroxybenzotriazole (HOBt) or 1- ethyl-(3- dimethylaminopropyl) carbodiimide (EDC) and 4- dimethylamino pyrrole
Pyridine (DMAP) is activator reaction, comes out polysaccharide precipitation using excessive acetone after reacting 12h~48h, filters and separate pure
Change sediment.Upper step sediment is dissolved in reaction dissolvent, with triethylamine (TEA) for catalyst, was used after reacting 12h~48h
The acetone of amount comes out polysaccharide precipitation, filters and isolate and purify sediment, and proper volume hydrazine hydrate is added, after reacting 12h~48h
Revolving, obtains polysaccharide intermediate.
Synthetic route is shown below:
2, polysaccharide-adriamycin conjugate synthesis
A certain amount of polysaccharide intermediate is dissolved in reaction dissolvent, a certain amount of adriamycin is added, after reacting 12h~48h,
Polysaccharide precipitation is come out using excessive propanone, filter and isolates and purifies sediment to get conjugate.
Synthetic route is shown below:
Two, amphiphilic polysaccharide-adriamycin conjugate nano-micelle preparation method
In the ratio for the amphiphilic polysaccharide derivative for dissolving 2~30mg in every 1mL water, by amphiphilic polysaccharide obtained-Ah
Mycin conjugate is soluble in water, and through ultrasound or high-pressure homogeneous processing, it is even to be prepared into polysaccharide-adriamycin that partial size is 10~1000nm
Join object micella.
Three, using amphiphilic polysaccharide-adriamycin micella as carrier, preparation contains the pharmaceutical composition of insoluble anti-tumor medicament
Object
Polysaccharide-adriamycin conjugate is dissolved in water, concentration 0.1%~5% (w/w), by insoluble anti-tumor medicament adriamycin
It is dissolved, is added in the micellar solution of conjugate with appropriate organic solvent, through ultrasound or high-pressure homogeneous processing, by dialysing or depressurizing
The method of distillation removes organic solvent, and the nano-micelle that partial size is 10~1000nm is made.So-called appropriate solvent, referring to pharmaceutically makes
The solvent of the drug can be dissolved.
Four, pharmaceutical composition is prepared as carrier using polysaccharide-adriamycin conjugate micella, it can be effective to anti-tumor drug
Load.
The amphiphilic polysaccharide derivative can be used to have as the drug of carrier: taxol, Docetaxel, Teniposide,
Hydroxycamptothecin, camptothecine, vincaleukoblastinum, vincristine, Vindesine, Etoposide, adriamycin, Epi-ADM, daunorubicin,
Mitomycin, silymarin, methotrexate (MTX), gambogicacid, Neo-garcinolic acid, all-trans retinoic acid, 9-cis-retinoic acid etc., but not
It is confined to these listed drugs.
Beneficial effects of the present invention:
One, the present invention introduces adriamycin group, this two sulphur with disulfide bond and the linking arm of hydrazone bond on the hydrazides key of polysaccharide
Key high stability in body circulation and extracellular interior environment, but easily by the reducing substances of the intracellular high concentration of lesion (such as
Glutathione etc.) degradation, and hydrazone bond is easily by lesion that special pH condition is degraded into the cell, thus specifically fast into the cell in lesion
Quick-release puts drug, avoids drug and fails to discharge, fails to play the shortcomings that drug effect is removed, is remarkably improved bioavilability
And curative effect.
Two, amphiphilic polysaccharide provided by the invention-adriamycin conjugate has good biological lesions position triggering drug release
Behavior, also with critical micelle concentration it is low, can active targeting tumour advantage.
Three, amphiphilic polysaccharide provided by the invention-adriamycin conjugate, can spontaneously form nano-micelle, to difficulty in water
Dissolubility anti-tumor drug is loaded with good physically encapsulation.Such as: 26.5% (w/w) is up to the physical load of adriamycin,
19.6% (w/w) is up to the physical load of taxol, 20.8% (w/w) is up to the physical load of hydroxycamptothecin, to first
The physical load of aminopterin is up to 17.2% (w/w), 19.8% (w/w) is up to the physical load of 5 FU 5 fluorouracil, to gamboge
The physical load of acid is up to 25.7% (w/w).
Four, amphiphilic polysaccharide provided by the invention-adriamycin conjugate can be used for injecting, take orally, external application or mucosa delivery.
This derivative has tight security, and size tunable system is in 10~1000nm.
Specific embodiment
Further instruction is subject to the present invention below by embodiment, but following embodiments are not intended to limit the power of this patent
Sharp range
Embodiment 1: hyaluronic acid-cystamine-adriamycin conjugate preparation
0.1mmol hyaluronic acid, 1mmol cystamine, 0.2mmol EDC and 0.2mmol NHS are dissolved in formamide, reaction
It uses excessive acetone precipitation afterwards for 24 hours, filters.Add water redissolve precipitating, and with distilled water dialyse 3d (MWCO=
3500), freeze-drying obtains the product containing disulfide bond.
Step product, 1mmol methyl acrylate and 0.2mmol triethylamine are dissolved in appropriate formamide on 0.1mmol and methanol is mixed
In bonding solvent, reaction afterwards using excessive cold acetone precipitation, filters for 24 hours.Add water redissolve precipitating and with distilled water dialyse 3d (MWCO=
3500) after, freeze-drying products therefrom and appropriate volume are hydrated hydrazine reaction for 24 hours, 50 DEG C rotate away extra hydrazine hydrate, with distillation
Water is dialysed 3d (MWCO=3500), and the hyaluronic acid intermediate of free one end hydrazides group is remembered in freeze-drying.
100mg hyaluronic acid intermediate and 10mg doxorubicin hydrochloride are dissolved in formamide, a little glacial acetic acid is added, is reacted
It is precipitated, is filtered using excessive propanone after 48h.Add water to redissolve precipitating, and dialysed 3d (MWCO=14000) with distilled water, freezing is dry
Dry hyaluronic acid-cystamine-adriamycin conjugate carrier to obtain the final product.
Embodiment 2: chondroitin sulfate-cystamine-adriamycin conjugate preparation
0.1mmol chondroitin sulfate, 1mmol cystamine, 0.4mmol EDC and 0.4mmol NHS are dissolved in formamide, reaction
It uses excessive acetone precipitation afterwards for 24 hours, filters.Add water to redissolve precipitating, and dialysed 3d (MWCO=3500) with distilled water, freezing is dry
It is dry to obtain the product containing disulfide bond.
Step product, 1mmol methyl acrylate and 0.2mmol triethylamine are dissolved in appropriate formamide on 0.1mmol and methanol is mixed
In bonding solvent, reaction afterwards using excessive cold acetone precipitation, filters for 24 hours.Add water redissolve precipitating and with distilled water dialyse 3d (MWCO=
3500) after, freeze-drying products therefrom and appropriate volume are hydrated hydrazine reaction for 24 hours, 50 DEG C rotate away extra hydrazine hydrate, with distillation
Water is dialysed 3d (MWCO=3500), and the chondroitin sulfate intermediate of free one end hydrazides group is remembered in freeze-drying.
100mg chondroitin sulfate intermediate and 10mg doxorubicin hydrochloride are dissolved in formamide, a little glacial acetic acid is added, instead
It is precipitated, is filtered using excessive propanone after answering 48h.Add water to redissolve precipitating, and is dialysed 3d (MWCO=14000) with distilled water, freezing
It is drying to obtain chondroitin sulfate-cystamine-adriamycin conjugate carrier.
Embodiment 3: heparin-cystamine-adriamycin conjugate preparation
0.1mmol heparin, 1mmol cystamine, 0.2mmol EDC and 0.2mmol NHS are dissolved in formamide, after reaction for 24 hours
Using excessive acetone precipitation, filter.Add water to redissolve precipitating, and dialysed 3d (MWCO=3500) with distilled water, freeze-drying is
Obtain the product containing disulfide bond.
Step product, 1mmol methyl acrylate and 0.2mmol triethylamine are dissolved in appropriate formamide on 0.1mmol and methanol is mixed
In bonding solvent, reaction afterwards using excessive cold acetone precipitation, filters for 24 hours.Add water redissolve precipitating and with distilled water dialyse 3d (MWCO=
3500) after, freeze-drying products therefrom and appropriate volume are hydrated hydrazine reaction for 24 hours, 50 DEG C rotate away extra hydrazine hydrate, with distillation
Water is dialysed 3d (MWCO=3500), and the chondroitin sulfate intermediate of free one end hydrazides group is remembered in freeze-drying.
100mg heparin intermediate and 10mg doxorubicin hydrochloride are dissolved in formamide, a little glacial acetic acid is added, reacts 48h
It is precipitated, is filtered using excessive propanone afterwards.Add water to redissolve precipitating, and dialysed 3d (MWCO=14000) with distilled water, freeze-drying is
Obtain heparin-cystamine-adriamycin conjugate carrier.
Embodiment 4: polysaccharide-adriamycin conjugate nano-micelle preparation and characterization
1, anti-tumor drug assay in amphiphilic polysaccharide-adriamycin conjugate: the measuring method of conjugate drugloading rate
Commonly use ultraviolet, fluorescence,1H-NMR, HPLC etc..
2, amphiphilic polysaccharide-adriamycin conjugate nano-micelle preparation: polysaccharide-adriamycin conjugate 20mg is dissolved in
1h is stirred at room temperature in 3mL water, then under ice bath ultrasound or it is high-pressure homogeneous after, 0.45 μm of membrane filtration to get.
3, partial size: Zetasizer 3000HS instrument (Malvem Instruments, Malvem, UK) exists
633nm, 25 DEG C, He-Ne laser determination sample particle diameter the results are shown in Table 1.
1 polysaccharide of table-adriamycin conjugate nano-micelle characterization
Embodiment 5: physics contains adriamycin amphiphilic polysaccharide-adriamycin conjugate self-assembled nano micelle composition system
Standby and characterization
1, preparation process
(1) Probe Ultrasonic Searching method
Amphiphilic polysaccharide-adriamycin conjugate 18mg, is dissolved in 3mL water and 1h is stirred at room temperature.Doxorubicin hydrochloride 10mg
It is dissolved in 600 μ .l DMF, 200 μ l TEA is added, is added dropwise into conjugate solution, 1h, ice-bath ultrasonic is stirred at room temperature
After 30min, with bag filter (MWCO14000), room temperature is dialysed 12h, with 0.45 μm of membrane filtration, freeze-drying in distilled water.
(2) high pressure homogenization method
Amphiphilic polysaccharide-adriamycin conjugate 18mg, is dissolved in 3mL water and 1h is stirred at room temperature.Doxorubicin hydrochloride 10mg
It is dissolved in 600 μ l DMF, 200 μ l TEA is added, are added dropwise into conjugate solution, it is high-pressure homogeneous, use bag filter
(MWCO14000) the room temperature dialysis 12h in distilled water, with 0.45 μm of membrane filtration, freeze-drying.
2, in amphiphilic polysaccharide-adriamycin conjugate nano-micelle physical load doxorubicin content measurement
The assay of adriamycin is carried out with fluorescent spectrometry (excitation wavelength/launch wavelength is 488nm/570nm).With public affairs
The physics that formula (1) calculates sample contains drug delivery amount.It the results are shown in Table 2.
Amphiphilic polysaccharide-antitumor medicine conjugate nano-micelle characterization of 2 Examples 1 to 3 of table load adriamycin
Embodiment 6: physics contains silymarin amphiphilic polysaccharide-antitumor medicine conjugate self-assembled nano micelle combination
The preparation and characterization of object
1, preparation process
Amphiphilic polysaccharide-adriamycin conjugate 18mg, is dissolved in 3mL water and 1h is stirred at room temperature.Silymarin 12mg is molten
Solution is in ethanol.Then the two solution mixes, after ice-bath ultrasonic 30min, with bag filter (MWCO14000) room temperature in distilled water
Dialyse 12h, is centrifuged (3000rpm) 15min, with 0.45 μm of membrane filtration, freeze-drying.
2, in amphiphilic polysaccharide-adriamycin conjugate nano-micelle physical load silymarin assay
The assay of silymarin is carried out with HPLC (LC-2010C, Shimadzu, Japan) method.Mobile phase is first
- 0.1% formic acid of alcohol (48: 52), flow velocity 1.0mL.min-1, 40 DEG C of column temperature, Detection wavelength 288nm, 10 μ L of sample introduction.Chromatographic column is
Lichrospher C18(4.6mm × 150mm, 5 μm).Drug delivery amount is contained with the physics that formula (1) calculates sample.As a result see
Table 3.
Amphiphilic polysaccharide-adriamycin conjugate nano-micelle characterization of 3 Examples 1 to 3 of table load silymarin
Embodiment 7: physics contains 7-Ethyl-10-hydroxycamptothecin amphiphilic polysaccharide-antitumor medicine conjugate self assembly
The preparation and characterization of nano-micelle composition
1, preparation process
Amphiphilic polysaccharide-adriamycin conjugate 18mg, is dissolved in 3mL water and 1h is stirred at room temperature.7- ethyl -10- hydroxyl
Camptothecine 12mg is dissolved in dimethyl sulfoxide.Then the two solution mixes, and after ice-bath ultrasonic 30min, uses bag filter
(MWCO14000) the room temperature dialysis 12h in distilled water, is centrifuged (3000rpm) 15min, and with 0.45 μm of membrane filtration, freezing is dry
It is dry.
2, in amphiphilic polysaccharide-adriamycin conjugate nano-micelle physical load 7-Ethyl-10-hydroxycamptothecin content
Measurement
Measure containing for 7-Ethyl-10-hydroxycamptothecin with HPLC (LC-2010C, Shimadzu, Japan) method
It is fixed.Mobile phase is 0.05mol/L phosphate buffer-methanol-acetonitrile (50: 55: 5), flow velocity 0.8mL.min-1, column temperature 40
DEG C, Detection wavelength 288nm, 10 μ L of sample introduction.Chromatographic column is Agilent Eclipse Plus C18(4.6mm × 250mm, 5 μm).
Drug delivery amount is contained with the physics that formula (1) calculates sample.It the results are shown in Table 4.
Amphiphilic polysaccharide-adriamycin conjugate nano-micelle of 4 Examples 1 to 3 of table load 7-Ethyl-10-hydroxycamptothecin
Characterization
Claims (7)
1. a kind of sensitive amphiphilic polysaccharide-adriamycin conjugate as pharmaceutical carrier, it is characterised in that lead on polysaccharide skeleton
It crosses and introduces hydrophobic anticancer drug adriamycin containing disulfide bond and the linking arm of hydrazone bond, polysaccharide-adriamycin conjugate is made to have two
Parent's property, in water can self assembly be nano-micelle；Disulfide bond in linking arm can be by the intracellular high concentration reducing substances of lesion
Selective degradation, while the hydrazone bond in linking arm can degrade in the special pH environment of lesions position, thus make micella degrade and
Drug quick release significantly improves the concentration, curative effect and bioavilability of lesions position free drug, for example following chemistry of structure
Shown in formula:
Wherein GLY is polysaccharide molecule chain, and n+m is alkylidene number contained by linking arm, and the integer that n+m is 2~16, D are Ah mould
Element, R is the number that anti-tumor drug replaces on polysaccharide molecule, and R is 2~600 integer.
2. sensitive amphiphilic polysaccharide-adriamycin conjugate as described in claim 1, it is characterised in that the polysaccharide includes height
Molecular weight hyaluronic acid, low-molecular-weight hyaluronic acid, unfraction heparin, low molecular weight heparin, desulfated heparin, chondroitin,
Poly-sulfated chondroitin, alginic acid, glucan, fungi polysaccharide, chitosan and to above-mentioned polysaccharide carry out carboxylated, amination,
The derivative of hydroxylating transformation.
3. the preparation method of sensitive amphiphilic polysaccharide-adriamycin conjugate described in claim 1, it is characterised in that including under
Column step: by the polysaccharide containing carboxyl or polysaccharide derivates with containing disulfide bond and both ends are the linking arm molecule of amino, or contain
The polysaccharide or polysaccharide derivates for having hydroxyl or contain with containing disulfide bond and one end is the linking arm molecule that carboxyl one end is amino
The polysaccharide or polysaccharide derivates of amino are dissolved in reaction with containing disulfide bond and one end is the linking arm molecule that carboxyl one end is amino
In solvent, with 1- ethyl-(3- dimethylaminopropyl) carbodiimide (EDC) and HOSu NHS (NHS) or EDC and
I-hydroxybenzotriazole (HOBt) or EDC and 4-dimethylaminopyridine (DMAP) are that activator carries out condensation reaction, polysaccharide or more
Esterification occurs with linking arm one end containing disulfide bond for sugar derivatives or amidation process obtains the polysaccharide product containing disulfide bond；It will
Free amine group and methyl acrylate and hydration hydrazine reaction in aforementioned polysaccharide product on disulfide bond linking arm, obtain containing disulfide bond
And the polysaccharide product of hydrazides key；Adriamycin is dissolved in appropriate solvent, by the carbonyl of adriamycin and it is aforementioned containing disulfide bond and
Free hydrazides in the polysaccharide product of hydrazides key reacts to get sensitive amphiphilic polysaccharide-adriamycin conjugate.
4. the preparation method of sensitive amphiphilic polysaccharide-adriamycin conjugate as claimed in claim 3, it is characterised in that described anti-
Answering solvent is water, methanol, n,N-Dimethylformamide, tetrahydrofuran, pyridine, ethyl acetate, methylene chloride, chloroform, four
Chlorination carbon, acetone, dimethyl sulfoxide, formamide, N-Methyl pyrrolidone or in which any two kinds of solvents mixed solvent.
5. the sensitive amphiphilic polysaccharide described in claim 1-application of adriamycin conjugate in medicine preparation, is used to prepare
The injection of intravascular or intramuscular, oral or external application the load drug carrier with pharmaceutical active or pharmacological activity molecule.
6. application according to claim 5, it is characterised in that the pharmaceutical active or pharmacological activity molecule is selected from: Japanese yew
Alcohol, Docetaxel, adriamycin, daunorubicin, Epi-ADM, camptothecine, hydroxycamptothecin, all-trans retinoic acid, 9- are cis-
Vitamin A acid, methotrexate (MTX), aminopterin, oleanolic acid, ursolic acid, gambogicacid, Neo-garcinolic acid, glycyrrhizic acid, enoxolone, Changchun
Alkali, vincristine.
7. application according to claim 5, it is characterised in that the sensitive of the load pharmaceutical active or pharmacological activity molecule
Amphiphilic polysaccharide-adriamycin conjugate preparation method is the following steps are included: amphiphilic polysaccharide-adriamycin conjugate and water press weight
Amount obtains polysaccharide-adriamycin conjugate nano-micelle than dissolving for 1~50: 1000 ratio；By the indissoluble of therapeutically effective amount
Or after being slightly soluble in the bioactive molecule pharmaceutically acceptable solvent dissolution of water, with the amphiphilic polysaccharide-adriamycin conjugate
Nano-micelle mixing, through ultrasound or high-pressure homogeneous processing, solution dialysis or ultrafiltration or post separation method remove organic molten
The nano drug-carrying micella for being made that partial size is 10~1000nm is lyophilized in agent and small molecule.
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