CN105727309A - Preparation and application of dual-sensitivity amphiphilic polysaccharide-doxorubicin conjugate and pharmaceutical composition thereof - Google Patents
Preparation and application of dual-sensitivity amphiphilic polysaccharide-doxorubicin conjugate and pharmaceutical composition thereof Download PDFInfo
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- CN105727309A CN105727309A CN201610205613.8A CN201610205613A CN105727309A CN 105727309 A CN105727309 A CN 105727309A CN 201610205613 A CN201610205613 A CN 201610205613A CN 105727309 A CN105727309 A CN 105727309A
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- Prior art keywords
- polysaccharide
- conjugate
- amycin
- micelle
- drug
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- 238000002360 preparation method Methods 0.000 title claims description 25
- 229960004679 doxorubicin Drugs 0.000 title abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 5
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 59
- 239000005017 polysaccharide Substances 0.000 claims abstract description 59
- 239000003814 drug Substances 0.000 claims abstract description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000000693 micelle Substances 0.000 claims abstract description 42
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 32
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 31
- 229940079593 drug Drugs 0.000 claims abstract description 19
- 230000000694 effects Effects 0.000 claims abstract description 15
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 15
- 239000000126 substance Substances 0.000 claims abstract description 8
- 150000004676 glycans Chemical class 0.000 claims abstract description 4
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 43
- 238000006243 chemical reaction Methods 0.000 claims description 29
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 20
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 claims description 18
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 14
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 13
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- 238000000034 method Methods 0.000 claims description 12
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- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 10
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
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- 125000001118 alkylidene group Chemical group 0.000 claims description 4
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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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Dispersion Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a dual-sensitivity amphiphilic polysaccharide-doxorubicin conjugate.According to the conjugate, hydrophobic antitumor drug doxorubicin is introduced in a polysaccharide framework through a connecting arm containing a disulfide bond and a hydrazone bond, so that the polysaccharide-doxorubicin conjugate has an amphiphilic property, can be self-assembled into a nano-micelle in water and directly used for tumor treatment, and can also be physically loaded with an antitumor drug to be used for antitumor treatment.The conjugate is mainly characterized in that after the nano-micelle reaches a focus, the disulfide bond in the connecting arm can be degraded specifically by high-concentration reduction substances in focus cells, and meanwhile the hydrazone bond in the connecting arm can be degraded in a special pH environment of the focus, so that the micelle is degraded, the drug is quickly released, and the treatment effect is improved; the antitumor drug is loaded in two modes of chemical conjugation and physical package, and therefore the joint treatment effect is achieved.The polysaccharide conjugate and a pharmaceutical composition can be used for injection or oral administration or external administration, can remarkably improve antitumor activity, and provides a new thought for development of the antitumor drug.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of sensitive amphiphilic polysaccharide-amycin conjugate conduct
Pharmaceutical carrier, the invention still further relates to the preparation method and applications of this carrier.
Background technology
Cancer occupies whole world morbidity and the row of main causes of death, and World Health Organization's statistical data shows
Within 2012, there are about 14,000,000 new cancer cases and 8,200,000 example cancer related mortality.Anticipated 20 years from now on new
Morbidity number of cases is by increase about 70%.
At present clinic relies primarily on pharmaceutical chemistry treatment cancer, but the most most of antitumor drug to be shipwreck molten
Property compound, have a disadvantage in that oral absorption is poor, bioavailability is relatively low, and internal metabolism is fast, dimension
Hold time of effective blood drug concentration shorter etc..Currently usually through add surfactant or be prepared as liposome,
Clathrate or microcapsule (ball) etc. increase the dissolubility of medicine.But due to some low-molecular-weight surfactants
Critical micelle concentration (CMC) is higher by (about 10-2G/L), it is injected in vivo through hemodilution rear stability poor,
And exhibiting high surface activating agent produces certain toxic and side effects, therefore current research emphasis be how to develop long-acting, slow
Release and possess the anti-tumor medicinal preparation of targeting.
Macromolecule-antitumor medicine conjugate is arisen at the historic moment, will water-soluble macromolecule and slightly water-soluble antitumor
Medicine forms Polymeric prodrug thing by covalent bond coupling.These conjugates can self assembly in an aqueous medium
Forming nucleocapsid structure, wherein dewatering medicament enters inside core, and dewatering medicament is at shell.Covalently bound raising medicine
LOADING RATES, extends circulation time in vivo, increases intracellular absorption, and optimal control discharges, and promotes therapeutic efficiency.
All there is the defects such as haemolysis in various degree, pyrogen reaction and permeability in view of great majority synthesis macromolecule；Raw
In thing macromole, water soluble protein is easily by protease hydrolysis, vivo degradation speed.Therefore, naturally occur
Polysaccharide highlight its unique advantage.
Polysaccharide is the important component of all Living organisms, is controlling cell division, regulation cell growth and dimension
Hold the aspects such as Living organism homergy to play an important role, and wide material sources, cheap and easy to get.Natural polysaccharide is made
A lot of advantage is possessed: 1. there is excellent biocompatibility and degradability, in vivo for pharmaceutical polymers
Biodegradable for little molecule, final metabolism is produced as CO2、H2O and carbamide etc.；2. some polysaccharide materials tool
There is broad-spectrum tumor targeting；3. containing substantial amounts of active group in polysaccharide structures, as carboxyl, amino, hydroxyl,
Aldehyde radical etc., thus chemically modifying polysaccharides is provided enough reaction site.Therefore using polysaccharide as macromolecule-
The water-soluble portion of antitumor medicine conjugate is more and more concerned.
It is known that the release of general polymer micelle Intracellular drug is typically due to lack tumor locus specificity thorn
Swash 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 drug dose of demand, but cause higher toxic and side effects therewith.Therefore environment-responsive and biology can drop
The polymer micelle solved, produces under specific behavior to obtain the quick release of medicine for corresponding tumor specific environment
Raw higher antitumous effect.Blood and normal structure physiological pH about 7.4, but pH about 6.5. in tumor cell
And intracellular kytoplasm/endosome pH value is from 4.0～6.5.Meanwhile, in tumor cell, GSH concentration can be broken
Split disulfide bond to disconnect polymer architecture, and rapid delivery of pharmaceuticals concentration is higher than extracellular 100～1000 times.Right
Intracellular sensitive drug delivery system researcher is stimulated to find, pH and reduction sensitive polymer and relevant
Nano-carrier receives significant attention, and therefore sensitive characteristic specific to tumor cell environment can strengthen swollen
Tumor fraction medicine is accumulated, and promotes curative effect and reduces side effect.
For problem above, this patent with natural polysaccharide as skeleton, the carboxyl at polysaccharide or the carboxylic through derivatization
Base, amino or the amino formed through derivatization, hydroxyl or on the hydroxyl that derivatization is formed, by disulfide bond and
The bonded arm of hydrazone connects hydrophobic anticancer drug amycin so that it is have dual-sensitivity and amphipathic characteristic, at water
Medium can self assembly be nano-micelle, solubilising medicine.Novel sensitive amphiphilic polysaccharide-amycin conjugate
Following characteristics is possessed: 1. polysaccharide-amycin conjugate has amphipathic characteristic, in aqueous as pharmaceutical carrier
It is self-assembly of nano-micelle, it is to avoid use a large amount of organic solvent, surfactant, cross-linking agent or heating condition；
2. under the hydrophobic forces of hydrophobic anticancer drug, more this kind of antitumor drug of physically encapsulation or other difficulties
Dissolubility antitumor drug, significantly improves drug loading, increases medicine stability；3. the company between polysaccharide and hydrophobic group
Connecing arm and contain disulfide bond, this disulfide bond is more stable in body circulation and extracellular interior environment, but can be by focus cell
The reducing substances glutathion degraded of interior high concentration.Additionally containing hydrazone key in linking arm, special at lesions position
Degrade under the conditions of pH, rapid delivery of pharmaceuticals, it is to avoid be chemically bonded in the amycin on carrier and bag
The antitumor drug being rolled in micelle fails to discharge, do not act on the shortcoming that active component is i.e. eliminated, can be notable
Improve bioavailability and drug effect.Double by introduce that hydrophobic group formed containing the linking arm of disulfide bond and hydrazone key
Sensitive amphiphilic polysaccharide-amycin conjugate there is no document and patent report.
Summary of the invention
It is an object of the invention to provide one and there is anti-tumor activity biodegradable amphiphilic polysaccharide-Ah mould
Element conjugate.This conjugate can be self-assembly of nano-micelle in aqueous medium, it is to avoid use chemical cross-linking agent,
A large amount of organic solvents and heating condition, preparation technology is simple；The hydrophobic inner core formed through hydrophobic antitumor drug can
Through more this kind of antitumor drug of physically encapsulation or other insoluble anti-tumor medicaments, thus significantly improve anti-swollen
The dissolubility of tumor medicine and drug loading；Additionally, through chemical coupling and physically encapsulation hydrophobic anticancer drug, same
Time reach treat cancer effect.This amphiphilic polysaccharide-amycin conjugate has many advantages: antitumor is lived
Property is strong, drug loading is high, the lifting of good stability, drug effect, toxic and side effects reduction etc..
It is a further object to provide the preparation method of above-mentioned carrier.
It is a still further object of the present invention to provide the application in pharmacy of the above-mentioned carrier.
For reaching above-mentioned purpose, present invention also offers a kind of sensitive amphiphilic polysaccharide-amycin conjugate and carry
Body, its structure is as shown in following chemical formula:
Wherein: GLY is polysaccharide molecule chain, n+m is alkylidene number contained by linking arm, and D is that hydrophobicity resists
Tumour medicine group, R is the substituted number of hydrophobic group on polysaccharide molecule.
Described sensitive amphiphilic polysaccharide-amycin conjugate, the polysaccharide wherein selected includes containing carboxyl
High molecular weight hyaluronic acid, low-molecular-weight hyaluronic acid, unfraction heparin, low molecular weight heparin, desulfation
Heparin, chrondroitin, poly-sulfated chrondroitin, alginic acid；Originally not there is carboxyl but introduce the carboxylic first of carboxyl
Base enclosure polysaccharide, succinyl-chitosan, glucosan, fungus polysaccharide；Chitosan containing amino, carboxymethyl shell
Polysaccharide, hydroxyethyl chitosan, succinyl-chitosan and script do not have amino but the high molecular of introducing amino is saturating
Bright matter acid, low-molecular-weight hyaluronic acid, unfraction heparin, low molecular weight heparin, desulfated heparin, cartilage
Chrondroitin plain, poly-sulfated, alginic acid, glucosan, fungus polysaccharide；High molecular containing hydroxyl is transparent
Matter acid, low-molecular-weight hyaluronic acid, unfraction heparin, low molecular weight heparin, desulfated heparin, chrondroitin,
Poly-sulfated chrondroitin, alginic acid, chitosan, hydroxyethyl chitosan, succinyl-chitosan, glucosan, true
Granulose.
Described sensitive amphiphilic polysaccharide-amycin conjugate, wherein linking arm contains lesions position specificity
The disulfide bond of degraded and hydrazone key, alkylidene number contained by linking arm is the integer of 2～16.
Described sensitive amphiphilic polysaccharide-amycin conjugate, wherein chemical coupling hydrophobic anticancer drug
For amycin, physically encapsulation antitumor drug include paclitaxel, Docetaxel, amycin, daunorubicin,
Epirubicin, camptothecine, hydroxy camptothecin, all-trans-retinoic acid, 9-cis-retinoic acid, methotrexate, ammonia
Base pterin, oleanolic acid, ursolic acid, gamlogic acid, neogambogic acid, glycyrrhizic acid, enoxolone, vinblastine,
Vincristine.
Described sensitive amphiphilic polysaccharide derivative carrier, wherein substituted of hydrophobic group on polysaccharide molecule chain
Number is the integer of 2～600.
Described sensitive amphiphilic polysaccharide-amycin conjugate, wherein polysaccharide molecule passes through with linking arm one end
Amido link or ester bond are connected, and the linking arm other end is connected by hydrazone key with amycin.
The preparation method of described sensitive amphiphilic polysaccharide-amycin conjugate comprises the following steps: to contain
The polysaccharide of carboxyl (amino, hydroxyl) or the polysaccharide derivates containing carboxyl (amino, hydroxyl) are dissolved in reaction dissolvent,
Use the linking arm being all amino (two ends are all carboxyl, Amino End Group one end carboxyl) containing disulfide bond and two ends,
Condensation reaction is carried out for activator with EDC and NHS or EDC and HOBt or EDC and DMAP, many
Sugar occurs esterification or amidation process to obtain the polysaccharide product containing disulfide bond with one end of linking arm.Upper step is produced
Thing reacts with acrylic acid methyl ester. and hydrazine hydrate, obtains the polysaccharide product containing disulfide bond and hydrazides key；Will be containing carbonyl
The hydrophobic anticancer drug of base or the antitumor drug derivant containing carbonyl are dissolved in appropriate solvent, by dredging
The carbonyl of aqueous antitumor drug group further with the hydrazinolysis of other end hydrazides key on polysaccharide intermediate linking arm
Reaction, must have sensitive amphiphilic polysaccharide-amycin conjugate carrier.
Described amphiphilic polysaccharide-amycin conjugate preparation method, wherein reaction dissolvent is water, methanol, N, N-
Dimethylformamide, Methanamide, oxolane, pyridine, ethyl acetate, dichloromethane, chloroform, four
Chlorination carbon, acetone, dimethyl sulfoxide, N-Methyl pyrrolidone or the mixed solvent of the most any two kinds of solvents.
The application of described sensitive amphiphilic polysaccharide-amycin conjugate, conjugate can be answered directly as preparation
With；Can also be used for antineoplastic pharmaceutical compositions, apply as other pharmaceutical actives or pharmacologically active molecular vehicle.
Wherein pharmaceutical active or pharmacologically active molecule are selected from: taxanes, camptothecin, vinca, dimension A
Acids, Anthraquinones, anthracycline, podophillotoxines, purine antagonist, Pyrimidine antagonists, antifol,
Any one of gambogic acid antineoplastic agent.
Described polysaccharide-amycin conjugate, can serve as intravascular injection, intramuscular injection, oral or external.
Wherein drug administration by injection optimizing injection, freeze-dried powder, oral administration preferred tablet, capsule, pill, syrup
Agent, granule, oral solution are the preferred patch of topical administration, liniment, lotion, gel, varnish, soft
Unguentum.
Described polysaccharide-amycin conjugate is prepared as micelle or carrier micelle method step is as follows: amphipathic many
Sugar-amycin and water are the ratio dissolving of 1～50: 1000 by weight, process, i.e. through ultrasonic or high pressure homogenize
Obtain the nano-micelle of polysaccharide-amycin conjugate；By the indissoluble of therapeutically effective amount or the organic medical that is slightly soluble in water
After thing dissolves with pharmaceutically acceptable solvent, mix with the aqueous solution of above-mentioned amphiphilic polysaccharide-amycin conjugate
After conjunction, processing through ultrasonic or high pressure homogenize, solution dialysis or ultrafiltration or post partition method remove organic solvent
With little molecule, lyophilized formulations particle diameter is the nano drug-carrying micelle of 10～1000nm.
Specific embodiments is as follows:
At carboxyl, amino or the hydroxyl of polysaccharide by can introduce by selective degradation linking arm containing disulfide bond and hydrazone key
Hydrophobic anticancer drug amycin so that it is there is dual-sensitivity and amphipathic, can be self-assembled in aqueous medium
Nano-micelle.Hydrophobic antitumor drug is gathered into kernel, and polysaccharide molecule hydrophilic chain forms highly hydrophilic shell,
Have and improve anti-tumor activity, stablize micelle, effectively hide the effect of the seizure of monokaryon-mononuclear phagocyte system.
The most this kind of amphiphilic polysaccharide-amycin conjugate is the pharmaceutical carrier that a class is excellent, resists particularly with slightly solubility
Tumour medicine.After this amphiphilic polysaccharide-conjugate micelle arrives lesions position, its disulfide bond linking arm can be sick
Stove intracellular high concentration reducing substances glutathion selective degradation, the bonded arm of hydrazone can be by the intracellular spy of focus
Different pH environment degradable, amycin and the sharp separation of hydrophilic group cause the quick release of medicine, act on
Lesions position, is remarkably improved lesions position free drug concentration, curative effect and bioavailability.This conjugate is also
Can be as pharmaceutical carrier, particle diameter is controlled 10～1000nm, smooth surface, good evenness, and redispersibility is good,
Drug loading and envelop rate are high.This conjugate can be used for Ink vessel transfusing or intramuscular injection, oral or external.
The synthesis of sensitive amphiphilic polysaccharide-amycin conjugate and pharmacy or physiologically active composition preparation method
Describe in detail as follows:
One, the synthesis of sensitive amphiphilic polysaccharide-amycin conjugate
1, the synthesis of polysaccharide intermediate
(1) polysaccharide reacts with the linking arm that two ends are amino
A certain amount of carboxylic polysaccharide or carboxylic polysaccharide derivates are dissolved in reaction dissolvent, add excess
The linking arm that two ends are amino, with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC)
With N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC)
It is activator reaction with I-hydroxybenzotriazole (HOBt), after reaction 12h～48h, uses the acetone of excess
By polysaccharide precipitation out, sucking filtration isolated and purified precipitate.Upper step precipitate is dissolved in reaction dissolvent, with three second
Amine (TEA) is catalyst, uses the acetone of excess by polysaccharide precipitation out, sucking filtration after reaction 12h～48h
And isolated and purified precipitate, adding proper volume hydrazine hydrate, after reaction 12h～48h, rotation is steamed, and obtains in polysaccharide
Mesosome.
Synthetic route is shown below:
(2) polysaccharide and one end be carboxyl one end be that the linking arm of amino reacts
By a certain amount of polysaccharide containing carboxyl (amino, hydroxyl) or the polysaccharide derivates containing carboxyl (amino, hydroxyl)
Be dissolved in reaction dissolvent, add excess one end be the carboxyl other end be the linking arm of amino, with 1-ethyl-(3-
Dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) or 1-ethyl-(3-
Dimethylaminopropyl) carbodiimide (EDC) and I-hydroxybenzotriazole (HOBt) or 1-ethyl-(3-
Dimethylaminopropyl) carbodiimide (EDC) and DMAP (DMAP) be that activator is anti-
Should, use the acetone of excess by polysaccharide precipitation out after reaction 12h～48h, sucking filtration isolated and purified precipitate.
Upper step precipitate is dissolved in reaction dissolvent, with triethylamine (TEA) as catalyst, makes after reaction 12h～48h
With the acetone of excess by polysaccharide precipitation out, sucking filtration isolated and purified precipitate, add proper volume hydrazine hydrate,
After reaction 12h～48h, rotation is steamed, and obtains polysaccharide intermediate.
Synthetic route is shown below:
2, the synthesis of polysaccharide-amycin conjugate
A certain amount of polysaccharide intermediate is dissolved in reaction dissolvent, adds a certain amount of amycin, reaction 12h～
After 48h, use excessive propanone by polysaccharide precipitation out, sucking filtration isolated and purified precipitate, obtain conjugate.
Synthetic route is shown below:
Two, the preparation method of amphiphilic polysaccharide-amycin conjugate nano-micelle
In every 1mL water dissolves 2～30mg the ratio of amphiphilic polysaccharide derivant, by prepared amphipathic
Polysaccharide-amycin conjugate is soluble in water, processes through ultrasonic or high pressure homogenize, be prepared as particle diameter be 10～
The polysaccharide of 1000nm-amycin conjugate micelle.
Three, the medicine group of insoluble anti-tumor medicament is carried using amphiphilic polysaccharide-amycin micelle as carrier, preparation bag
Compound
Polysaccharide-amycin conjugate is dissolved in water, concentration 0.1%～5% (w/w), by insoluble anti-tumor medicament Ah
Mycin dissolves with suitable organic solvent, adds in the micellar solution of conjugate, processes through ultrasonic or high pressure homogenize,
Removing organic solvent by the method for dialysis or decompression distillation, prepared particle diameter is the nano-micelle of 10～1000nm.
So-called appropriate solvent, refers to the solvent that can dissolve this medicine pharmaceutically used.
Four, use polysaccharide-amycin conjugate micelle to prepare pharmaceutical composition as carrier, antitumor drug can be had
Effect load.
This amphiphilic polysaccharide derivant can be used to have as the medicine of carrier: paclitaxel, Docetaxel, for Buddhist nun
Pool glycosides, hydroxy camptothecin, camptothecine, vinblastine, vincristine, vindesine, etoposide, amycin,
Epirubicin, daunorubicin, mitomycin, silymarin, methotrexate, gamlogic acid, neogambogic acid, complete
Retinotic acid, 9-cis-retinoic acid etc., but it is not limited to medicine listed by these.
Beneficial effects of the present invention:
One, the present invention introduces amycin group with the linking arm of disulfide bond and hydrazone key on the hydrazides key of polysaccharide, this
Disulfide bond stability in body circulation and extracellular interior environment is higher, but easily going back by the intracellular high concentration of focus
Immunogenic substance (such as glutathion etc.) is degraded, and hydrazone key is easily degraded by the intracellular special pH condition of focus, from
And at the intracellular specifically rapid delivery of pharmaceuticals of focus, it is to avoid medicine fail release, fail to play drug effect i.e.
The shortcoming being eliminated, is remarkably improved bioavailability and curative effect.
Two, amphiphilic polysaccharide-amycin conjugate that the present invention provides has good biological lesions position triggering
Drug release behavior, also have critical micelle concentration low, can the advantage of active targeting tumor.
Three, amphiphilic polysaccharide-amycin conjugate that the present invention provides, can spontaneously form nano-micelle in water,
Insoluble anti-tumor medicament is had good physically encapsulation load.Such as: the physical load of amycin is up to
26.5% (w/w), is up to 19.6% (w/w), the physical load to hydroxy camptothecin to the physical load of paclitaxel
Up to 20.8% (w/w), is up to 17.2% (w/w), the thing to 5-fluorouracil to the physical load of methotrexate
Reason load up to 19.8% (w/w), is up to 25.7% (w/w) to the physical load of gamlogic acid.
Four, amphiphilic polysaccharide-amycin conjugate that the present invention provides can be used for injecting, be administered orally, external or glue
Film is administered.This derivant has tight security, and size tunable system is 10～1000nm.
Detailed description of the invention
Below by embodiment to present invention further instruction in addition, but following embodiment is not limiting as this patent
Interest field
Embodiment 1: the preparation of hyaluronic acid-cystamine-amycin conjugate
0.1mmol hyaluronic acid, 1mmol cystamine, 0.2mmol EDC and 0.2mmol NHS are dissolved in formyl
In amine, reaction
The acetone precipitation of excess, sucking filtration is used after 24h.Add water redissolution precipitation, and dialyses with distilled water
3d (MWCO=3500), lyophilization i.e. obtains the product containing disulfide bond.
Walk on 0.1mmol product, 1mmol acrylic acid methyl ester. and 0.2mmol triethylamine be dissolved in appropriate Methanamide with
In methanol mixed solvent, after reaction 24h, use excess cold acetone precipitation, sucking filtration.The redissolution that adds water precipitates and with steaming
Distilled water dialysis 3d (MWCO=3500), after lyophilization products therefrom reacts 24h with appropriate volume hydrazine hydrate,
50 DEG C of rotations steam unnecessary hydrazine hydrate, dialyse 3d (MWCO=3500) with distilled water, and trip is remembered in lyophilization
Hyaluronic acid intermediate from one end hydrazides group.
100mg hyaluronic acid intermediate and 10mg doxorubicin hydrochloride are dissolved in Methanamide, add a little ice vinegar
Acid, uses excessive propanone precipitation, sucking filtration after reaction 48h.Add water redissolution precipitation, and dialyses 3d with distilled water
(MWCO=14000), lyophilization i.e. obtains hyaluronic acid-cystamine-amycin conjugate carrier.
Embodiment 2: the preparation of chondroitin sulfate-cystamine-amycin conjugate
0.1mmol chondroitin sulfate, 1mmol cystamine, 0.4mmol EDC and 0.4mmol NHS are dissolved in first
In amide, after reaction 24h, use the acetone precipitation of excess, sucking filtration.Add water redissolution precipitation, and saturating with distilled water
Analysis 3d (MWCO=3500), lyophilization i.e. obtains the product containing disulfide bond.
Walk on 0.1mmol product, 1mmol acrylic acid methyl ester. and 0.2mmol triethylamine be dissolved in appropriate Methanamide with
In methanol mixed solvent, after reaction 24h, use excess cold acetone precipitation, sucking filtration.The redissolution that adds water precipitates and with steaming
Distilled water dialysis 3d (MWCO=3500), after lyophilization products therefrom reacts 24h with appropriate volume hydrazine hydrate,
50 DEG C of rotations steam unnecessary hydrazine hydrate, dialyse 3d (MWCO=3500) with distilled water, and trip is remembered in lyophilization
Chondroitin sulfate intermediate from one end hydrazides group.
100mg chondroitin sulfate intermediate and 10mg doxorubicin hydrochloride are dissolved in Methanamide, add a little ice
Acetic acid, uses excessive propanone precipitation, sucking filtration after reaction 48h.Add water redissolution precipitation, and dialyses with distilled water
3d (MWCO=14000), lyophilization i.e. obtains chondroitin sulfate-cystamine-amycin conjugate carrier.
Embodiment 3: the preparation of heparin-cystamine-amycin conjugate
0.1mmol heparin, 1mmol cystamine, 0.2mmol EDC and 0.2mmol NHS are dissolved in Methanamide,
The acetone precipitation of excess, sucking filtration is used after reaction 24h.Add water redissolution precipitation, and dialyses with distilled water
3d (MWCO=3500), lyophilization i.e. obtains the product containing disulfide bond.
Walk on 0.1mmol product, 1mmol acrylic acid methyl ester. and 0.2mmol triethylamine be dissolved in appropriate Methanamide with
In methanol mixed solvent, after reaction 24h, use excess cold acetone precipitation, sucking filtration.The redissolution that adds water precipitates and with steaming
Distilled water dialysis 3d (MWCO=3500), after lyophilization products therefrom reacts 24h with appropriate volume hydrazine hydrate,
50 DEG C of rotations steam unnecessary hydrazine hydrate, dialyse 3d (MWCO=3500) with distilled water, and trip is remembered in lyophilization
Chondroitin sulfate intermediate from one end hydrazides group.
100mg heparin intermediate and 10mg doxorubicin hydrochloride are dissolved in Methanamide, add a little glacial acetic acid,
Excessive propanone precipitation, sucking filtration is used after reaction 48h.Add water redissolution precipitation, and dialyses 3d (MWCO with distilled water
=14000), lyophilization i.e. obtains heparin-cystamine-amycin conjugate carrier.
Embodiment 4: the preparation of polysaccharide-amycin conjugate nano-micelle and sign
1, antitumor drug assay in amphiphilic polysaccharide-amycin conjugate: the mensuration of conjugate drug loading
Method commonly use ultraviolet, fluorescence,1H-NMR, HPLC etc..
2, the preparation of amphiphilic polysaccharide-amycin conjugate nano-micelle: conjugate 20mg is molten for polysaccharide-amycin
Solution is stirred at room temperature 1h in 3mL water, after then ultrasonic under ice bath or high pressure homogenize, and 0.45 μm filter membrane mistake
Filter, to obtain final product.
3, particle diameter: 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.
The sign of table 1 polysaccharide-amycin conjugate nano-micelle
Embodiment 5: physics bag carries the system of amycin amphiphilic polysaccharide-amycin conjugate self-assembled nano micelle compositions
Standby and characterize
1, preparation technology
(1) Probe Ultrasonic Searching method
Amphiphilic polysaccharide-amycin conjugate 18mg, is dissolved in 3mL water and 1h is stirred at room temperature.Hydrochloric acid Ah
Mycin 10mg is dissolved in 600 μ .l DMF, adds 200 μ l TEA, is dripped in conjugate solution,
1h is stirred at room temperature, after ice-bath ultrasonic 30min, with bag filter (MWCO14000) room temperature dialysis in distilled water
12h, with 0.45 μm membrane filtration, lyophilization.
(2) high pressure homogenization method
Amphiphilic polysaccharide-amycin conjugate 18mg, is dissolved in 3mL water and 1h is stirred at room temperature.Hydrochloric acid Ah
Mycin 10mg is dissolved in 600 μ l DMF, adds 200 μ l TEA, is dripped in conjugate solution,
High pressure homogenize, with bag filter (MWCO14000) room temperature dialysis 12h in distilled water, with 0.45 μm filter membrane
Filter, lyophilization.
2, the mensuration of physical load doxorubicin content in amphiphilic polysaccharide-amycin conjugate nano-micelle
The assay (a length of 488nm/570nm of excitation wavelength/transmitted wave) of amycin is carried out with fluorescent spectrometry.
The physics bag medicine carrying thing drug loading of sample is calculated with formula (1).The results are shown in Table 2.
Table 2 embodiment 1～3 carries the table of the amphiphilic polysaccharide-antitumor medicine conjugate nano-micelle of amycin
Levy
Embodiment 6: physics bag carries silymarin amphiphilic polysaccharide-antitumor medicine conjugate self-assembled nano micelle combination
The preparation of thing and sign
1, preparation technology
Amphiphilic polysaccharide-amycin conjugate 18mg, is dissolved in 3mL water and 1h is stirred at room temperature.Herba Silybi mariani
Element 12mg dissolves in ethanol.Then the two solution mixing, after ice-bath ultrasonic 30min, uses bag filter
(MWCO14000) room temperature dialysis 12h in distilled water, centrifugal (3000rpm) 15min, with 0.45 μm filter membrane
Filter, lyophilization.
2, the assay of physical load silymarin in amphiphilic polysaccharide-amycin conjugate nano-micelle
The assay of silymarin is carried out by HPLC (LC-2010C, Shimadzu, Japan) method.Stream
Dynamic is methanol-0.1% formic acid (48: 52) mutually, and flow velocity is 1.0mL.min-1, column temperature 40 DEG C, detect wavelength 288nm,
Sample introduction 10 μ L.Chromatographic column is Lichrospher C18(4.6mm × 150mm, 5 μm).In terms of formula (1)
Calculate the physics bag medicine carrying thing drug loading of sample.The results are shown in Table 3.
Table 3 embodiment 1～3 carries the sign of the amphiphilic polysaccharide-amycin conjugate nano-micelle of silymarin
Embodiment 7: physics bag carries SN38 amphiphilic polysaccharide-antitumor medicine conjugate self assembly
The preparation of nano-micelle compositions and sign
1, preparation technology
Amphiphilic polysaccharide-amycin conjugate 18mg, is dissolved in 3mL water and 1h is stirred at room temperature.7-ethyl
-10-hydroxycamptothecine 12mg is dissolved in dimethyl sulfoxide.Then the two solution mixing, ice-bath ultrasonic 30min
After, with bag filter (MWCO14000) room temperature dialysis 12h in distilled water, centrifugal (3000rpm) 15min, use
0.45 μm membrane filtration, lyophilization.
2, physical load SN38 in amphiphilic polysaccharide-amycin conjugate nano-micelle
Assay
SN38 is carried out by HPLC (LC-2010C, Shimadzu, Japan) method
Assay.Flowing is 0.05mol/L phosphate buffer-methanol-acetonitrile (50: 55: 5) mutually, and flow velocity is
0.8mL.min-1, column temperature 40 DEG C, detects wavelength 288nm, sample introduction 10 μ L.Chromatographic column is Agilent Eclipse
Plus C18(4.6mm × 250mm, 5 μm).The physics bag medicine carrying thing drug loading of sample is calculated with formula (1).
The results are shown in Table 4.
Table 4 embodiment 1～3 carries the amphiphilic polysaccharide-amycin conjugate nanometer of SN38
The sign of micelle
Claims (10)
1. sensitive amphiphilic polysaccharide-amycin conjugate is as pharmaceutical carrier, it is characterized in that introducing hydrophobic anticancer drug amycin by the linking arm containing disulfide bond and hydrazone key on polysaccharide skeleton, make polysaccharide-amycin conjugate have amphipathic character, can self assembly be nano-micelle in water.Disulfide bond in linking arm can be by focus intracellular high concentration reducing substances selective degradation, the hydrazone bond energy being simultaneously connected with in arm is enough degrades in lesions position special pH environment, so that micelle degraded and medicine quickly discharge, significantly improving the concentration of lesions position free drug, curative effect and bioavailability, its structure is as shown in following chemical formula:
。
Wherein: GLY is polysaccharide molecule chain, the polysaccharide of selection includes the high molecular weight hyaluronic acid containing carboxyl, low-molecular-weight hyaluronic acid, unfraction heparin, low molecular weight heparin, desulfated heparin, chrondroitin, poly-sulfated chrondroitin, alginic acid；Originally not there is carboxyl but introduce the carboxymethyl chitosan of carboxyl, succinyl-chitosan, glucosan, fungus polysaccharide；Chitosan, carboxymethyl chitosan, hydroxyethyl chitosan, succinyl-chitosan and script containing amino do not 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, chrondroitin, poly-sulfated chrondroitin, alginic acid, glucosan, fungus polysaccharide；High molecular weight hyaluronic acid containing hydroxyl, low-molecular-weight hyaluronic acid, unfraction heparin, low molecular weight heparin, desulfated heparin, chrondroitin, poly-sulfated chrondroitin, alginic acid, chitosan, hydroxyethyl chitosan, succinyl-chitosan, glucosan, fungus polysaccharide；N+m is alkylidene number contained by linking arm；D is amycin；R is the substituted number of antitumor drug on polysaccharide molecule.
3. sensitive amphiphilic polysaccharide-amycin conjugate as claimed in claim 1, it is characterised in that linking arm contains disulfide bond and the hydrazone key of lesions position selective degradation, and in linking arm, alkylidene number n+m is the integer of 2～16.
4. antitumor drug as claimed in claim 1 replaces number, it is characterised in that the substituted number of described antitumor drug is the integer of 2～600.
5. the preparation method of the sensitive amphiphilic polysaccharide-amycin conjugate described in claims 1, it is characterized in that comprising the following steps: containing carboxyl (amino, hydroxyl) polysaccharide or containing carboxyl (amino, hydroxyl) polysaccharide derivates be dissolved in reaction dissolvent, employing is all amino containing disulfide bond and two ends, and (two ends are all carboxyl, one Amino End Group one end carboxyl) linking arm, it is that activator carries out condensation reaction with 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and N-Hydroxysuccinimide (NHS) or EDC and I-hydroxybenzotriazole (HOBt) or EDC and DMAP (DMAP), polysaccharide and the linking arm one end containing disulfide bond occur esterification or amidation process to obtain the polysaccharide product containing disulfide bond.Upper step product is reacted with acrylic acid methyl ester. and hydrazine hydrate, obtains the polysaccharide product containing disulfide bond and hydrazides key；Hydrophobic anticancer drug containing carbonyl or the antitumor drug derivant containing carbonyl are dissolved in appropriate solvent, reacted with the hydrazinolysis of other end hydrazides key on polysaccharide intermediate linking arm further by the carbonyl of hydrophobic anticancer drug group, must have sensitive amphiphilic polysaccharide-amycin conjugate carrier.
6. sensitive amphiphilic polysaccharide-amycin conjugate as claimed in claim 1, wherein chemical coupling hydrophobic anticancer drug is amycin, and physically encapsulation antitumor drug includes paclitaxel, Docetaxel, amycin, daunorubicin, epirubicin, camptothecine, hydroxy camptothecin, all-trans-retinoic acid, 9-cis-retinoic acid, methotrexate, aminopterin, oleanolic acid, ursolic acid, gamlogic acid, neogambogic acid, glycyrrhizic acid, enoxolone, vinblastine, vincristine.
7. the preparation method of the sensitive amphiphilic polysaccharide-amycin conjugate described in claim 5, it is characterized in that described reaction dissolvent is water, methanol, DMF, oxolane, pyridine, ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, acetone, dimethyl sulfoxide, Methanamide, N-Methyl pyrrolidone or the mixed solvent of the most any two kinds of solvents.
8. the sensitive amphiphilic polysaccharide-amycin conjugate described in claim 1 or 5, it is characterised in that have amphipathic, nano-micelle can be spontaneously formed in aqueous medium.
9. the application of the sensitive amphiphilic polysaccharide-amycin conjugate described in claim 1 or 5, for Ink vessel transfusing or intramuscular injection or oral, external with pharmaceutical active or the carrier of pharmacologically active azo aromatic.
Application the most according to claim 9, it is characterized in that the preparation method of the sensitive amphiphilic polysaccharide-amycin conjugate of this load pharmaceutical active or pharmacologically active molecule comprises the following steps: amphiphilic polysaccharide-amycin conjugate and water are the ratio dissolving of 1～50: 1000 by weight, obtain the nano-micelle of polysaccharide-amycin conjugate；By the indissoluble of therapeutically effective amount or be slightly soluble in after the pharmaceutically acceptable solvent of organic drug of water dissolves, after mixing with the nano-micelle of described amphiphilic polysaccharide-amycin conjugate, process through ultrasonic or high pressure homogenize, solution dialysis or ultrafiltration or post partition method remove organic solvent and little molecule, and lyophilizing prepares the nano drug-carrying micelle that particle diameter is 10～1000nm.
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