CN101791411A - Preparation and application of amphiphilic polysaccharide conjugate and medicinal compositions thereof - Google Patents
Preparation and application of amphiphilic polysaccharide conjugate and medicinal compositions thereof Download PDFInfo
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Abstract
The invention relates to preparation and application of amphiphilic polysaccharide conjugate and medicinal compositions thereof with anti-tumor activity and biodegradability. The conjugate has amphiphilicity by using alkylenediamine as a connecting arm and introducing hydrophobic segmer, namely a carboxyl-containing anti-tumor medicament, on a polysaccharide framework, and are formed into nanometer micelles by self-assembly in water. The invention is characterized in that 1) the anti-tumor medicament is physically coated by a hydrophobic inner core consisting of hydrophobic groups so as to remarkably improve the solubility of the anti-tumor medicament; and 2) the anti-tumor medicament obtained by chemical conjugation and physical coating can jointly achieve treatment effect and improve medicament action. The polysaccharide conjugate and the medicinal compositions thereof can be used for injection, oral administration, external use or mucosa administration. The invention has the advantages of simple preparation method, mature technology, high yield, and suitability for large-scale continuous production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of amphiphilic polysaccharide conjugate that has anti-tumor activity and biodegradability concurrently, the invention still further relates to the preparation method and the application thereof of this conjugate as pharmaceutical carrier.
Background technology
Cancer is one of major disease that threatens human health.According to World Health Organization's statistics, there are 2,460 ten thousand cancer patients in the whole world at present, almost has every year 7000000 people to die from cancer, and is the trend that rises year by year.
Antitumor drug treatment cancer is one of main method of present clinical treatment, but because existing antitumor drug mostly is the slightly water-soluble micromolecular compound, oral absorption is relatively poor, bioavailability is lower, and metabolism is very fast in vivo, it is shorter to keep the blood drug level time, often need increased dosage amount or increase administration number of times in order to improve curative effect, normal cell and cancerous cell are lacked selectivity in addition, therefore bring bigger toxic and side effects thus, developing long-acting, slow release and targeting antineoplastic medicine thing preparation is the emphasis of current research.
Antitumor drug is prepared into liposome, microcapsule drug-supplying system intensifier target tropisms such as (balls), improve curative effect, relax toxicity, become the effective way of cancer target administration, but liposome is as pharmaceutical carrier, to have still that envelop rate is low, targeting distributes undesirable, store in shortcomings such as stability is not good enough; Microcapsule (ball) particle diameter is bigger, can't see through mucosa or directly drug conveying be arrived target tissue through the body circulation, is not suitable for injecting drug use; And liposome, microcapsule (ball) effect aspect some solid tumor of treatment (as breast carcinoma, carcinoma of prostate, colon cancer etc.) is not satisfactory.Macromolecule-antitumor drug conjugate arises at the historic moment, and is about to chemotherapeutics and water-soluble macromolecule and forms the macromolecule prodrug by the covalent bond coupling.Its outstanding advantage is: 1. solid tumor is had the tendentiousness deposition, i.e. the EPR effect; 2. passive target and slow-releasing and controlled-releasing action; 3. avoid being removed fast the prolong drug plasma half-life by kidney; 4. discharge antitumor drug by specific enzyme or the hydrolysis of pH condition, reduce its toxic and side effects, improve bioavailability normal structure; 5. increase dewatering medicament solubility etc.Yet the material that can be used as macromolecule-antitumor drug must satisfy: have suitable reactive group; Excellent biological compatibility and biodegradability; Avirulence and immunogenicity; Have certain targeting for tumor, before reaching target site, keep the activity of medicine etc.Most of synthetic high polymers all exist aspect defectives such as haemolysis, heat source response and permeability more or less; Various water soluble proteins are then easily by protease hydrolysis in the biomacromolecule, and degradation in vivo speed is very fast.Therefore, naturally occurring polysaccharide just shows its special advantages.
Polysaccharide is the important component of all Living organisms, plays an important role at aspects such as control cell division, the growth of adjusting cell and the organism homergys that earns a bare living.Simultaneously; polysaccharide have good biocompatibility and can be in organism the enzymolysis Cheng Yi small-molecule substance that absorbed, have no side effect by live body; in addition; polysaccharide origin is extensive, cheap and easy to get; its backbone structure also has a large amount of amino and carboxyl, is easy to chemical modification (as acidylate, Sulfation, grafting and crosslinked etc.) and improves its physicochemical property.So with the water-soluble portion of polysaccharide, can overcome that macromolecule optionally limits in the above-mentioned conjugate as macromolecule-antitumor drug conjugate.Now existing the part polysaccharide-the antitumor drug conjugate is in conceptual phase, but still there is following defective in these conjugates: synthesis condition is comparatively harsh; Connect medicine and high molecular bridge formation group and be difficult for seeking, in the time can not directly carrying out condensation by functional groups such as hydroxyl, amino, employed linking arm is comparatively complicated, as aminoacid or polypeptide; Prodrug itself does not show pharmacologically active, have only former medicine wherein just to have curative effect, but the percent grafting of antitumor drug is lower, cause slow release after dose be not enough to reach antitumaous effect, influence therapeutic effect; With macromolecule prodrug forms treatment tumor, mechanism of action is single separately, and therapeutic effect does not reach the best etc.
At above problem, this patent is skeleton with the natural polysaccharide, at the carboxyl of polysaccharide or on the carboxyl that derivatization forms, be linking arm by simple Alkylenediamine, introducing contains the carboxyl hydrophobic anticancer drug, because this polysaccharide-antitumor drug conjugate contains hydrophilic polysaccharide part, with the hydrophobic anticancer drug part, it is amphipathic that it has been had, so this conjugate can be used as the antitumor drug carrier, make up a kind of novel antitumor drug transmission system, have the feature of polymer micelle concurrently: 1) but in aqueous solution self assembly form nano-micelle, avoided organic solvent, surfactant, the use of cross-linking agent or heating condition; 2) micellar hydrophobic inner core is wrapped up mode by physics, and the solubilising hydrophobic anticancer drug significantly improves drug loading, plays a role with the antitumor drug of chemical coupling is collaborative, has avoided the problem of single chemical coupling antitumor drug drug effect fluctuation; 3) because solubilising is to combine with carrier in non-covalent mode at the antitumor drug of conjugate kernel, make the medicine of delivery more or less freelyly to discharge, auxiliary mutually with the antitumor drug release behavior of chemical coupling, reach procedural release effect; The mechanism of action complementation of antitumor drug that 4) can be by physics solubilising and chemical coupling strengthens active anticancer, reaches the therapeutic alliance effect.
Summary of the invention
The purpose of this invention is to provide a kind of have anti-tumor activity and biodegradable amphiphilic polysaccharide conjugate.But the self assembly in aqueous medium of this conjugate forms nano-micelle, avoids the use of chemical cross-linking agent, a large amount of organic solvent, heating condition, and preparation technology is simple; Can significantly improve the dissolubility of antitumor drug by the formed hydrophobic inner core physics parcel of hydrophobic group antitumor drug; In addition, can reach the effect of treatment cancer jointly by chemical coupling and physics parcel hydrophobic anticancer drug.This amphiphilic polysaccharide conjugate has that anti-tumor activity is strong, drug loading is high, good stability, drug effect improves, toxic and side effects reduces feature.
Another object of the present invention provides the pharmaceutical composition that comprises above-mentioned amphiphilic polysaccharide conjugate.
Another object of the present invention provides above-mentioned amphiphilic polysaccharide conjugate and comprises above-mentioned conjugate preparation of drug combination method.
A further object of the invention provides above-mentioned amphiphilic polysaccharide conjugate and the application of pharmaceutical composition in pharmacy thereof.
For achieving the above object, the invention provides a kind of novel amphiphilic polysaccharide conjugate, this conjugate is on the carboxyl of polysaccharide molecule or the carboxyl through derivatization formation, by Alkylenediamine is linking arm, introduce hydrophobic group---contain the carboxyl antitumor drug, make it have amphipathic character, but self assembly is a nano-micelle in aqueous medium.Because hydrophobic group is an antitumor drug, so this conjugate has anti-tumor activity.
Described amphiphilic polysaccharide conjugate, the polysaccharide of wherein selecting for use comprise polysaccharide unfraction heparin, low molecular weight heparin, desulfurization acidify heparin, hyaluronic acid, chrondroitin, poly-sulfated chrondroitin, the alginic acid that contains carboxyl originally and do not have carboxyl originally but polysaccharide chitosan, carboxymethyl chitosan, succinyl-chitosan, glucosan, the fungus polysaccharide of introducing carboxyl.
Described amphiphilic polysaccharide conjugate, wherein hydrophobic group is carboxylic antitumor drug, comprises all-trans-retinoic acid, 9-cis-retinoic acid, methotrexate, aminopterin, Raltitrexed, pemetrexed, chlorambucil, amino-laevulic acid, ginsenoside, oleanolic acid, ursolic acid.
The preparation method of described amphiphilic polysaccharide conjugate comprises the following steps:
To contain the carboxyl antitumor drug and be dissolved in the suitable organic solvent, the employing Alkylenediamine is a linking arm, and dicyclohexyl carbodiimide (DCC), N-Hydroxysuccinimide (NHS) obtain the reactive intermediate of a free end amino for activator carries out condensation reaction; To contain carboxyl or change into carboxylic polysaccharide and be dissolved in the reaction dissolvent through deriving, with the reactive intermediate that obtains be activator by 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC), further carboxyl and amino condensation reaction.
Described preparation method, wherein suitably organic solvent is selected from N, dinethylformamide, oxolane, dimethyl sulfoxide.
Described preparation method, wherein linking arm is the Alkylenediamine structure of carbon number 2～12.
Described preparation method, wherein reaction dissolvent is selected from water or Methanamide or N, dinethylformamide and water or Methanamide and water or N, the mixed solvent of dinethylformamide and Methanamide.
Described antineoplastic pharmaceutical compositions comprises amphiphilic polysaccharide conjugate of the present invention and has pharmaceutical active or pharmacologically active molecule.Wherein the molecule of this pharmaceutical active or pharmacologically active is selected from: taxanes, camptothecin, vincristine class, anthraquinone class, podophillotoxines, amycin class, tretinoin antitumor drug.
Described antineoplastic pharmaceutical compositions can be as injection, oral, external or mucosa delivery.Wherein drug administration by injection optimizing injection, freeze-dried powder, oral administration preferred tablet, capsule, pill, syrup, granule, oral solution, the preferred patch of topical administration, liniment, lotion, gel, varnish, ointment, the preferred spray of mucosa delivery, aerosol, nasal formulations.
This amphiphilic polysaccharide conjugate pharmaceutical composition, the method operating procedure that is prepared into medicament-carried nano micelle is as follows: amphiphilic polysaccharide conjugate and water are 3～50: 1000 ratio dissolving by weight, obtain the amphiphilic polysaccharide conjugate nano-micelle; With the indissoluble of treatment effective dose or the antitumor drug that is slightly soluble in water with after the acceptable solvent dissolving pharmaceutically, after described amphiphilic polysaccharide conjugate nano-micelle mixes, handle through ultrasonic or high pressure homogenize, solution is removed organic solvent and micromolecule with dialysis or ultrafiltration or post partition method, and lyophilizing makes the nano-micelle that particle diameter is 10～1000nm.
Concrete scheme is as follows:
Introduce hydrophobic group (containing the carboxyl antitumor drug) on the carboxylic polysaccharide molecule chain containing carboxyl or form through derivatization, it is amphipathic that it is had, in aqueous medium, can be self-assembled into nano-micelle, the hydrophobic relatively carboxyl antitumor drug that contains is gathered into kernel, the polysaccharide molecule hydrophilic chain forms highly hydrophilic shell, has to improve anti-tumor activity, stablize micelle, effectively hide the effect of the seizure of organism reticuloendothelial system.Therefore this class amphiphilic polysaccharide conjugate is the good pharmaceutical carrier of a class, especially for insoluble anti-tumor medicament.This conjugate is as pharmaceutical carrier, and particle diameter is controlled at 10～1000nm, smooth surface, and good evenness, redispersibility is good, drug loading and envelop rate height.This conjugate can be used for injection, oral, external or mucosa delivery.
Synthetic and the pharmaceutical compositions preparation method that has the amphiphilic polysaccharide conjugate of anti-tumor activity and biodegradability concurrently is described in detail as follows:
One, amphiphilic polysaccharide conjugate is synthetic
1, reactive intermediate preparation
A. will contain the carboxyl antitumor drug and be dissolved in the suitable organic solvent, be the agent of living with dicyclohexyl carbodiimide (DCC), N-Hydroxysuccinimide (NHS), and the temperature control reaction is to complete, and sucking filtration is removed precipitation, adds the washing of excessive acetic acid ethyl ester; Sucking filtration liquid is extracted, and the combined ethyl acetate layer removes and desolvates, ester in the middle of obtaining activating.
B. ester in the middle of Alkylenediamine and the activation is dissolved in respectively in the suitable organic solvent by proper proportion, 0～4 ℃ slowly splashes into Alkylenediamine in the middle of the activation in the solution of ester, and the monitoring reaction is to fully; Reactant liquor is extracted, merge organic solvent layer.
C. separation and purification the said goods obtains amidized medicine, i.e. reactive intermediate.
Described graphical Synthetic Routes is as follows:
In the preparation method of above-mentioned reactive intermediate: the described organic solvent of step a is preferably N, dinethylformamide, oxolane, dimethyl sulfoxide, N more preferably, dinethylformamide; The temperature control reaction is preferably 0～4 ℃ of reaction, the 10～120min of elder generation, rises to room temperature reaction again to complete, and more preferably 0 ℃ of reaction 30min rises to room temperature reaction again and arrives fully; Response time is preferably 6～36h, more preferably 24h.
The ratio of ester is preferably 2～20 in the middle of Alkylenediamine described in the step b and the activation: 1, and more preferably 3: 1; Described organic solvent is preferably dichloromethane.
2, amphiphilic polysaccharide conjugate is synthetic
To contain carboxyl or change into carboxylic polysaccharide and reactive intermediate and be dissolved in the reaction dissolvent, at N through deriving
2Protection is an activator with 1-ethyl-(3-dimethylaminopropyl) carbodiimide down, and room temperature reaction is to complete; After reaction finishes, add the acetone precipitation product, sucking filtration must precipitate; Add water redissolution precipitation, dialysis, lyophilization promptly gets the end product amphiphilic polysaccharide conjugate.
Described graphical Synthetic Routes is as follows:
In the preparation method of above-mentioned amphiphilic polysaccharide conjugate: described reaction dissolvent is preferably water or Methanamide or N, dinethylformamide and water or Methanamide and water or N, the mixed solvent of dinethylformamide and Methanamide, N more preferably, the mixed solvent of dinethylformamide and Methanamide; Response time is preferably 6～48h, more preferably 24h; Dialysis time is preferably 1～5d, more preferably 3d.
Two, the micellar preparation method of amphiphilic polysaccharide conjugate
In the ratio of dissolving the amphiphilic polysaccharide conjugate of 3～30mg in every 1ml water, the amphiphilic polysaccharide conjugate that makes is soluble in water, handle through ultrasonic or high pressure homogenize, being prepared into particle diameter is the polysaccharide conjugate micelle of 10～1000nm.
Three, with amphiphilic polysaccharide conjugate as carrier, preparation contains the pharmaceutical composition of insoluble anti-tumor medicament
Amphiphilic polysaccharide conjugate is water-soluble, insoluble anti-tumor medicament such as paclitaxel are dissolved with appropriate solvent, with the amphiphilic polysaccharide conjugate aqueous solution, handle through ultrasonic or high pressure homogenize, remove organic solvent and micromolecule by dialysis or ultrafiltration or post partition method, make the nano-micelle that particle diameter is 10～1000nm.So-called appropriate solvent refers to the solvent that can dissolve this medicine that pharmaceutically uses.
Four, adopt amphiphilic polysaccharide conjugate as the preparing carriers pharmaceutical composition, can be to antitumor drug payload
Can use this amphiphilic polysaccharide conjugate to have as the medicine of carrier: all-trans-retinoic acid, 9-cis-retinoic acid, paclitaxel, hydroxy camptothecin, camptothecine, vindesine, etoposide, amycin, Docetaxel, daunorubicin, mitomycin, methotrexate, etoposide etc., but be not limited to these listed medicines.
Beneficial effect of the present invention:
One, the present invention is linking arm with the Alkylenediamine and contains the condensation of carboxyl antitumor drug, obtain having the reactive intermediate of an end dissociative amino, with a kind of simple economy and the method that realizes easily suitability for industrialized production with this reactive intermediate with contain carboxyl or can form carboxylic polysaccharide reaction by derivatization, prepared a series of amphiphilic polysaccharide conjugates, mild condition, reaction is simple, productive rate is high;
Two, amphiphilic polysaccharide conjugate provided by the invention has good biocompatibility and biodegradability, have also that critical micelle concentration is low, good stability, anti-tumor activity is strong, toxic and side effects is low advantage, above antitumor drug is had good solubilization;
Three, amphiphilic polysaccharide conjugate provided by the invention, can be in water spontaneous formation nano-micelle, the bag that not only can be used for antitumor drug carries, and because the nano-micelle structure that hydrophilic shell and hydrophobic core are formed, can the extension body internal recycle, reduce engulfing of reticuloendothelial cell, increase cancer target, so can reach the effect of therapeutic alliance cancer by the mode of physics parcel and chemical coupling antitumor drug;
Four, amphiphilic polysaccharide conjugate provided by the invention can be used for injection, oral, external or mucosa delivery.This conjugate has tight security, and particle diameter can be controlled in 10～1000nm.
Description of drawings:
Fig. 1: the particle diameter collection of illustrative plates of heparin-all-trans-retinoic acid conjugate.
Fig. 2: the particle diameter collection of illustrative plates that is loaded with the heparin-all-trans-retinoic acid conjugate of paclitaxel.
Specific embodiments
To the present invention's further instruction in addition, but following embodiment does not limit the interest field of this patent below by embodiment.
Embodiment 1: heparin-all-trans-retinoic acid synthetic
Get 10mmol all-trans-retinoic acid, 12mmol dicyclohexyl carbodiimide (DCC), 15mmol N-Hydroxysuccinimide (NHS); be dissolved in 30ml N, in the dinethylformamide, under lucifuge, the nitrogen protection; ice bath reaction 30min rises to room temperature reaction 24h then.After reaction finishes, the elimination precipitation, and add a large amount of ethyl acetate washing precipitations.Filtrate is extracted, and combined ethyl acetate layer, rotary evaporation remove to desolvate and obtain the middle ester of all-trans-retinoic acid activation.Ester in the middle of the activation of 1mmol all-trans-retinoic acid is dissolved in the 10ml dichloromethane, under condition of ice bath, slowly splash in the dichloromethane solution of 3mmol/ml ethylenediamine, after thin layer chromatography (TLC method) the monitoring reaction extremely fully, reactant liquor is extracted, merge organic layer, silica gel column chromatography separation and purification products therefrom, i.e. all-trans-retinoic acid reactive intermediate.Get 26mmol 1-ethyl-(3-dimethylaminopropyl) carbodiimide, add and contain in the formamide solution of 0.1mmol heparin, room temperature reaction 15min, the N that will contain 26mmol all-trans-retinoic acid reactive intermediate, the solution of dinethylformamide slowly adds in the above-mentioned reactant liquor, room temperature reaction 24h.After reaction finishes, add the acetone precipitation product, sucking filtration must precipitate.Add water redissolution precipitation, the 3d that in water, dialyses, lyophilization promptly gets end product heparin-all-trans-retinoic acid conjugate.
Embodiment 2: chondroitin sulfate-all-trans-retinoic acid synthetic
Get 10mmol all-trans-retinoic acid, 12mmol dicyclohexyl carbodiimide (DCC), 15mmol N-Hydroxysuccinimide (NHS); be dissolved in 30mlN, in the dinethylformamide, under lucifuge, the nitrogen protection; ice bath reaction 30min rises to room temperature reaction 24h then.After reaction finishes, the elimination precipitation, and add a large amount of ethyl acetate washing precipitations.Filtrate is extracted, and combined ethyl acetate layer, rotary evaporation remove to desolvate and obtain the middle ester of all-trans-retinoic acid activation.Ester in the middle of the activation of 1mmol all-trans-retinoic acid is dissolved in the 10ml dichloromethane, under condition of ice bath, slowly splash in the dichloromethane solution of 3mmol/ml ethylenediamine, after thin layer chromatography (TLC method) the monitoring reaction extremely fully, reactant liquor is extracted, merge organic layer, silica gel column chromatography separation and purification products therefrom, i.e. all-trans-retinoic acid reactive intermediate.Get 30mmol 1-ethyl-(3-dimethylaminopropyl) carbodiimide, add and contain in the formamide solution of 0.2mmol chondroitin sulfate, room temperature reaction 20min, the N that will contain 30mmol all-trans-retinoic acid reactive intermediate, the solution of dinethylformamide slowly adds in the above-mentioned reactant liquor, room temperature reaction 24h.After reaction finishes, add the acetone precipitation product, sucking filtration must precipitate.Add water redissolution precipitation, the 2d that in water, dialyses, lyophilization promptly gets end product chondroitin sulfate-all-trans-retinoic acid conjugate.
Embodiment 3: heparin-methotrexate synthetic
Get 10mmol methotrexate, 15mmol dicyclohexyl carbodiimide (DCC), 15mmol N-Hydroxysuccinimide (NHS), be dissolved in 20mlN, in the dinethylformamide, under lucifuge, the nitrogen protection, ice bath reaction 30min rises to room temperature reaction 24h then.After reaction finishes, the elimination precipitation, and add a large amount of ethyl acetate washing precipitations.Filtrate is extracted, and combined ethyl acetate layer, rotary evaporation remove to desolvate and obtain the middle ester of methotrexate activation.Ester in the middle of the activation of 1mmol methotrexate is dissolved in the 20ml dichloromethane, under condition of ice bath, slowly splash in the dichloromethane solution of 1.5mmol/ml ethylenediamine, after thin layer chromatography (TLC method) the monitoring reaction extremely fully, reactant liquor is extracted, merge organic layer, silica gel column chromatography separation and purification products therefrom, i.e. methotrexate reactive intermediate.Get 30mmol 1-ethyl-(3-dimethylaminopropyl) carbodiimide, add and to contain in the formamide solution of 0.1mmol heparin, room temperature reaction 30min will contain the N of 30mmol methotrexate reactive intermediate, the solution of dinethylformamide slowly adds in the above-mentioned reactant liquor, room temperature reaction 24h.After reaction finishes, add the acetone precipitation product, sucking filtration must precipitate.Add water redissolution precipitation, the 3d that in water, dialyses, lyophilization promptly gets end product heparin-methotrexate conjugate.
Embodiment 4: chrondroitin-oleanolic acid synthetic
Get 10mmol oleanolic acid, 16mmol dicyclohexyl carbodiimide (DCC), 16mmol N-Hydroxysuccinimide (NHS), be dissolved in 25ml N, in the dinethylformamide, under lucifuge, the nitrogen protection, ice bath reaction 30min rises to room temperature reaction 24h then.After reaction finishes, the elimination precipitation, and add a large amount of ethyl acetate washing precipitations.Filtrate is extracted, and combined ethyl acetate layer, rotary evaporation remove to desolvate and obtain the middle ester of oleanolic acid activation.Ester in the middle of the activation of 2mmol oleanolic acid is dissolved in the 20ml dichloromethane, under condition of ice bath, slowly splash in the dichloromethane solution of 6mmol/ml ethylenediamine, after thin layer chromatography (TLC method) the monitoring reaction extremely fully, reactant liquor is extracted, merge organic layer, silica gel column chromatography separation and purification products therefrom, i.e. oleanolic acid reactive intermediate.Get 35mmol 1-ethyl-(3-dimethylaminopropyl) carbodiimide, add and to contain in the formamide solution of 0.2mmol chrondroitin, room temperature reaction 15min will contain the N of 35mmol oleanolic acid reactive intermediate, the solution of dinethylformamide slowly adds in the above-mentioned reactant liquor, room temperature reaction 24h.After reaction finishes, add the acetone precipitation product, sucking filtration must precipitate.Add water redissolution precipitation, the 2d that in water, dialyses, lyophilization promptly gets end product chrondroitin-oleanolic acid conjugate.
Embodiment 5: the preparation of amphiphilic polysaccharide conjugate nano-micelle and sign
1, the preparation of amphiphilic polysaccharide conjugate nano-micelle
Embodiment 1-4 amphiphilic polysaccharide conjugate 40mg is dissolved in the 7ml water in stirring at room 1h, then under the ice bath behind the ultrasonic or high pressure homogenize, and 0.45 μ m membrane filtration, promptly.
2, particle diameter
Prepare the amphiphilic polysaccharide conjugate nano-micelle with 1, get 1ml and be diluted with water to 3ml, (Malvern Instruments, Malvern UK) measures, and the results are shown in Table 1 with the particle size determination instrument.
3, critical micelle concentration (CMC)
Adopt the most sensitive fluorescent probe method to measure CMC.With the pyrene is fluorescent probe, and pyrene is a kind of hydrophobicity aromatic, extremely responsive to environment polarity.When the concentration of amphipathic molecule was lower than CMC, solution can not form micelle, and pyrene is dissolved in the polar water; Along with the concentration of amphipathic molecule is higher than CMC, micelle formation.The pyrene hydrophobic part of micelle kernel in opposite directions distributes, thereby enter nonpolar environment, then in its fluorescence spectrum, can observe a series of variations, increase as fluorescence intensity, vibrating fine structure (the vibrational fine structure of theemission spectra) in the emission spectrum changes, laser spectrum (0,0) wave band red shift.Therefore, by with the I in the emission spectra of pyrene
1/ I
3Than (under fixed excitation wavelength, scanning I
1, I
3Represent respectively in the emission spectra first and the fluorescence intensity ratio at three strongest ones peak) or excitation spectrum in I
338/ I
333Mapping can obtain the apparent CMC of amphipathic molecule to the concentration of amphipathic molecule than (the excitation spectrum medium wavelength is respectively the fluorescence intensity ratio of 338nm and 333nm), the results are shown in Table 1.
The micellar sign of table 1 amphiphilic polysaccharide conjugate
Embodiment 6: comprise paclitaxel amphiphilic polysaccharide conjugate self-assembled nano micelle preparation of compositions and sign
1, preparation technology
(1) dialysis
Amphiphilic polysaccharide conjugate 18mg is dissolved in the 3ml water and stirs 1h.Paclitaxel 10mg is dissolved in the ethanol (methanol, acetonitrile).The two mixing then, behind the ultrasonic 30min that pops one's head in, the redistilled water dialysed overnight, centrifugal (3000rpm) 15min is with 0.45 μ m membrane filtration, lyophilization.
(2) emulsion-solvent evaporation method
Amphiphilic polysaccharide conjugate 18mg is dissolved in the 3ml water and stirs 1h.Paclitaxel 10mg is dissolved in the dichloromethane.The two mixing then, the ultrasonic 30min that pops one's head in, the uncovered stirring of room temperature is spent the night, and makes the dichloromethane volatilization, and centrifugal (3000rpm) 15min is with 0.45 μ m membrane filtration, lyophilization.
2, the mensuration of content of taxol in the amphiphilic polysaccharide conjugate self-assembled nano micelle
(Japan) method is carried out assay for LC-2010C, Shimadzu with HPLC.Mobile phase is methanol: water=75: 25 (v/v), chromatographic column are LichrospherC
18(150 * 4.6 μ m), pillar particle diameter are 5 μ m.Flow velocity is 1.0mL/min, the detection wavelength be 227nm (SPD-10A, UVdetector, Shimadzu, Japan), column temperature is 30 ℃, the injected sample volume is 20 μ l.Drug loading with formula (1) calculation sample.The results are shown in Table 2.
Table 2 embodiment 1～4 is loaded with the amphiphilic polysaccharide conjugate self-assembled nano micelle of paclitaxel
Embodiment 7: comprise amycin amphiphilic polysaccharide conjugate self-assembled nano micelle preparation of compositions and sign
1, preparation technology
Amphiphilic polysaccharide conjugate 18mg is dissolved in the 3ml water and stirs 1h.Amycin 9mg is dissolved in the dimethyl sulfoxide (N, dinethylformamide).The two mixing then, behind the ultrasonic 30min that pops one's head in, the redistilled water dialysed overnight, centrifugal (3000rpm) 15min is with 0.45 μ m membrane filtration, lyophilization.
2, amycin Determination on content in the amphiphilic polysaccharide conjugate self-assembled nano micelle
Use ultraviolet spectrophotometry, measure the content of amycin in 480nm wavelength place.Drug loading with formula (1) calculation sample.The results are shown in Table 3.
Table 3 embodiment 1～4 is loaded with the amphiphilic polysaccharide conjugate self-assembled nano micelle of amycin
Embodiment 8: comprise methotrexate amphiphilic polysaccharide conjugate self-assembled nano micelle preparation of compositions and sign
1, preparation technology
Amphiphilic polysaccharide conjugate 20mg is dissolved in the 3ml water and stirs 1h.Methotrexate 40mg is dissolved in N, in the dinethylformamide (dimethyl sulfoxide).The two mixing then, behind the ultrasonic 30min that pops one's head in, the redistilled water dialysed overnight, centrifugal (3000rpm) 15min is with 0.45 μ m membrane filtration, lyophilization.
2, methotrexate Determination on content in the amphiphilic polysaccharide conjugate self-assembled nano micelle
(Japan) method is carried out assay for LC-2010C, Shimadzu with HPLC.Mobile phase is the second eyeball: 0.05mol/L potassium phosphate buffer (pH=4.85)=10: 90 (v/v), chromatographic column is Lichrospher C
18(150 * 4.6 μ m), pillar particle diameter are 5 μ m.Flow velocity is 1.0mL/min, the detection wavelength be 313nm (SPD-10A, UV detector, Shimadzu, Japan), column temperature is 25 ℃, the injected sample volume is 20 μ l.Drug loading with formula (1) calculation sample.The results are shown in Table 4.
Table 4 embodiment 1～4 is loaded with the amphiphilic polysaccharide conjugate self-assembled nano micelle of methotrexate
Embodiment 9: comprise all-trans-retinoic acid amphiphilic polysaccharide conjugate self-assembled nano micelle preparation of compositions and sign
1, preparation technology
Amphiphilic polysaccharide conjugate 20mg is dissolved in the 3ml water and stirs 1h.All-trans-retinoic acid 10mg is dissolved in N, in the dinethylformamide (dimethyl sulfoxide).The two mixing then, behind the ultrasonic 30min that pops one's head in, the redistilled water dialysed overnight, centrifugal (3000rpm) 15min is with 0.45 μ m membrane filtration, lyophilization.
2, all-trans-retinoic acid Determination on content in the amphiphilic polysaccharide conjugate self-assembled nano micelle
(Japan) method is carried out assay for LC-2010C, Shimadzu with HPLC.Mobile phase is methanol: water: formic acid=95: 5: 0.5 (v/v), chromatographic column are Lichrospher C
18(150 * 4.6 μ m), pillar particle diameter are 5 μ m.Flow velocity is 1.0mL/min, the detection wavelength be 345nm (SPD-10A, UV detector, Shimadzu, Japan), column temperature is 25 ℃, the injected sample volume is 20 μ l.Drug loading with formula (1) calculation sample.The results are shown in Table 5.
Table 5 embodiment 1～4 is loaded with the amphiphilic polysaccharide conjugate self-assembled nano micelle of all-trans-retinoic acid
Embodiment 10: comprise etoposide amphiphilic polysaccharide conjugate self-assembled nano micelle preparation of compositions and sign
1, preparation technology
Amphiphilic polysaccharide conjugate 20mg is dissolved in the 3ml water and stirs 1h.Etoposide 10mg is dissolved in N, in the dinethylformamide (dimethyl sulfoxide).The two mixing then, behind the ultrasonic 30min that pops one's head in, the redistilled water dialysed overnight, centrifugal (3000rpm) 15min is with 0.45 μ m membrane filtration, lyophilization.
2, etoposide Determination on content in the amphiphilic polysaccharide conjugate self-assembled nano micelle
(Japan) method is carried out assay for LC-2010C, Shimadzu with HPLC.Mobile phase is methanol: acetonitrile: water=50: 10: 40 (v/v), chromatographic column are Lichrospher C
18(150 * 4.6 μ m), pillar particle diameter are 5 μ m.Flow velocity is 1.0mL/min, the detection wavelength be 254nm (SPD-10A, UVdetector, Shimadzu, Japan), column temperature is 25 ℃, the injected sample volume is 20 μ l.Drug loading with formula (1) calculation sample.The results are shown in Table 6.
Table 6 embodiment 1～4 is loaded with the amphiphilic polysaccharide conjugate self-assembled nano micelle of etoposide
Embodiment 11: comprise hydroxy camptothecin amphiphilic polysaccharide conjugate self-assembled nano micelle preparation of compositions and sign
1, preparation technology
Amphiphilic polysaccharide conjugate 20mg is dissolved in the 3ml water and stirs 1h.Hydroxy camptothecin 10mg is dissolved in N, in the dinethylformamide (dimethyl sulfoxide).The two mixing then, behind the ultrasonic 30min that pops one's head in, the redistilled water dialysed overnight, centrifugal (3000rpm) 15min is with 0.45 μ m membrane filtration, lyophilization.
2, the mensuration of hydroxy camptothecin content in the amphiphilic polysaccharide conjugate self-assembled nano micelle
Carry out assay with high performance liquid chromatogram-fluorescence detection method.Mobile phase is citrate buffer: acetonitrile: 75nmol/ml potassium dihydrogen phosphate=70: 23: 7 (v/v), chromatographic column are Lichrospher C
18(150 * 4.6 μ m), pillar particle diameter are 5 μ m.Flow velocity is 1.0mL/min, and the fluoroscopic examination wavelength is λ ex363nm and λ em530nm, and column temperature is 50 ℃, and the injected sample volume is 20 μ l.Drug loading with formula (1) calculation sample.The results are shown in Table 7.
Table 7 embodiment 1～4 is loaded with the amphiphilic polysaccharide conjugate self-assembled nano micelle of hydroxy camptothecin
Embodiment 12:MTT method is measured the anti-tumor activity of amphiphilic polysaccharide conjugate medicament-carried nano micelle compositions
The HepG2 cell that will be in exponential phase digests with 0.02%EDTA, makes cell suspension, respectively with 1 * 10
5/ ml cell concentration adds in the 96 hole ELISA Plate, and every hole 100 μ l establish five multiple holes, put 37 ℃ of 5%CO
2Cultivate about 24h in the incubator.
Reference substance paclitaxel, amycin, methotrexate, all-trans-retinoic acid, etoposide, hydroxy camptothecin are mixed with 5 concentration of 0.01,0.1,1,10,100 μ g/ml respectively; Get the carrying anti-tumor medicament nano micelle composition of embodiment 1-4 synthesis of coupling thing to be measured and prepare 5 concentration that are equivalent to corresponding antineoplastic agent substrate concentration with complete culture solution respectively.Add respectively in the above-mentioned cell culture fluid, after hatching 72h, every hole adds 5mg/mlMTT solution 20 μ l, continue to cultivate 4h, discard whole supernatants, add DMSO 100 μ l/ holes, vibrate 5min on the microoscillator, crystallization is dissolved fully, and the place measures absorbance (A) in enzyme connection instrument 570nm wavelength, and the high more viable count of A value is also many more.Can calculate the activity inhibition rate of medicine pair cell according to A.
According to experimental result, under variable concentrations, to analyze by statistics, the anti-tumor activity of the carrying anti-tumor medicament nano micelle composition of embodiment 1-4 synthesis of coupling thing all increases than corresponding antitumor drug.
Claims (9)
1. amphiphilic polysaccharide conjugate, it is characterized in that this conjugate is at the carboxyl of polysaccharide or on the carboxyl that derivatization forms, by Alkylenediamine is that linking arm is introduced hydrophobic group, make it have amphipathic characteristic, but self assembly is a nano-micelle in aqueous medium; Described polysaccharide comprises polysaccharide unfraction heparin, low molecular weight heparin, desulfurization acidify heparin, hyaluronic acid, chrondroitin, poly-sulfated chrondroitin, the alginic acid that contains carboxyl originally and does not have carboxyl originally but polysaccharide chitosan, carboxymethyl chitosan, hydroxyethyl chitosan, succinyl-chitosan, glucosan, the fungus polysaccharide of introducing carboxyl; Described hydrophobic group is carboxylic antitumor drug, comprises all-trans-retinoic acid, 9-cis-retinoic acid, methotrexate, aminopterin, Raltitrexed, pemetrexed, chlorambucil, amino-laevulic acid, ginsenoside, oleanolic acid, ursolic acid.
2. linking arm according to claim 1 is characterized in that, linking arm is the Alkylenediamine structure of carbon number 2～12.
3. the preparation method of amphiphilic polysaccharide conjugate according to claim 1 is characterized in that comprising the following steps:
To contain the carboxyl antitumor drug and be dissolved in the suitable organic solvent, the employing Alkylenediamine is a linking arm, and dicyclohexyl carbodiimide (DCC), N-Hydroxysuccinimide (NHS) obtain the reactive intermediate of a free end amino for activator carries out condensation reaction; To contain carboxyl or change into carboxylic polysaccharide and be dissolved in the reaction dissolvent through deriving, with the reactive intermediate that obtains be activator by 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC), further carboxyl and amino condensation reaction; The gained polysaccharide conjugate promptly has well amphipathic, can spontaneous formation nano-micelle in aqueous medium.
4. an antineoplastic pharmaceutical compositions is characterized in that comprising amphiphilic polysaccharide conjugate as claimed in claim 1 and pharmaceutical active or pharmacologically active molecule.
5. antineoplastic pharmaceutical compositions according to claim 4 is characterized in that it can be as injection, oral, external or mucosa delivery.
6. the application of antineoplastic pharmaceutical compositions according to claim 5, it is characterized in that drug administration by injection optimizing injection, freeze-dried powder, oral administration preferred tablet, capsule, pill, syrup, granule, oral solution, the preferred patch of topical administration, liniment, lotion, gel, varnish, ointment, the preferred spray of mucosa delivery, aerosol, nasal formulations.
7. antineoplastic pharmaceutical compositions according to claim 4, but it is characterized in that wherein both solubilising insoluble anti-tumor medicaments of amphiphilic polysaccharide conjugate, can unite its chemically combined antitumor drug again, combined effect reaches the effect of treatment cancer.
8. antineoplastic pharmaceutical compositions according to claim 4 is characterized in that described pharmaceutical active or pharmacologically active molecule are selected from: taxanes, camptothecin, vincristine class, anthraquinone class, podophillotoxines, amycin class, tretinoin antitumor drug.
9. antineoplastic pharmaceutical compositions according to claim 4, it is characterized in that this amphiphilic polysaccharide conjugate and pharmaceutical active or pharmacologically active molecule make medicament-carried nano micelle, its method comprises the steps: that amphiphilic polysaccharide conjugate and water are 3～50: 1000 ratio dissolving by weight, obtain the amphiphilic polysaccharide conjugate nano-micelle; With the indissoluble of treatment effective dose or the antitumor drug that is slightly soluble in water with pharmaceutically acceptable solvent dissolving, after described amphiphilic polysaccharide conjugate nano-micelle mixes, handle through ultrasonic or high pressure homogenize, solution is removed organic solvent and micromolecule with dialysis or ultrafiltration or post partition method, and lyophilizing makes the nano-micelle that particle diameter is 10～1000nm.
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