CN108451906A - A kind of nanometer formulation and preparation method for antitumor and anti-metastatic therapy cholesterol-low molecular weight heparin - Google Patents
A kind of nanometer formulation and preparation method for antitumor and anti-metastatic therapy cholesterol-low molecular weight heparin Download PDFInfo
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Abstract
The present invention relates to a kind of nanometer formulations and preparation method of cholesterol-low molecular weight heparin for antitumor and anti-metastatic therapy load antitumor drug.Specially using the cholesterol with superior bio compatibility as hydrophobic patch and dewatering medicament storage cavern, contain antitumor drug, shell is the hydrophily low molecular weight heparin with antimetastatic activity, to prepare a kind of novel nano preparation for postoperative anti-recurrence, the effect for inhibiting Nasopharyngeal neoplasms is realized while killing tumour cell.For the drugloading rate of the nanometer formulation between 5wt% 20wt%, prepared nanometer formulation has syringeability, is administered by tail vein injection, can play the antimetastatic activity of low molecular weight heparin while improving drug anticancer effect.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to for one kind using cholesterol as hydrophobic inner core, low molecular weight heparin is parent
Water shell and the nano-micelle and preparation method thereof for containing antitumor drug.
Background technology
Metastases have become the one of the major reasons of cancer patient death.Nasopharyngeal neoplasms are one complicated more
Step cascade process generally comprises following continuous step：Initial primary tumors cells obtain changing for gene phenotype
It after change, obtains metastatic potential and is detached from from tumor tissues, after vascular wall barrier, extravasation enters adjacent blood vessel, is followed in blood
Other tissues and organ are invaded with the help of ring, and then in the new transfer stove of secondary tissue orga- nogenesis.It blocks in above-mentioned steps and appoints
A step of anticipating may inhibit metastases.Currently, solving the problems, such as metastases using novel Nano medication delivery system
Through as nowadays important research direction.
Nano-micelle is a kind of colloid of the thermodynamic stability for the amphipathic nature block polymer being self-assembly of in water
Solution, with Nano Particle and spherical nucleocapsid.Nano-micelle has the advantages that many uniquenesses, therefore is passed as one kind
Medicine system shows wide application prospect.
At present for the design of the pharmaceutical carrier of Nano medication delivery system, not only needs to have drug and excellent contain energy
Power can be achieved drug controlled release and with certain targeting etc., more emphasize the biocompatibility and biodegradability of carrier,
To ensure that carrier is entered internal nontoxic, non-immunogenicity.Natural polysaecharides material such as hyaluronic acid, chitosan and heparin etc. are because of it
Excellent nontoxic, nothing is immunized prototype and is applied in the design of pharmaceutical carrier.In numerous natural polysaecharides materials, heparin because
Its unique antimetastatic activity and by researchers' extensive concern because heparin can interfere it is a variety of during metastases
Access, such as：Inhibit the activity of metastases relevant enzyme (heparitinase)；The cell adherence for inhibiting adhesion factor to mediate；Suppression
Tumor angiogenesis processed；Inhibit platelet-mediated epithelial cell to transition of mesenchymal cells etc..Due to specific in heparin chain
Five glycosylation sequences can identify and combination in antithrombase, since the 1930s, heparin exists as anti-coagulants always
It clinically uses, causes to be also easy to produce the side effects such as bleeding, decrease of platelet when playing antimetastatic activity using heparin, to greatly
Ground limits the clinical application of heparin.Therefore researcher develops low molecular weight heparin (low molecular weight
Heparin, LMWH), it is digested by heparin and is obtained, and molecular weight is relatively low, and generally 4000~7000.Compared to heparin, LMWH tools
Have it is oral easily absorb, bioavilability is high, Half-life in vivo is long, hemorrhagic tendency is small while even showing better anti-angiogenic life
At, anti-tumor metastasis isoreactivity, to by the extensive favor of researchers.
Breast cancer is one of most common malignant tumour of women worldwide, and it is pernicious swollen that incidence in big city is sure to occupy women
Tumor forefront.Although Clinics increase in recent years, has most of or die of recurrence and transfer.Chemotherapeutics by
It is widely used in antitumor treatment, is mainly based upon the ability of the cancer cell of their destruction fast-growths.However, the range of chemotherapy
It is extremely limited with efficiency.Since chemotherapeutics is more toxic, long-term use will produce irreversible Myocardial damage, marrow suppression
The serious adverse reactions such as system, leucocyte and decrease of platelet.In order to overcome the clinical limitation of chemotherapeutics, Recent study person
Antitumor drug is loaded by nano-carrier, changes its bio distribution, achievees the purpose that attenuation synergistic.
Based on background above, cholesterol is grafted on low molecular weight heparin, the courage with superior bio compatibility is consolidated
Alcohol contains antitumor drug as hydrophobic patch and dewatering medicament storage cavern, and shell is the hydrophily LMWH with antimetastatic activity,
A kind of novel nano preparation of high-biocompatibility is prepared, the double action of anti-tumor metastasis is realized while antitumor.Courage
Sterol is the important component of vivo biodistribution film, and LMWH is the polyose medicament being clinically commonly used, and the two all has
High-biocompatibility, nontoxic non-immunogenicity and biodegradability, using cholesterol-LMWH nano-micelles as pharmaceutical carrier
Antitumor drug is contained, the strong hydrophobic structure realization of cholesterol can not only be utilized efficiently to contain, but also can be by LMWH parents
Water shell realizes long circulating, extends the half-life period of antitumor drug and LMWH.In addition, using hydrophobic patch to the carboxyl on heparin
It is modified, intends reducing its anticoagulation, reduce bleeding risk when patient medication.The drug delivery system can be used for treating breast
Gland cancer and its Lung metastases realize high-effect, hypotoxicity therapeutic effect.
Invention content
It is the low molecular weight heparin derivative that cholesterol is modified present invention aims at a kind of drug carrier material of proposition,
Under aqueous conditions, it is the nano-micelle of hydrophobic inner core to be formed by hydrophilic outer shell, cholesterol of low molecular weight heparin, can contain anticancer
Drug plays the antimetastatic activity of low molecular weight heparin while chemotherapeutics plays antitumor action.
The nano-micelle preparations of the present invention, which is characterized in that its grain size can be used for tail vein note between 20nm-200nm
It penetrates, passive concentration improves effect of drugs in tumor locus, reduces toxic side effect.
The nano-micelle preparations of the present invention, which is characterized in that the molecular weight of the low molecular weight heparin of polymer carrier materials
Between 1000-10000.
The nano-micelle preparations of the present invention, which is characterized in that the modification rate of the cholesterol of polymer carrier materials is in 3%-
Between 20%.
The nano-micelle preparations of the present invention, which is characterized in that the cholesterol in polymer carrier materials is repaiied by linking arm
Decorations are to low molecular weight heparin, and the end of linking arm can be amino, ester bond or hydrazone bond, and connection arm configuration is alkyl chain.
The present invention nano-micelle preparations, which is characterized in that the antitumor drug contained can be adriamycin, Epi-ADM,
Taxol, Docetaxel, cis-platinum, methotrexate (MTX), cytarabine, gemcitabine, camptothecine, mitomycin, 5- fluorodeoxyglucose urines
Glycosides, cantharidin etc..
The nano-micelle preparations of the present invention, which is characterized in that the nano-micelle for carrying medicine is prepared using dialysis.Encapsulation rate exists
Between 50%-99%, drugloading rate is between 5wt%-20wt%.
The nano-micelle preparations of the present invention, which is characterized in that solvent can be pure water, buffer solution, body fluid, tissue cultures
Liquid or other solvent mediums not based on organic solvent.
The preparation method of nano-micelle preparations of the present invention is selected from one of following：
(1) aqueous solution of first prepared polymer material, is added dropwise a certain amount of antineoplastic drug solution, so under stiring
Probe Ultrasonic Searching 30min afterwards, then be transferred in bag filter and dialyse 24 hours, dialysis medium is distilled water, obtains medicament-carried nano micelle system
Agent.It is stored for future use after freeze-drying.Use preceding redissolution, internal injection；
(2) polymer and antitumor drug are dissolved with organic solvent, then rotary evaporation removes organic solvent, adds steaming
Distilled water stirring is redissolved, and Probe Ultrasonic Searching 30min is transferred in bag filter and dialyses 24 hours again, and dialysis medium is distilled water, obtains carrying medicine
Nano-micelle preparations.It is stored for future use after freeze-drying.Use preceding redissolution, internal injection；
(3) polymer and antitumor drug are dissolved with organic solvent, then is transferred in bag filter and dialyses 48 hours, medium of dialysing
For distilled water, medicament-carried nano micelle preparation is obtained.It is stored for future use after freeze-drying.Use preceding redissolution, internal injection；
The nano-micelle preparations of the present invention, which is characterized in that the nano-micelle is improving antitumor drug anticancer effect
While, the antimetastatic activity of low molecular weight heparin is played, is the treatment of primary tumor, metastatic tumo(u)r and postoperative anti-recurrence
Better choice is provided.
Description of the drawings
Fig. 1 nano-micelles play antitumor and antimetastatic activity legend in the cell.
The synthetic route of Fig. 2 cholesterol-low molecular weight heparin derivative.
Fig. 3 .MTT methods investigate vitro cytotoxicity.
Fig. 4 dissociate in DOX and DOX/LHC rat bodies blood concentration through when curve.
The living body fluorescent image of Fig. 5 evaluation Lung metastases.
Specific implementation mode
Embodiment 1
2.3g cholesteryl chloroformates (Chol, 5mmol) are dissolved in 50mL anhydrous methylene chlorides, in nitrogen and condition of ice bath
Under, above-mentioned solution is slowly added dropwise into 6.7mL (100mmol) ethylenediamines and 0.7mL (5mmol) triethylamine mixed solution, after
Continuous reaction 10h.After reaction, it is filtered to remove precipitation, filtrate is washed with deionized water three times, and anhydrous magnesium sulfate drying and mistake is added
Filter, filtrate decompression are dried overnight, and obtain white solid cholesterol-ethylenediamine that linking arm is ethylenediamine.
Embodiment 2
2.3g cholesteryl chloroformates (Chol, 5mmol) are dissolved in 50mL anhydrous methylene chlorides, in nitrogen and condition of ice bath
Under, above-mentioned solution is slowly added dropwise into 100mmol 2-aminoethyl disulfide dihydrochlorides and 0.7mL (5mmol) triethylamine mixed solution, is continued
React 10h.After reaction, it is filtered to remove precipitation, filtrate is washed with deionized water three times, and anhydrous magnesium sulfate drying and mistake is added
Filter, filtrate decompression are dried overnight, and obtain white solid cholesterol-cystamine that linking arm is cystamine.
Embodiment 3
Precision weighs the low molecular weight heparin that 100mg (0.25mmol) molecular weight is 1000 in round-bottomed flask, is added
10mL formamides, 50 DEG C of oil bath heating magnetic agitations make it dissolve, and 143.8mg (0.8mmol) carbon two is added after being cooled to room temperature
Inferior amine salt hydrochlorate (EDC) and 101.6mg (0.8mmol) I-hydroxybenzotriazole (HOBT) stir 15min, and it is solid that courage is then added
Reaction is stirred at room temperature for 24 hours in alcohol-ethylenediamine or cholesterol-cystamine or (0.05mmol).The 48h that dialyses is transferred in bag filter water, thoroughly
Analysis medium is followed successively by DMF and distilled water.It is cholesterol-low molecular weight heparin grafting that freeze-drying, which obtains white loose solid powder,
Copolymer, reaction step such as Fig. 2.The use of ammonium ferric sulfate colorimetric method for determining cholesterol degree of substitution is 20.0%.
Embodiment 4
Precision weighs the low molecular weight heparin that 100mg (0.25mmol) molecular weight is 4500 in round-bottomed flask, is added
10mL formamides, 50 DEG C of oil bath heating magnetic agitations make it dissolve, and 143.8mg (0.8mmol) carbon two is added after being cooled to room temperature
Inferior amine salt hydrochlorate (EDC) and 101.6mg (0.8mmol) I-hydroxybenzotriazole (HOBT) stir 15min, and it is solid that courage is then added
Reaction is stirred at room temperature for 24 hours in alcohol-ethylenediamine (0.1mmol).Be transferred in bag filter water the 48h that dialyses, dialysis medium be followed successively by DMF and
Distilled water.It is cholesterol-low molecular weight heparin graft copolymer that freeze-drying, which obtains white loose solid powder, and reaction step is such as
Fig. 2.The use of ammonium ferric sulfate colorimetric method for determining cholesterol degree of substitution is 7.8%.
Embodiment 5
Precision weighs the low molecular weight heparin that 100mg (0.25mmol) molecular weight is 10000 in round-bottomed flask, is added
10mL formamides, 50 DEG C of oil bath heating magnetic agitations make it dissolve, and 143.8mg (0.8mmol) carbon two is added after being cooled to room temperature
Inferior amine salt hydrochlorate (EDC) and 101.6mg (0.8mmol) I-hydroxybenzotriazole (HOBT) stir 15min, and it is solid that courage is then added
Reaction is stirred at room temperature for 24 hours in alcohol-ethylenediamine (0.3mmol).Be transferred in bag filter water the 48h that dialyses, dialysis medium be followed successively by DMF and
Distilled water.It is cholesterol-low molecular weight heparin graft copolymer that freeze-drying, which obtains white loose solid powder, and reaction step is such as
Fig. 2.The use of ammonium ferric sulfate colorimetric method for determining cholesterol degree of substitution is 3.1%.
Embodiment 6
First prepare 10mg/mL polymer materials aqueous solution 5mL, be added dropwise under stiring the 10mg/mL of 0.3mL Ah
Mycin (DOX) drug solution, then Probe Ultrasonic Searching 30min, then be transferred in bag filter and dialyse 24 hours, dialysis medium is distillation
Water obtains medicament-carried nano micelle preparation.
Drug-carrying nanometer particle is diluted to suitable concentration with DMSO, using ultraviolet specrophotometer determination sample at 482nm
Absorbance value, and the quality of DOX in polymer is calculated, according to formula：
Calculating drugloading rate is 5.0wt%.
Embodiment 7
The aqueous solution 5mL for first preparing 10mg/mL polymer materials, is added dropwise the 10mg/mL's of 0.75mL under stiring
Adriamycin (DOX) drug solution, then Probe Ultrasonic Searching 30min, then be transferred in bag filter and dialyse 24 hours, dialysis medium is distillation
Water obtains medicament-carried nano micelle preparation.
Drug-carrying nanometer particle is diluted to suitable concentration with DMSO, using ultraviolet specrophotometer determination sample at 482nm
Absorbance value, and the quality of DOX in polymer is calculated, according to formula：
Calculating drugloading rate is 12wt%.
Embodiment 8
First prepare 10mg/mL polymer materials aqueous solution 5mL, be added dropwise under stiring the 10mg/mL of 1.5mL Ah
Mycin (DOX) drug solution, then Probe Ultrasonic Searching 30min, then be transferred in bag filter and dialyse 24 hours, dialysis medium is distillation
Water obtains medicament-carried nano micelle preparation.
Drug-carrying nanometer particle is diluted to suitable concentration with DMSO, using ultraviolet specrophotometer determination sample at 482nm
Absorbance value, and the quality of DOX in polymer is calculated, according to formula：
Calculating drugloading rate is 19.8wt%.
Embodiment 9
10mg/mL polymer material 5mL are configured using organic solvent, and the camptothecine of 5mg is added, then rotary evaporation removes
Organic solvent is removed, distilled water stirring is added and redissolves, then Probe Ultrasonic Searching 30min, then be transferred in bag filter and dialyse 24 hours, thoroughly
Analysis medium is distilled water, obtains medicament-carried nano micelle preparation.
Drug-carrying nanometer particle is diluted to suitable concentration with DMSO, utilizes the absorbance of ultraviolet specrophotometer determination sample
Value, and the quality of camptothecine in polymer is calculated, according to formula： It calculates
Drugloading rate is 5wt%.
Embodiment 10
10mg/mL polymer material 5mL are configured using organic solvent, and the taxol of 10mg is added, then are transferred to bag filter
Middle dialysis 48 hours, dialysis medium is distilled water, obtains medicament-carried nano micelle preparation.
Drug-carrying nanometer particle is diluted to suitable concentration with DMSO, utilizes the absorbance of ultraviolet specrophotometer determination sample
Value, and the quality of taxol in polymer is calculated, according to formula： It calculates
Drugloading rate is 8wt%.
Embodiment 11
The 4T-1 cell suspensions for removing exponential phase, by 1 × 104A/hole concentration is inoculated in 96 porocyte culture plates, mistake
Night grows.Culture medium is abandoned in suction, and the free DOX and DOX/LHC of series concentration is added, and is cultivated respectively for 24 hours and 48h.After culture
Suction abandons culture medium and 100 μ L culture mediums and 20 μ L MTT solution is added, and continues to cultivate 4h.It finally inhales and 150 μ L is added after abandoning culture medium
DMSO, survey absorbance under 491nm wavelength with microplate reader, calculate cell survival rate, such as Fig. 3 as follows.
Embodiment 12
SD rats 6 are randomly divided into 2 groups, every group 3.It is molten that the free DOX and DOX/LHC of tail vein injection is distinguished after weighing
Liquid, dosage are 2.5mg DOX/kg.After administration respectively at 0.08,0.25,0.5,1,2,4,6,8,12, it is quiet after eye for 24 hours
Arteries and veins clump takes blood 0.5mL or so, in the centrifuge tube loaded on test tube of hepari.Whole blood centrifuges (1500rpm, 10min) separated plasma.In excitation
At wavelength 494nm, launch wavelength 587nm measure fluorescent intensity, draw rat body in blood concentration through when curve such as Fig. 4,
And main pharmacokinetic parameters are calculated.
The pharmacokinetic parameters (n=3) of DOX after 1 tail vein injection of table
Embodiment 13
40 Balb/c mouse tail vein inoculum densities are 5 × 105It is a/only 4T1-Luc cell suspensions establish breast cancer
Lung metastases model.After 12h, mouse is divided into 5 groups, every group 8, tail vein injection saline, unbound heparin, blank are received respectively
Rice glue beam LHC, free DOX and DOX/LHC solution (DOX5mg/kg, LMWH 20mg/kg), are administered once, exist respectively every three days
Photo is acquired with living imaging instrument within 11st day and the 17th day, observe Lung metastases situation, such as Fig. 5.
Claims (9)
1. a kind of nano-micelle preparations, which is characterized in that drug carrier material is that the low molecular weight heparin of cholesterol modification derives
Object, under aqueous conditions, it is the nano-micelle of hydrophobic inner core to be formed by hydrophilic outer shell, cholesterol of low molecular weight heparin, can be wrapped
Carried anticancer medicine object plays the antimetastatic activity of low molecular weight heparin while chemotherapeutics plays antitumor action.The present invention
Nanometer formulation, grain size can be used for tail vein injection between 20nm-200nm, and passive concentration improves medicine in tumor locus
Object drug effect reduces toxic side effect.
2. polymer carrier materials according to claim 1, the molecular weight of low molecular weight heparin is between 1000-10000.
3. polymer carrier materials according to claim 1, the modification rate of cholesterol is between 3%-20%.
4. polymer carrier materials according to claim 1, cholesterol is modified to low molecular weight heparin, even by linking arm
The end for connecing arm can be amino, ester bond or hydrazone bond, and connection arm configuration is alkyl chain.
5. nanometer formulation according to claim 1, the antitumor drug contained can be adriamycin, Epi-ADM, taxol,
Docetaxel, cis-platinum, methotrexate (MTX), cytarabine, gemcitabine, camptothecine, mitomycin, floxuridine, Chinese blister beetle
Element etc..
6. nano-micelle preparations according to claim 1, which is characterized in that prepare the nanometre glue for carrying medicine using dialysis
Beam, encapsulation rate is between 50%-99%, and drugloading rate is between 5wt%-20wt%.
7. nano-micelle preparations according to claim 1, which is characterized in that solvent can be pure water, buffer solution, body
Liquid, tissue culture medium or other solvent mediums not based on organic solvent.
8. a kind of nano-micelle of cholesterol-low molecular weight heparin load antitumor drug as described in one of claim 1-7
Preparation prepares preparation method selected from one of following：
(1) aqueous solution of first prepared polymer material, is added dropwise a certain amount of antineoplastic drug solution, then visits under stiring
Head ultrasound 30min, then be transferred in bag filter and dialyse 24 hours, dialysis medium is distilled water, obtains medicament-carried nano micelle preparation.It is cold
Be lyophilized it is dry after store for future use, use preceding redissolution, internal injection；
(2) polymer and antitumor drug are dissolved with organic solvent, then rotary evaporation removes organic solvent, adds distilled water
Stirring is redissolved, and Probe Ultrasonic Searching 30min turns to dialyse 24 hours in bag filter again, and dialysis medium is distilled water, obtains medicament-carried nano glue
Beam preparation stores for future use after freeze-drying, uses preceding redissolution, internal injection；
(3) polymer and antitumor drug are dissolved with organic solvent, then is transferred in bag filter and dialyses 48 hours, dialysis medium is to steam
Distilled water obtains medicament-carried nano micelle preparation, is stored for future use after freeze-drying, uses preceding redissolution, internal injection.
9. a kind of nano-micelle preparations of cholesterol as described in one of claim 1-8-low molecular weight heparin load adriamycin
Application, which is characterized in that the nano-micelle while improving antitumor drug anticancer effect, play low molecular weight heparin
Antimetastatic activity, the treatment for primary tumor, metastatic tumo(u)r and postoperative anti-recurrence provides better choice.
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| CN201810604630.8A CN108451906A (en) | 2018-06-08 | 2018-06-08 | A kind of nanometer formulation and preparation method for antitumor and anti-metastatic therapy cholesterol-low molecular weight heparin |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111135312A (en) * | 2020-01-10 | 2020-05-12 | 中国药科大学 | Preparation and application of mixed nano preparation based on tumor pan-metabolism regulation |
| CN112608397A (en) * | 2020-11-30 | 2021-04-06 | 西安交通大学 | Platinum antitumor drug-polysaccharide polymer nano prodrug and preparation method and application thereof |
| CN113061180A (en) * | 2021-04-02 | 2021-07-02 | 山东大学 | Conjugate of ES2 peptide without anticoagulation activity heparin modification and combination with paclitaxel, preparation method and application thereof |
-
2018
- 2018-06-08 CN CN201810604630.8A patent/CN108451906A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| HAIFENG SUN,ET AL: "Development of low molecular weight heparin based nanoparticles for metastatic breast cancer therapy", 《INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111135312A (en) * | 2020-01-10 | 2020-05-12 | 中国药科大学 | Preparation and application of mixed nano preparation based on tumor pan-metabolism regulation |
| CN112608397A (en) * | 2020-11-30 | 2021-04-06 | 西安交通大学 | Platinum antitumor drug-polysaccharide polymer nano prodrug and preparation method and application thereof |
| CN113061180A (en) * | 2021-04-02 | 2021-07-02 | 山东大学 | Conjugate of ES2 peptide without anticoagulation activity heparin modification and combination with paclitaxel, preparation method and application thereof |
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Application publication date: 20180828 |