CN105708848A - Environmentally responsive tumor targeted combined administration transfer system - Google Patents
Environmentally responsive tumor targeted combined administration transfer system Download PDFInfo
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- CN105708848A CN105708848A CN201610079030.5A CN201610079030A CN105708848A CN 105708848 A CN105708848 A CN 105708848A CN 201610079030 A CN201610079030 A CN 201610079030A CN 105708848 A CN105708848 A CN 105708848A
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- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention discloses an environmentally responsive tumor targeted combined administration transfer system.Adriamycin amycin and carboxymethyl chitosan are connected through a disulfide bond, and therefore an adriamycin amycin macromolecular prodrug is synthesized.The other chemotherapy drug is ingeniously encapsulated in the adriamycin amycin macromolecular prodrug, and therefore the combined administration nano transfer system is prepared.The system has good systemic circulation stability and intelligent drug release performance, few drug ingredients are released in simulated blood, the release quantity of the drug ingredients in a cancer cell environment is very large, and meanwhile high applicability is achieved.
Description
Technical field
The invention belongs to pharmaceutical arts, be specifically related to a kind of environment-responsive cancer target administering drug combinations transmission system and preparation method thereof.
Background technology
As the Main Means of oncotherapy, there is therapeutic effect difference, problem that side effect is big in chemotherapy always.Clinical experiment and research show, single drug is difficult to tumor is played significant therapeutic effect, and easily produces drug resistance and lessen the curative effect, so administering drug combinations becomes a developing direction of oncotherapy.
Adriamycin and Platinol cisplatin is the medicine of two kinds of different antitumor mechanism, often combines clinically for treating tumor, and clinical effectiveness shows, Papillary has synergism.Amycin is a kind of antitumor antibiotics, can suppress the synthesis of RNA and DNA, but it has the toxic and side effects such as very strong bone marrow depression, cardiac toxicity, digestive tract reaction.Cisplatin is similar to bifunctional alkylating agents, is combined with DNA after entering cell, forms platinum-DNA complex, destroys the function of DNA, hinders DNA replication dna, the apoptosis of inducing tumor cell.Although tumor is had good therapeutic effect by adriamycin and Platinol cisplatin drug combination, but creates serious toxic and side effects and untoward reaction.The selectivity of sick cell is lacked and reveals in body circulates by existing pharmaceutical preparation is the basic reason causing these problems.Therefore, improve the body cyclical stability of pharmaceutical preparation and the selectivity to sick cell is the important topic that chemotherapeutics is badly in need of solving.
Active targeting drug-supplying system is with sick cell for target spot, drug target specificity being delivered to sick cell and imported the drug-supplying system in born of the same parents by cellular uptake, such system is solve the pharmaceutical preparation selectivity disappearance to sick cell to provide effective way.At present, active targeting drug-supplying system gives its active targeting function by nanoparticle surface coupling targeted molecular or targeting group mostly.In order to ensure the efficient targeting sick cell of drug-supplying system, the design of targeted molecular or targeting group is very crucial.
After active targeting drug-supplying system enters target cell, it is necessary to specific environment release medicine in born of the same parents can be responded.The drug release trigger mechanism of bibliographical information mainly has pH sensitivity release Mechanisms, enzyme sensitivity release Mechanisms and the sensitive release Mechanisms of reduction etc..Reduction sensitive medicaments carrier utilizes the difference of intraor extracellular reducing substances concentration, makes carrier in tumor cell, disulfide bonds occur thus being discharged rapidly by medicine.The content (2-10mM) of cell GSH-PX activity is from far away higher than extracellular concentration (close to 2-20 μM), the content of tumor cell GSH-PX activity is higher than normal cell, therefore design is based on the reduction responsive nano drug-supplying system of disulfide bond, it is advantageously implemented medicine and inspires release in target cell.
Carboxymethyl chitosan is a kind of water-solubility chitosan derivative that chitosan obtains after carboxymethylation reaction, carboxymethyl chitosan good water solubility, stable in properties, nontoxic, no antigen, good biocompatibility, biodegradable, in medicine and health food, application is relatively broad.
In recent years, molecular biology and molecular pathology research disclose, activity and the quantity of the folacin receptor on many human cancer cell surfaces are significantly higher than normal tissue cell, and folacin receptor is had the affinity of height by folic acid, so this characteristic can be utilized the folic acid targeted molecular as antitumor drug, with medicine or carrier conjugation to realize the targeted of medicine.
Polymeric materials prepares the focus that nanoparticle is delivery system research in recent years for the transmission of antitumor drug, but there is the defects such as drug loading is low, and administering drug combinations can make up the defect that drug loading is low, plays the synergism of medicine simultaneously.Therefore targeting administering drug combinations transmission system has big advantage in the treatment of tumor.
Summary of the invention
It is an object of the invention to provide a kind of environment-responsive cancer target administering drug combinations transmission system and preparation method thereof, this system has obvious advantage when for chemotherapy of tumors, and tumor cell has targeting, and Normocellular toxic and side effects is only small.
Environment-responsive cancer target administering drug combinations transmission system provided by the present invention, including the nanoparticle being made up of antitumor drug and the high molecular polymer for encapsulating described antitumor drug and surface coupling targeted molecular, described high molecular polymer is connected with another kind of antitumor drug amycin also by disulfide bond.
Described high molecular polymer prepares by the following method:
1) doxorubicin hydrochloride and triethylamine are obtained by reacting base amycin (DOX)；
2) with 3, double; two (N-hydroxy-succinamide) ester (DSP) of 3-dithiodipropionic acid is cross-linking agent, base amycin is reacted with carboxymethyl chitosan, obtains carboxymethyl chitosan-disulfide bond-amycin high molecular polymer (DOX-DSP-CMCS)；
3) by the carboxyamino on folic acid, the carboxymethyl chitosan-disulfide bond-amycin high molecular polymer of the ammonification folic acid and 10-50 weight portion that then take 10-50 weight portion reacts, and obtains the high molecular polymer of surface coupling targeted molecular.
Preferably, step 3) in course of reaction be: by the carboxymethyl chitosan-disulfide bond-amycin high molecular polymer of 10-50 weight portion first with water dissolution, obtain the aqueous solution of 1-5mg/mL, then the ammonification folic acid of 10-50 weight portion is joined in described aqueous solution, add 1-(3-the dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride of 1-10 weight portion, react 12h, deionized water dialysis 48h, lyophilization, obtains the high molecular polymer of surface coupling targeted molecular.
The preparation method of environment-responsive cancer target administering drug combinations transmission system provided by the present invention is: by soluble in water for the high molecular polymer of the 20-100 weight portion surface coupling targeted molecular adopting said method to prepare, add 5-10 weight portion antitumor drug, lucifuge stirs, ultrasonic, dialyse with deionized water again, lyophilization, the nanoparticle obtained is environment-responsive cancer target administering drug combinations transmission system.
The beneficial effects of the present invention is:
1) nanometer transmission system of administering drug combinations is prepared
Chemotherapeutics administration nano-drug administration system is that a kind of medicine is as model drug mostly, and in the chemotherapeutic treatment process of tumor, what mostly adopt is two kinds of medication combined chemotherapy, amycin is connected with carboxymethyl chitosan by the present invention by disulfide bond, thus having synthesized the Macromolecule Prodrug DOX-DSP-CMCS of amycin, and be encapsulated in DOX-DSP-CMCS by another kind chemotherapeutics cleverly, thus prepare nanometer transmission system of administering drug combinations.
(2) the body cyclical stability of system and intelligent medicine releasing
Sulfydryl-cystine linkage exchange reaction has quick, easy and reversible feature, and in the cell of animal and human's body, glutathion is the abundantest low molecule bioactive sulfhydryl material, is topmost reducing substances.The present invention designs controlled-release administrating system by disulfide bond, thus avoiding nanoparticle to disintegrate in body circulates and medicine leakage, and once be combined by receptor-specific, enters in tumor cell, and disulfide bond will rupture because of intracellular reducing environment and discharge medicine.Therefore, the reduction sensitive mechanism of disulfide bond makes targeted nano granule form good body cyclical stability and intelligent medicine releasing.
Test shows, tumor cell is had obvious inhibitory action by drug-supplying system of the present invention, and adriamycin and Platinol cisplatin release in simulation blood is little, and burst size is significantly high in tumor cell environment, it was demonstrated that this drug-supplying system has good environment-responsive.
(3) broad applicability of system
The targeted nano transmission system of the present invention can be passed through carboxymethyl chitosan activity group and connect the different activities material containing reactive groups such as-NH2 or-COOH, such as tumor monoclonal antibody, anti-tumor chemotherapeutic medicine and absorption gene etc., thus expanding its operation strategies further, there is wide applicability.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of DOX-DSP-CMCS.
Fig. 2 is the synthetic route chart of ammonification folic acid.
Fig. 3 is the synthetic route chart of the high molecular polymer of surface coupling targeted molecular.
Fig. 4 is amycin drug release profiles figure in variable concentrations glutathione solution in embodiment 1.
Fig. 5 is cisplatin drug release profiles figure in variable concentrations glutathione solution in embodiment 1.
Detailed description of the invention
Embodiment 1
1. the preparation of high molecular polymer
(1) synthesis of DOX-DSP-CMCS
Take doxorubicin hydrochloride, accurately weighed, it is dissolved in pure water, addition triethylamine (doxorubicin hydrochloride and triethylamine mol ratio are 1: 2) lucifuge is drawn and is mixed reaction overnight, reactant liquor puts pure water lucifuge dialysis in bag filter, frozen centrifugation, will retain liquid lyophilization, obtain base amycin (DOX).
Take DSP40mg, accurately weighed, it is dissolved in 2.0mL dimethyl sulfoxide, and adds the triethylamine dimethyl sulfoxide solution of 0.1mL0.1%.Separately take DOX54mg, accurately weighed, it is dissolved in 2.7mL dimethyl sulfoxide solution, is slowly added dropwise in above-mentioned DSP solution (mol ratio of DOX and DSP is 1: 0.9), 2h is stirred at room temperature, obtains intermediate DOX-DSP.
Precision weighs DOX-DSP, is dissolved in dimethyl sulfoxide so that DOX concentration is 10mg/mL.Another precision weighs carboxymethyl chitosan (CMCS) 100mg, being dissolved in deionized water, concentration is 2mg/mL, adjusts PH to 7.4, obtain CMCS solution, it is slowly added dropwise the above-mentioned DOX-DSP solution of 1.0mL again, 12h is stirred at room temperature, reactant liquor is moved to bag filter, dialyse 2 days with dimethyl sulfoxide water mixed solvent (deionized water: dimethyl sulfoxide=9: 1) (volume ratio), distilled water continues dialysis 1 day, and the centrifugal 10min of 6000rpm removes precipitation, lyophilization supernatant.Lyophilized products adds 20mL dimethyl sulfoxide solution, ultrasonic, filtration, removes the reactant being dissolved in dimethyl sulfoxide, repeat 3 times and do not show redness to filtrate.It is dissolved in water, moves to dialysis 1 day, lyophilization in bag filter, obtain DOX-DSP-CMCS (synthetic route is as shown in Figure 1).
(2) preparation of the high molecular polymer of surface coupling targeted molecular
Folic acid 44.1mg, it is dissolved in 3mL dimethyl sulfoxide, add 27mgEDC and 24mgN-hydroxysuccinimide (NHS), reacting 6h in 50 DEG C, reactant liquor is cooled to room temperature, adds 66.7uL ethylenediamine and 50uL pyridine reacts overnight, use excess acetonitrile precipitated product, filtering, with washed with diethylether, vacuum drying obtains the folic acid (synthetic route is as shown in Figure 2) of carboxyamino.
Take in the DOX-DSP-CMCS aqueous solution (5ml) that 10mg ammonification folic acid joins 2mg/mL, add 6.12mgEDC and react 12h, deionized water dialysis 48h, lyophilization obtains the high molecular polymer (synthetic route is as shown in Figure 3) of surface coupling targeted molecular.
2. the preparation of environment-responsive cancer target administering drug combinations transmission system
Taking the high molecular polymer 10mg obtained in step 1 and be scattered in 10mL water, add cisplatin 2mg, lucifuge stirs 3 days, Probe Ultrasonic Searching 30 times, then dialyses 24h with deionized water, removes excessive cisplatin, lyophilization, prepares nanoparticle.
3. the cytotoxicity experiment of environment-responsive cancer target administering drug combinations transmission system
(1) cell is cultivated
Being placed in the MEM culture medium containing 10% hyclone by HeLa cell, penicillin, streptomycin concentration are 100U/mL, 37 DEG C, 5%CO2Cultivating continuously in incubator, trophophase cell of taking the logarithm is stand-by.
(2) inoculating cell
It is in the HeLa cell of exponential phase with 0.25% trypsinization, washs by PBS solution, after the centrifugal 5min of 1000rpm, add fresh culture and form cell suspending liquid, with every hole 2 × 103Individual cell (cell density 0.2 × 105Individual/mL, takes 100 μ L) it is inoculated in 96 well culture plates, move to CO2Cultivation 24h in incubator, condition of culture: MEM culture medium, 10% hyclone, 37 DEG C, 5%CO2.Microscope observation of cell whether adherent growth.
(3) medicine is added
After cultivating 24h, inhale and abandon culture medium, every hole adds the nanoparticle suspension of 200 μ L variable concentrations, continue to cultivate 1d, 3d, 5d.
(4) colour generation
Culture medium is abandoned in suction, rinses 3 times with PBS, and every hole adds 100 μ L culture medium and 10 μ LCCK-8 solution, continues to hatch 4h.
(5) colorimetric
Measure each hole absorbance at 450nm place by microplate reader, detect wavelength 450nm, reference wavelength 600nm, calculate cell survival rate.
(6) experimental result
Result shows that tumor cell is had obvious inhibitory action by drug-supplying system of the present invention, and strengthens along with concentration increases inhibitory action, and inhibitory action also strengthens as time went on.
4. the extracorporeal releasing experiment of environment-responsive cancer target administering drug combinations transmission system
Sulfydryl-cystine linkage exchange reaction has quick, easy and reversible feature, in the cell of animal and human's body, glutathion is the abundantest low molecule bioactive sulfhydryl material, it it is topmost reducing substances, on body fluid or cell membrane, protein is intended to make cystine linkage stable, and the concentration that reason is exactly glutathion is very low.On the contrary, it is up to 2-10mM in intracellular concentration so that in cell, present very strong reducing environment.What it should be noted that reproducibility compared with normal tissue in tumor tissues wants high a lot, the concentration of its GSH-PX activity be in normal structure more than 4 times.
Therefore, it can PBS (PH7.4) solution by preparing variable concentrations glutathion is that release medium simulates blood and tumor cell environment.Take a certain amount of amycin-cisplatin environment-responsive cancer target administering drug combinations transmission system and be scattered in appropriate PBS (PH7.4) solution, ultrasonic 10min, it is packaged in bag filter, it is placed in containing glutathion respectively 2 μMs, 100 μMs, 2mM, in PBS (PH7.4) release medium of 10mM, keep constant temperature 37 ± 1 DEG C, rotating speed 65 revs/min, respectively at 0, 0.5, 1, 2, 4, 8, 12, dialysis solution 1mL is taken during 24h, supplement 1mL fresh phosphoric salt buffer simultaneously and maintain release medium constancy of volume, the burst size of adriamycin and Platinol cisplatin in release medium is measured with UV detector, result is Fig. 4 such as, shown in Fig. 5.
From Fig. 4,5 find out, adriamycin and Platinol cisplatin in simulation blood (glutathione content is 2 μMs) release seldom, and in tumor cell environment, release in 24 hours is the highest can reach 90%, it was demonstrated that this drug-supplying system has good environment-responsive.
Embodiment 2
The preparation of 1.DOX-DSP-CMCS
Identical with the method for embodiment 1.
2. the preparation of the high molecular polymer of surface coupling targeted molecular
Taking in the DOX-DSP-CMCS aqueous solution (25ml) that 10mg ammonification folic acid joins 2mg/mL, add 8mgEDC and react 12h, deionized water dialysis 48h, lyophilization obtains the high molecular polymer of surface coupling targeted molecular.
3. the preparation of environment-responsive cancer target administering drug combinations transmission system
Taking the high molecular polymer 20mg obtained in step 2 and be scattered in 10mL water, add curcumin 2mg, lucifuge stirs 3 days, Probe Ultrasonic Searching 30 times, then dialyses 24h with deionized water, removes excessive curcumin, lyophilization, to obtain final product.
3. cytotoxicity experiment
Test method is identical with embodiment 1, and result of the test is shown in following table.
4. extracorporeal releasing experiment
Test method is identical with embodiment 1 with result, the release in simulation blood (glutathione content is 2 μMs) of amycin and curcumin is little, and 24 hours burst sizes are significantly high in tumor cell environment, it was demonstrated that this drug-supplying system has good environment-responsive.
In the present invention, theoretically, the medicine of package-contained refers to tumour medicine, including general small-molecule drug and have bioactive polypeptide protein class macromolecular drug.In an embodiment of the present invention, only cisplatin and curcumin having been tested, by that analogy, the present invention should also be able to the targeted nano granule for being produced similar to the antitumor drug such as 5-fluorouracil, paclitaxel, and obtains similar effect.
Claims (4)
1. an environment-responsive cancer target administering drug combinations transmission system, including the nanoparticle being made up of antitumor drug and the high molecular polymer for encapsulating described antitumor drug and surface coupling targeted molecular, described high molecular polymer is connected with another kind of antitumor drug amycin also by disulfide bond, and described high molecular polymer is prepared by the following method:
1) doxorubicin hydrochloride and triethylamine are obtained by reacting base amycin；
2) with double; two (N-hydroxy-succinamide) ester of 3,3-dithiodipropionic acids for cross-linking agent, base amycin is reacted with carboxymethyl chitosan, obtains carboxymethyl chitosan-disulfide bond-amycin high molecular polymer；
3) by the carboxyamino on folic acid, the carboxymethyl chitosan-disulfide bond-amycin high molecular polymer of the ammonification folic acid and 10-50 weight portion that then take 10-50 weight portion reacts, and obtains the high molecular polymer of surface coupling targeted molecular.
2. environment-responsive cancer target administering drug combinations transmission system as claimed in claim 1, it is characterized in that: step 3) in course of reaction be: by the carboxymethyl chitosan-disulfide bond-amycin high molecular polymer of 10-50 weight portion first with water dissolution, obtain the aqueous solution of 1-5mg/mL, then the ammonification folic acid of 10-50 weight portion is joined in described aqueous solution, add 1-(3-the dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride of 1-10 weight portion, reaction 12h, deionized water dialysis 48h, lyophilization, obtain the high molecular polymer of surface coupling targeted molecular.
3. environment-responsive cancer target administering drug combinations transmission system as claimed in claim 1, it is characterised in that: described antitumor drug is cisplatin or curcumin.
4. the preparation method of an environment-responsive cancer target administering drug combinations transmission system, it is characterised in that comprise the following steps:
1) doxorubicin hydrochloride and triethylamine are obtained by reacting base amycin；
2) with double; two (N-hydroxy-succinamide) ester of 3,3-dithiodipropionic acids for cross-linking agent, base amycin is reacted with carboxymethyl chitosan, obtains carboxymethyl chitosan-disulfide bond-amycin high molecular polymer；
3) by the carboxyamino on folic acid, the carboxymethyl chitosan-disulfide bond-amycin high molecular polymer of the ammonification folic acid and 10-50 weight portion that then take 10-50 weight portion reacts, and obtains the high molecular polymer of surface coupling targeted molecular.
4) taking in 20-100 weight portion high molecular polymer disperse water, add 5-10 weight portion antitumor drug, lucifuge stirs, ultrasonic, then dialyses with deionized water, and lyophilization, the nanoparticle obtained is environment-responsive cancer target administering drug combinations transmission system.
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Cited By (15)
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| CN106750047A (en) * | 2016-11-28 | 2017-05-31 | 北京化工大学 | A kind of preparation method of the pH response doxorubicin nanometer medicament capsules of positive surface charge |
| CN107753465A (en) * | 2017-03-22 | 2018-03-06 | 温州医科大学 | A kind of preparation method and application of the nanometer formulation of Legumain responses substep release adriamycin/curcumin sustained release |
| CN108187063A (en) * | 2018-01-09 | 2018-06-22 | 沈阳药科大学 | Albumin combination type antineoplastic-maleimide amine molecule prodrug |
| CN111053911A (en) * | 2019-12-20 | 2020-04-24 | 西南大学 | Reduction response type cross-linking agent and preparation and application of cross-linked hydroxyl drug molecule thereof |
| CN111544596A (en) * | 2020-06-08 | 2020-08-18 | 山西大学 | GSH response type nano-diamond targeted drug and preparation method and application thereof |
| CN112480289A (en) * | 2020-11-30 | 2021-03-12 | 西安交通大学 | Core-shell structure type chitosan-based nano prodrug carrying doxorubicin and platinum drugs together, and preparation method and application thereof |
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