CN105708848B - A kind of environment-responsive cancer target administering drug combinations transmission system - Google Patents
A kind of environment-responsive cancer target administering drug combinations transmission system Download PDFInfo
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Abstract
The invention discloses a kind of environment-responsive cancer target administering drug combinations transmission systems, adriamycin is connect by the present invention by disulfide bond with carboxymethyl chitosan, to synthesize adriamycin Macromolecule Prodrug, and cleverly another chemotherapeutics is encapsulated in adriamycin Macromolecule Prodrug, to prepare the nanometer transmission system of administering drug combinations, the system has good body circulation stability and intelligent medicine releasing, drug ingedient discharges seldom in simulating blood, and burst size is very high in tumour cell environment, while also there is wide applicability.
Description
Technical field
The invention belongs to pharmaceutical arts, and in particular to a kind of environment-responsive cancer target administering drug combinations transmission system and its
Preparation method.
Background technology
Main means of the chemotherapy as oncotherapy, always exist the problem that therapeutic effect is poor, side effect is big.Clinical trial
With studies have shown that single drug is difficult to play significant therapeutic effect to tumour, and easy tos produce drug resistance and lessen the curative effect, institute
Become a developing direction of oncotherapy with administering drug combinations.
Adriamycin and Platinol cisplatin is the drug of two kinds of different antitumor mechanisms, is clinically often combined for treating tumour, clinical
The results show that Papillary has synergistic effect.Adriamycin is a kind of antitumor antibiotics, can inhibit the synthesis of RNA and DNA, but
It has the toxic side effects such as very strong bone marrow suppression, cardiac toxic, digestive tract reaction.Cis-platinum is similar to bifunctional alkylating agents, enters
It is combined with DNA after cell, forms platinum-DNA complex, destroy the function of DNA, hindered DNA replication dna, induce withering for tumour cell
It dies.Although adriamycin and Platinol cisplatin drug combination has good therapeutic effect to tumour, but produce serious toxic side effect and not
Good reaction.To the selectivity of sick cell missing and in body circulation, leakage is lead to these problems basic to existing pharmaceutical preparation
Reason.Therefore, improve pharmaceutical preparation body circulation stability and to the selectivity of sick cell be chemotherapeutics be badly in need of solve
Important topic.
Active targeting drug delivery system is drug target specificity to be delivered to sick cell simultaneously using sick cell as target spot
The drug delivery system of intracellular is imported by cellular uptake, such system is to solve pharmaceutical preparation to lack the selectivity of sick cell
Provide effective way.Currently, active targeting drug delivery system is coupled targeted molecular or targeting base by nanoparticle surface mostly
Group assigns its active targeting function.In order to ensure drug delivery system efficiently targets sick cell, targeted molecular or targeting group are set
Meter is very crucial.
After active targeting drug delivery system enters target cell, it is necessary to intracellular specific environment release drug can be responded.Document report
Drug release trigger mechanism mainly have pH sensitivities release Mechanisms, enzyme sensitivity release Mechanisms and the sensitive release Mechanisms of reduction etc..Also
Former sensitive medicaments carrier utilizes the difference of intraor extracellular reducing substances concentration, makes carrier that disulfide bonds occur in tumour cell
To which drug rapidly be released.The content (2-10mM) of cell GSH-PX activity is higher than extracellular concentration from far away
(close to 2-20 μM), the content of tumour cell GSH-PX activity is higher than normal cell, therefore designs the reduction response based on disulfide bond
Property administration nano-drug administration system, is advantageously implemented drug and inspires release in target cell.
Carboxymethyl chitosan is a kind of water-solubility chitosan derivative that chitosan obtains after carboxymethylation reaction, carboxylic first
Base enclosure glycan good water solubility, property are stablized, and nontoxic, no antigen, good biocompatibility is biodegradable, in medicine and health care
Application is relatively broad in terms of food.
In recent years, molecular biology and molecular pathology research disclose, the folacin receptor on many human cancer cell surfaces
Activity and quantity are significantly higher than normal tissue cell, and folic acid has folacin receptor the compatibility of height, so this can be utilized
One characteristic is using folic acid as the targeted molecular of antitumor drug, with drug or carrier conjugation to realize that the targeting of drug conveys.
It is delivery system research in recent years that polymeric materials, which prepare nanoparticle for the transmission of antitumor drug,
Hot spot, but there are the defects such as drugloading rate is low, and administering drug combinations can make up the low defect of drugloading rate, while play the collaboration of drug
Effect.Therefore targeting administering drug combinations transmission system has big advantage in terms of the treatment of tumour.
Invention content
The object of the present invention is to provide a kind of environment-responsive cancer target administering drug combinations transmission system and preparation method thereof,
The system has apparent advantage when for chemotherapy of tumors, has targeting to tumour cell, and secondary to the poison of normal cell
Act on very little.
Environment-responsive cancer target administering drug combinations transmission system provided by the present invention, including by antitumor drug and use
In the nanoparticle for the high molecular polymer composition for encapsulating the antitumor drug and surface coupling targeted molecular, the polyphosphazene polymer
Object is closed also to connect with another antitumor drug adriamycin by disulfide bond.
The high molecular polymer is prepared as follows to obtain：
1) doxorubicin hydrochloride and triethylamine react are obtained into base adriamycin (DOX)；
2) with bis- (n-hydroxysuccinimide) esters (DSP) of 3,3- dithiodipropionic acids for crosslinking agent, by base adriamycin
It is reacted with carboxymethyl chitosan, obtains carboxymethyl chitosan-disulfide bond-adriamycin high molecular polymer (DOX-DSP-CMCS)；
3) by the carboxyamino on folic acid, the ammonification folic acid of 10-50 parts by weight and the carboxylic first of 10-50 parts by weight are then taken
Base enclosure glycan-disulfide bond-adriamycin high molecular polymer reacts, and obtains the high molecular polymer of surface coupling targeted molecular.
Preferably, the reaction process in step 3) is：By carboxymethyl chitosan-disulfide bond-adriamycin of 10-50 parts by weight
High molecular polymer first uses water dissolution, obtains the aqueous solution of 1-5mg/mL, is then added to the ammonification folic acid of 10-50 parts by weight
In the aqueous solution, 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides of 1-10 parts by weight are added, are reacted
12h, deionized water dialysis 48h, freeze-drying obtain 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：It will use upper
The high molecular polymer for stating the 20-100 parts by weight surface coupling targeted molecular of method preparation is soluble in water, and 5-10 parts by weight are added
Antitumor drug is protected from light stirring, ultrasound, then use deionized water dialysis, be freeze-dried, obtained nanoparticle is environment-responsive
Cancer target administering drug combinations transmission system.
The beneficial effects of the present invention are：
1) the nanometer transmission system of administering drug combinations is prepared
Chemotherapeutics administration nano-drug administration system is a kind of drug mostly as model drug, and in the chemotherapeutic treatment process of tumour
In, mostly using two kinds of medication combined chemotherapy, adriamycin is connect by the present invention by disulfide bond with carboxymethyl chitosan, from
And the Macromolecule Prodrug DOX-DSP-CMCS of adriamycin has been synthesized, and another chemotherapeutics is cleverly encapsulated in DOX-DSP-
In CMCS, to prepare the nanometer transmission system of administering drug combinations.
(2) the body circulation stability and intelligent medicine releasing of system
It is quick, easy and reversible that sulfydryl-cystine linkage exchange reaction has the characteristics that, in intracellular, the paddy of animal and human body
The sweet peptide of Guang is most abundant low molecule bioactive sulfhydryl substance, is most important reducing substances.The present invention is set by disulfide bond
Controlled-release administrating system is counted, to avoid nanoparticle from disintegrating in body circulation and drug leakage, and is once combined by receptor-specific,
Into in tumour cell, disulfide bond will be broken because of intracellular reducing environment and discharge drug.Therefore, the reduction of disulfide bond
Sensitive mechanism makes targeted nano granule form good body circulation stability and intelligent medicine releasing.
Experiments have shown that drug delivery system of the present invention significantly inhibits tumour cell, adriamycin and Platinol cisplatin is in mould
It is discharged seldom in quasi- blood, and burst size is very high in tumour cell environment, it was demonstrated that the drug delivery system is rung with preferable environment
Ying Xing.
(3) broad applicability of system
The targeted nano transmission system of the present invention can be connected by carboxymethyl chitosan active group containing-NH2 or-COOH etc.
The different activities substance of reactive group, such as tumour monoclonal antibody, anti-tumor chemotherapeutic medicine and absorption gene, to further expand its fortune
With range, there is wide applicability.
Description of the drawings
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 drug release profiles figure of the adriamycin in various concentration glutathione solution in embodiment 1.
Fig. 5 is drug release profiles figure of the cis-platinum in various concentration glutathione solution in embodiment 1.
Specific implementation mode
Embodiment 1
1. the preparation of high molecular polymer
(1) synthesis of DOX-DSP-CMCS
Doxorubicin hydrochloride is taken, it is accurately weighed, it is dissolved in pure water, triethylamine (doxorubicin hydrochloride and triethylamine molar ratio is added
It is 1: 2) is protected from light to draw and mixes reaction overnight, reaction solution sets pure water in bag filter and is protected from light dialysis, and refrigerated centrifuge will retain liquid cooling freeze-drying
It is dry to get base adriamycin (DOX).
DSP 40mg are taken, it is accurately weighed, it is dissolved in 2.0mL dimethyl sulfoxides, and the triethylamine diformazan of 0.1mL 0.1% is added
Sulfoxide solution.DOX 54mg separately are taken, it is accurately weighed, it is dissolved in 2.7mL dimethyl sulfoxide solutions, is slowly dropped to above-mentioned DSP solution
In (molar ratio of DOX and DSP be 1: 0.9), 2h is stirred at room temperature to get intermediate DOX-DSP.
Precision weighs DOX-DSP, is dissolved in dimethyl sulfoxide so that a concentration of 10mg/mL of DOX.Another precision weighs carboxymethyl shell
Glycan (CMCS) 100mg, is dissolved in deionized water, a concentration of 2mg/mL, adjusts PH to 7.4, obtains CMCS solution, then be slowly added dropwise
The above-mentioned DOX-DSP solution of 1.0mL, is stirred at room temperature 12h, reaction solution is moved to bag filter, with dimethyl sulfoxide water mixed solvent (go from
Sub- water：Dimethyl sulfoxide=9: 1) (volume ratio) dialyses 2 days, distilled water continue dialysis 1 day, and 6000rpm, which centrifuges 10min and removes, to sink
It forms sediment, is freeze-dried supernatant.20mL dimethyl sulfoxide solutions, ultrasound, filtering are added in lyophilized products, removing is dissolved in dimethyl sulfoxide
Reactant is repeated 3 times to the not aobvious red of filtrate.It is dissolved in water, moves to dialysis 1 day in bag filter, freeze-drying obtains 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 is dissolved in 3mL dimethyl sulfoxides, adds 27mg EDC and 24mg N- hydroxysuccinimides
(NHS), 6h is reacted in 50 DEG C, reaction solution is cooled to room temperature, and 66.7uL ethylenediamines and the reaction of 50uL pyridines is added overnight, with excess
Acetonitrile precipitation product, filtering, washed with ether, be dried in vacuo carboxyamino folic acid (synthetic route is as shown in Figure 2).
It takes 10mg ammonification folic acid to be added in the DOX-DSP-CMCS aqueous solutions (5ml) of 2mg/mL, 6.12mg EDC is added
React 12h, deionized water dialysis 48h, be freeze-dried surface coupling targeted molecular high molecular polymer (synthetic route as scheme
Shown in 3).
2. the preparation of environment-responsive cancer target administering drug combinations transmission system
It takes the high molecular polymer 10mg obtained in step 1 to be scattered in 10mL water, cis-platinum 2mg is added, is protected from light stirring 3
It, Probe Ultrasonic Searching 30 times, then for 24 hours with deionized water dialysis, excessive cis-platinum is removed, it is freeze-dried, nanoparticle is made.
3. the cytotoxicity of environment-responsive cancer target administering drug combinations transmission system is tested
(1) cell culture
HeLa cells are placed in the MEM culture mediums containing 10% fetal calf serum, a concentration of 100U/ of penicillin, streptomysin
ML, 37 DEG C, 5%CO2It is continuously cultivated in incubator, logarithmic growth phase cell is for use.
(2) inoculating cell
The HeLa cells in exponential phase are handled with 0.25% trypsin digestion, are washed with PBS solution,
After 1000rpm centrifuges 5min, fresh culture is added and forms cell suspending liquid, with every hole 2 × 103A cell (cell density 0.2
×105A/mL takes 100 μ L) it is inoculated in 96 well culture plates, move to CO2It is cultivated in incubator for 24 hours, condition of culture：MEM is cultivated
Base, 10% fetal calf serum, 37 DEG C, 5%CO2.Micro- sem observation cell whether adherent growth.
(3) dosing object
After culture for 24 hours, culture medium is abandoned in suction, and the nanoparticle suspension of 200 μ L various concentrations is added in every hole, continues to cultivate 1d,
3d, 5d.
(4) colour generation
Culture medium is abandoned in suction, is rinsed 3 times with PBS, and 100 μ L culture mediums and 10 μ L CCK-8 solution are added per hole, continue to be incubated
4h。
(5) colorimetric
Absorbance of each hole at 450nm is measured with microplate reader, Detection wavelength 450nm, reference wavelength 600nm are calculated thin
Born of the same parents' survival rate.
(6) experimental result
The result shows that drug delivery system of the present invention significantly inhibits tumour cell, and as concentration increase presses down
Making enhances, and inhibiting effect also enhances as time went on.
4. the extracorporeal releasing experiment of environment-responsive cancer target administering drug combinations transmission system
It is quick, easy and reversible that sulfydryl-cystine linkage exchange reaction has the characteristics that, in intracellular, the paddy of animal and human body
The sweet peptide of Guang is most abundant low molecule bioactive sulfhydryl substance, is most important reducing substances, in body fluid either cell membrane
On, protein is intended to make cystine linkage stabilization, and reason is exactly that the concentration of glutathione is very low.On the contrary, in the cell dense
Degree is up to 2-10mM so that shows very strong reducing environment into the cell.It is worth noting that, the reproducibility in tumor tissues
Much higher compared with normal structure, the concentration of GSH-PX activity is in normal structure more than 4 times.
Therefore, blood can be simulated for dissolution medium by preparing PBS (PH7.4) solution of various concentration glutathione
With tumour cell environment.A certain amount of adriamycin-cis-platinum environment-responsive cancer target administering drug combinations transmission system is taken to be scattered in
In appropriate PBS (PH7.4) solution, ultrasonic 10min is packaged in bag filter, to be placed in containing glutathione be respectively 2 μM, 100 μM,
In PBS (PH7.4) dissolution medium of 2mM, 10mM, keep 37 ± 1 DEG C of constant temperature, 65 revs/min of rotating speed, respectively at 0,0.5,1,2,4,
Dialyzate 1mL is taken when 8,12, for 24 hours, while supplementing 1mL fresh phosphoric salt buffers and maintaining dissolution medium constancy of volume, use ultraviolet
The burst size of adriamycin and Platinol cisplatin in spectrophotometric determination dissolution medium, as a result as shown in Figure 4, Figure 5.
To find out from Fig. 4,5, adriamycin and Platinol cisplatin release in simulation blood (glutathione content is 2 μM) is seldom, and
24 hours release highests can reach 90% in tumour cell environment, it was demonstrated that the drug delivery system has preferable environment-responsive.
Embodiment 2
The preparation of 1.DOX-DSP-CMCS
It is identical as the method for embodiment 1.
2. surface is coupled the preparation of the high molecular polymer of targeted molecular
It takes 10mg ammonification folic acid to be added in the DOX-DSP-CMCS aqueous solutions (25ml) of 2mg/mL, it is anti-that 8mg EDC is added
Answer 12h, deionized water dialysis 48h, be freeze-dried surface coupling targeted molecular high molecular polymer.
3. the preparation of environment-responsive cancer target administering drug combinations transmission system
It takes the high molecular polymer 20mg obtained in step 2 to be scattered in 10mL water, curcumin 2mg is added, is protected from light stirring 3
It, Probe Ultrasonic Searching 30 times, then for 24 hours with deionized water dialysis removes excessive curcumin, freeze-drying to get.
3. cytotoxicity is tested
Test method is same as Example 1, and test result see the table below.
4. extracorporeal releasing experiment
Test method and result are same as Example 1, and (glutathione content is 2 μ in simulation blood for adriamycin and curcumin
M release is seldom in), and 24 hours burst sizes are very high in tumour cell environment, it was demonstrated that the drug delivery system has preferable environment
Response.
In the present invention, theoretically, the drug of package-contained refers to tumour medicine, including general small-molecule drug and
Biologically active polypeptide protein class macromolecular drug.In an embodiment of the present invention, only cis-platinum and curcumin are carried out
Experiment, and so on, the present invention should also can be used in the target for being produced similar to the antitumor drugs such as 5 FU 5 fluorouracil, taxol
To nanoparticle, and obtain similar effect.
Claims (4)
1. a kind of environment-responsive cancer target administering drug combinations transmission system, including by antitumor drug and for encapsulating described resist
The nanoparticle of the high molecular polymer composition of tumour medicine and surface coupling targeted molecular, the high molecular polymer also pass through two
Sulfide linkage is connect with another antitumor drug adriamycin, the environment-responsive cancer target administering drug combinations transmission system be by with
Prepared by lower section method：
1) doxorubicin hydrochloride and triethylamine react are obtained into base adriamycin；
2) with bis- (n-hydroxysuccinimide) esters of 3,3- dithiodipropionic acids for crosslinking agent, by base adriamycin and carboxymethyl shell
Formose Reaction obtains carboxymethyl chitosan-disulfide bond-adriamycin high molecular polymer；
3) by the carboxyamino on folic acid, the ammonification folic acid of 10-50 parts by weight and the carboxymethyl shell of 10-50 parts by weight are then taken
Glycan-disulfide bond-adriamycin high molecular polymer reaction, obtains the high molecular polymer of surface coupling targeted molecular；
4) it takes in 20-100 parts by weight high molecular polymer disperse waters, 5-10 parts by weight antitumor drugs is added, are protected from light stirring, surpass
Sound, then with deionized water dialysis, freeze-drying, obtained nanoparticle is that environment-responsive cancer target administering drug combinations transmit system
System.
2. environment-responsive cancer target administering drug combinations transmission system as described in claim 1, it is characterised in that：In step 3)
Reaction process be：Carboxymethyl chitosan-disulfide bond-adriamycin high molecular polymer of 10-50 parts by weight is first used into water dissolution,
The aqueous solution of 1-5mg/mL is obtained, then the ammonification folic acid of 10-50 parts by weight is added in the aqueous solution, adds 1-10
1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides of parts by weight react 12h, deionized water dialysis 48h, freezing
It is dry, obtain the high molecular polymer of surface coupling targeted molecular.
3. environment-responsive cancer target administering drug combinations transmission system as described in claim 1, it is characterised in that：It is described anti-swollen
Tumor medicine is cis-platinum or curcumin.
4. a kind of preparation method of environment-responsive cancer target administering drug combinations transmission system, it is characterised in that including following step
Suddenly：
1) doxorubicin hydrochloride and triethylamine react are obtained into base adriamycin；
2) with bis- (n-hydroxysuccinimide) esters of 3,3- dithiodipropionic acids for crosslinking agent, by base adriamycin and carboxymethyl shell
Formose Reaction obtains carboxymethyl chitosan-disulfide bond-adriamycin high molecular polymer；
3) by the carboxyamino on folic acid, the ammonification folic acid of 10-50 parts by weight and the carboxymethyl shell of 10-50 parts by weight are then taken
Glycan-disulfide bond-adriamycin high molecular polymer reaction, obtains the high molecular polymer of surface coupling targeted molecular；
4) it takes in 20-100 parts by weight high molecular polymer disperse waters, 5-10 parts by weight antitumor drugs is added, are protected from light stirring, surpass
Sound, then with deionized water dialysis, freeze-drying, obtained nanoparticle is that environment-responsive cancer target administering drug combinations transmit system
System.
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| CN115505047B (en) * | 2022-08-17 | 2024-03-29 | 浙江怡辉生物科技有限公司 | Polymer of nitrogen mustard-glucan, preparation method of polymer, self-assembled nanoparticle, drug-loaded complex and application of polymer |
| CN115990144A (en) * | 2022-11-23 | 2023-04-21 | 武汉理工大学 | Adriamycin and tanshinone IIA combined anti-tumor nano-delivery system and preparation method thereof |
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