CN109620967A - A kind of supramolecular hydrogel and preparation method thereof of the load adriamycin of targeting - Google Patents
A kind of supramolecular hydrogel and preparation method thereof of the load adriamycin of targeting Download PDFInfo
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Abstract
The present invention provides a kind of supramolecular hydrogels of the load adriamycin of targeting, which is characterized in that reacts to obtain by alpha-cyclodextrin, Pluronic F127, DOX-2N- β-CD and FA-2N- β-CD.The preparation method of the supramolecular hydrogel of the load adriamycin of the targeting, which comprises the following steps: weigh DOX-2N- β-CD, Pluronic F127 and FA-2N- β-CD in reactor, deionized water is added, is stirred to react；α-CD is added, continues to be stirred to react, after reaction, the supramolecular hydrogel of the load adriamycin of targeting is obtained after so that reaction system is stood 10-15h.Drug molecule folic acid and adriamycin are carried in hydrogel network in the form of covalent bond respectively in the present invention, can not only reduce the toxic side effect of drug adriamycin, and can also effectively improve the targeting of hydrogel.
Description
Technical field
The invention belongs to supramolecular hydrogels to carry medicine field, and in particular to a kind of load anticancer drug hydrogel of targeting
Preparation method.
Background technique
Adriamycin also known as Doxorubicin are a kind of anthraquinone series antineoplastic medicaments of broad spectrum high-effect, and it is various to be widely used in treatment
Cancer, such as breast cancer, oophoroma, bladder cancer, thyroid cancer and lung cancer in non-cellule type are used alone or combine other
Anti-tumor drug uses, and a kind of strong methods of chemotherapy for the treatment of solid tumor is regarded as, almost to all malignant proliferations
Tumour has certain effect.Its mechanism of action is to destroy the three-level of DNA by causing topoisomerase II crack DNA in conjunction with DNA
Structure, thus blocks cellular proliferation, promotion Apoptosis.By the observation and research to clinical picture, researcher find Ah
Mycin also will appear biggish toxic side effect while playing therapeutic effect, such as cardiac toxic, gastrointestinal reaction, alopecia, bone
Marrow inhibition etc., hinders its application clinically.
Folic acid is water-soluble B family vitamin, also referred to as Vitamin B9 in one, and folate molecule is by pteridine, p-aminophenyl first
Acid and glutamic acid collectively form.In traditional chemotherapy of tumors, most anti-tumor drugs are distributed in whole body everywhere with blood, because
Anticancer drug all has lethal effect to the normal cell of tumour cell and human body, so producing to human body, very big poison is secondary to be made
With making chemotherapeutics lack certain selectivity.Scientific research personnel has found that folacin receptor is prevalent in malignant cell
A kind of receptor, it is can be internalized by with mediated cell with a kind of membrane glycoprotein that connect of glycosylation phosphatidic acid inositol, be one kind
The receptor that high affinity can be generated to folic acid, express in the normal tissue it is highly conserved, and in oophoroma, breast cancer, son
Height is expressed in the cancer cells such as endometrial carcinoma, lung cancer, kidney, colon cancer and nasopharyngeal carcinoma, and therefore, folic acid is as a kind of good
Targeted drug is widely used in clinical test.
Summary of the invention
The object of the present invention is to provide load anticancer drug hydrogels of a kind of targeting and preparation method thereof.Institute of the present invention
Raw material is easy to get, and operating procedure is simple, and the hydrogel medicine-carried system prepared carries out drug in a manner of covalent bond grafting
Load, so that medicine-carried system is more stable.
To achieve the above object, the present invention adopts the following technical scheme:
A kind of supramolecular hydrogel of the load adriamycin of targeting, which is characterized in that by alpha-cyclodextrin (α-CD), F127
The cyclodextrine derivatives (DOX-2N- β-CD) and modified with folic acid of (pluronic F127, Pluronic F127), adriamycin modification
Cyclodextrine derivatives (FA-2N- β-CD) reaction obtain.
Further, adriamycin is loaded into hydrogel network in such a way that chemical bond is grafted.
The present invention also provides the preparation method of the supramolecular hydrogel of the load adriamycin of above-mentioned targeting, features
It is, comprising the following steps: weigh DOX-2N- β-CD, F127 and FA-2N- β-CD in reactor, deionized water is added, stirs
Mix reaction；α-CD is added, continues to be stirred to react, after reaction, the negative of targeting is obtained after so that reaction system is stood 10-15h
Carry the supramolecular hydrogel of adriamycin.The preferred 12h of the time of repose.
Further, the ratio between quality volume of F127, the DOX-2N- β-CD and FA-2N- β-CD be respectively 5%,
2%-8%, 5%, the temperature being stirred to react are 50-60 DEG C, time 4-5h, and continuing the temperature being stirred to react is 50-60 DEG C, when
Between be 4-5h, the ratio between quality volume of α-CD of addition be 10%-20%.
Further, the ratio between quality volume of F127, the DOX-2N- β-CD and FA-2N- β-CD be respectively 5%,
2%, 5%, the temperature being stirred to react is 60 DEG C, time 4h, and continuing the temperature being stirred to react is 60 DEG C, time 4h, is added
The ratio between the quality volume of α-CD be 20%.
Further, the synthetic method of the DOX-2N- β-CD includes:
Step a: dry beta-cyclodextrin, paratoluensulfonyl chloride and sodium hydroxide are reacted in deionized water, stopped
It is filtered after only reacting, after obtained filtrate is adjusted PH, sets diel in 2-5 DEG C of low temperature white precipitate is precipitated,
It filters and intermediate compound list (6- oxygen-p-toluenesulfonyl)-beta-cyclodextrin (6-OTs- β-CD) can be obtained after recrystallizing；
Step b: take list (6- oxygen-p-toluenesulfonyl)-beta-cyclodextrin (6-OTs- β-CD) and 1,3- propane diamine in N- first
Reaction in base pyrrolidones (NMP), reaction is instilled after stopping is precipitated precipitating in acetone, is collected by filtration and precipitates up to product
Mono- 6- propane diamine-beta-cyclodextrin (2N- β-CD)；
Step c: by drug adriamycin, mono- 6- propane diamine-beta-cyclodextrin and trifluoroacetic acid water and ethyl alcohol mixed solvent
In reacted, stop reaction after is instilled in acetone be precipitated precipitating, be collected by filtration precipitating and wash in acetone, can obtain
To prodrugs DOX-2N- β-CD.
Further, the reaction temperature in the step a is 10-20 DEG C, and beta-cyclodextrin and paratoluensulfonyl chloride rub
That ratio are as follows: 1:0.8-0.9, the solvent water consumption determine that the reaction time controls in 2- according to every gram of beta-cyclodextrin 5-10mL
2.5h, PH are controlled in 7-8.Preferably, the reaction temperature in the step a is 10-20 DEG C, beta-cyclodextrin and paratoluensulfonyl chloride
Molar ratio are as follows: 1:0.84, the solvent water consumption determine according to every gram of beta-cyclodextrin 7ml, reaction time control in 2-2.5h,
PH is controlled in 7-8.
Further, the reaction in the step b is carrying out under nitrogen atmosphere, and reaction temperature is 70-80 DEG C, instead
It is 10-12h, the molar ratio of 1,3- propane diamine, 6-OTs- β-CD and NMP are as follows: 1:3-6:20-30 between seasonable.Preferably, described
Reaction in step b is carrying out under nitrogen atmosphere, and reaction temperature is 80 DEG C, reaction time 10-12h, 1,3- propane diamine, 6-
The molar ratio of OTs- β-CD and NMP are as follows: 1:5:25.
Further, the reaction in the step c carries out under the conditions of being protected from light, and reaction temperature is room temperature, when reaction
Between be 48-60h, the molar ratio of adriamycin and 2N- β-CD are 1.3-1.8:1.Preferably, the reaction in the step c is being kept away
It is carried out under the conditions of light, reaction temperature is room temperature, reaction time 48h, and the molar ratio of adriamycin and 2N- β-CD are 1.5:1.
Further, the synthetic method of the FA-2N- β-CD includes: that folic acid, 2N- β-CD, dicyclohexyl carbon two is sub-
Amine (DCC) and n-hydroxysuccinimide (NHS) are protected from light in DMSO solvent, are stopped being instilled in acetone after reacting and be analysed
It precipitates, be collected by filtration and wash in acetone out, yellow solid FA-2N- β-CD can be obtained.
Further, the molar ratio of the 2N- β-CD, folic acid, DCC, NHS are as follows: 1-1.1:1.1-1.8:4-4.6:4-
4.6, reaction temperature is room temperature, reaction time 48-60h.Preferably, the molar ratio of the 2N- β-CD, folic acid, DCC, NHS
Are as follows: 1:1.5:4:4.Reaction temperature is room temperature, reaction time 48h.
The present invention is first chemically modified beta-cyclodextrin, prepares containing amino cyclodextrin derivatives 2N- β-CD；So
Group folate molecule will be targeted afterwards and 2N- β-CD carries out condensation reaction, medicine body FA-2N- β-CD before synthesizing at the same time will
Anticancer drugs, doxorubicin and 2N- β-CD carry out condensation reaction, synthesize another preceding medicine body DOX-2N- β-CD；Finally with α-ring paste
Essence, F127, DOX-2N- β-CD, FA-2N- β-CD are to construct primitive to construct supramolecular hydrogel glue material.
Compared with prior art, the beneficial effects of the present invention are:
The raw material of subject hydrogel medicine-carried system is easy to get, and manufacturing process is simple, and property is easy to regulate and control, adriamycin and folic acid
It is carried in hydrogel network in the form of covalent bond respectively, the toxic side effect of drug adriamycin can not only be reduced, and also
The targeting for improving hydrogel of effect.
Manufacturing process of the present invention is simple, and load is made by the interaction between the cavity and F127 strand of cyclodextrin
The pseudopolyrotaxane of adriamycin and folic acid, then using the hydrogen bond action between hydroxyl in cyclodextrin molecular, further expanding is three
The supramolecular hydrogel glue material of dimension.Drug molecule folic acid and adriamycin are carried in hydrogel network in the form of covalent bond respectively,
The toxic side effect of drug adriamycin can not only be reduced, and can also effectively improve the targeting of hydrogel.
Detailed description of the invention
Fig. 1 is the nucleus magnetic hydrogen spectrum figure of intermediate 6-OTs- β-CD.
Fig. 2 is the nucleus magnetic hydrogen spectrum figure of intermediate 2N- β-CD.
Fig. 3 is the nucleus magnetic hydrogen spectrum figure of intermediate DOX-2N- β-CD.
Fig. 4 is the nucleus magnetic hydrogen spectrum figure of intermediate FA-2N- β-CD.
Fig. 5, which is that embodiment 5 is obtained, carries liquid medicine gel rubber system scanning electron microscope (SEM) photograph.
Fig. 6 is the modulus of four kinds of supramolecular hydrogels with frequency variation curve figure.
Fig. 7 is the X-ray diffraction comparison diagram for carrying liquid medicine gel and raw material；
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In addition, it should also be understood that, after reading the content taught by the present invention, those skilled in the art
Member can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited
Range.
The synthesis of embodiment 1:DOX-2N- β-CD:
Beta-cyclodextrin is chemically modified by 1,3- propane diamine, novel cyclodextrine derivatives are prepared, by Ah mould
Element and the cyclodextrine derivatives of amido modification carry out condensation reaction, further synthesize prodrugs DOX-2N- β-CD, specific steps
Are as follows:
A, by 0.19mol dry beta-cyclodextrin, 0.16mol paratoluensulfonyl chloride, 6.16mol sodium hydroxide in 1500mL
It is reacted in deionized water, reaction temperature is 15 DEG C, reaction time 2h, is filtered after stopping reaction, obtained filtrate
After adjusting PH is 7, diel is placed at a temperature of 2 DEG C a large amount of white precipitates are precipitated, filter and centre can be obtained after recrystallizing
Compound list (6- oxygen-p-toluenesulfonyl)-beta-cyclodextrin (6-OTs- β-CD).It is characterized by nuclear-magnetism technology, such as Fig. 1 institute
Show.
B, mono- (6- oxygen-the p-toluenesulfonyl)-beta-cyclodextrin (6-OTs- β-CD) of 1.6mmol and 8mmol1,3- the third two is taken
Amine is reacted under nitrogen atmosphere in 41.5mmol N-Methyl pyrrolidone, and reaction temperature is 80 DEG C, and the reaction time is
10h, reaction is instilled after stopping is precipitated precipitating in acetone.It is collected by filtration and precipitates up to the mono- 6- propane diamine-beta-cyclodextrin of product
(2N-β-CD).It is characterized by nuclear-magnetism technology, as shown in Figure 2.
C, it is in 20mL volume ratio by 0.7mmol drug adriamycin, 0.4mmol 2N- β-CD, 0.001mmol trifluoroacetic acid
Room temperature is reacted under the conditions of being protected from light in the water and alcohol mixed solvent of 1:1, reaction time 48h, is stopped it after reacting
It instills and precipitating is precipitated in acetone, precipitating and in acetone repeatedly washing is collected by filtration, preceding medicine body DOX-2N- β-CD can be obtained.
It is characterized by nuclear-magnetism technology, as shown in Figure 3.
The synthesis of embodiment 2:FA-2N- β-CD
Condensation reaction, further synthetic intermediate FA-2N- β-are carried out by the cyclodextrine derivatives of folic acid and amido modification
CD, specific steps are as follows:
By 1.1mmol folic acid, 1mmol 2N- β-CD, 4.6mmol DCC and 4.6mmol NHS in 15mL DMSO solvent
It is protected from light, reaction temperature is room temperature, and reaction time 48h is instilled precipitation precipitating in acetone after stopping reaction, and filtering is received
Collect and repeatedly wash in acetone, yellow solid FA-2N- β-CD can be obtained, and characterized by nuclear-magnetism technology, such as Fig. 4
It is shown.
Embodiment 3
A kind of supramolecular hydrogel of the load adriamycin of targeting, by alpha-cyclodextrin, F127, DOX-2N- β-CD and FA-
2N- β-CD reacts to obtain, and adriamycin is loaded into hydrogel network in such a way that chemical bond is grafted.The targeting load Ah
The supramolecular hydrogel of mycin the preparation method comprises the following steps:
It takes 0.12g DOX-2N- β-CD, 0.15g F127,0.15g FA-2N- β-CD in reactor, going for 3ml is added
Ionized water, 60 DEG C at a temperature of be stirred to react 4h.Then 0.6g α-CD is added in reaction system, under conditions of 60 DEG C
Continue to be stirred to react 4h, entire reaction carries out under the conditions of being protected from light.After reaction, it is slowly cooled to room temperature reaction system,
After standing 12h, 12h is freeze-dried to get the supramolecular hydrogel of the load adriamycin of dry targeting.F127,DOX-2N-
The mass/volume content of β-CD, FA-2N- β-CD and α-CD are respectively 5%, 4%, 5%, 20%.
Embodiment 4
A kind of supramolecular hydrogel of the load adriamycin of targeting, by α-CD, F127, DOX-2N- β-CD and FA-2N-
β-CD reacts to obtain, and adriamycin is loaded into hydrogel network in such a way that chemical bond is grafted.Load Ah mould of the targeting
Element supramolecular hydrogel the preparation method comprises the following steps:
0.18g DOX-2N- β-CD, 0.15g F127,0.15g FA-2N- β-CD are weighed in reactor, is added 3ml's
Deionized water, 60 DEG C at a temperature of be stirred to react 4h.Then 0.3g α-CD is added in reaction system, in 60 DEG C of condition
Under continue to be stirred to react 4h, entire reaction carries out under the conditions of being protected from light.After reaction, reaction system is made to progressively cool to room
Temperature after standing 12h, is freeze-dried 12h to get the supramolecular hydrogel of the load adriamycin of dry targeting.F127,DOX-
The mass/volume content of 2N- β-CD, FA-2N- β-CD and α-CD are respectively 5%, 6%, 5%, 10%.
Embodiment 5
A kind of supramolecular hydrogel of the load adriamycin of targeting, by α-CD, F127, DOX-2N- β-CD and FA-2N-
β-CD reacts to obtain, and adriamycin is loaded into hydrogel network in such a way that chemical bond is grafted.Load Ah mould of the targeting
Element supramolecular hydrogel the preparation method comprises the following steps:
0.24g DOX-2N- β-CD, 0.15g F127,0.15g FA-2N- β-CD are weighed in reactor, is added 3ml's
Deionized water, 60 DEG C at a temperature of be stirred to react 4h.Then 0.3g α-CD is added in reaction system, in 60 DEG C of condition
Under continue to be stirred to react 4h, entire reaction carries out under the conditions of being protected from light.After reaction, reaction system is made to progressively cool to room
Temperature after standing 12h, is freeze-dried 12h to get the supramolecular hydrogel of the load adriamycin of dry targeting.F127,DOX-
The mass/volume content of 2N- β-CD, FA-2N- β-CD and α-CD are respectively 5%, 8%, 5%, 10%.
Embodiment 6
A kind of supramolecular hydrogel of the load adriamycin of targeting, by α-CD, F127, DOX-2N- β-CD and FA-2N-
β-CD reacts to obtain, and adriamycin is loaded into hydrogel network in such a way that chemical bond is grafted.Load Ah mould of the targeting
Element supramolecular hydrogel the preparation method comprises the following steps:
0.15g F127,0.15g FA-2N- β-CD and 0.06g DOX-2N- β-CD are weighed first in reactor, are added
The deionized water of 3ml is stirred to react 4h under conditions of 60 DEG C.Then 0.6g α-CD is added in reaction system, at 60 DEG C
Under conditions of continue to be stirred to react 4h, entire reaction carries out under the conditions of being protected from light.After reaction, make reaction system Slow cooling
To room temperature, after standing 12h, 12h is freeze-dried to get dry supramolecular hydrogel glue material.F127,DOX-2N-β-CD,FA-
The mass/volume content of 2N- β-CD and α-CD is respectively 5%, 2%, 5%, 20%.
As shown in figure 5, carrying liquid medicine gel rubber system scanning electron microscope (SEM) photograph for embodiment 5 is obtained.As shown in fig. 6, being embodiment
The modulus of four kinds of supramolecular hydrogels made from 3-6 is with frequency variation curve figure, it can be seen from the figure that the elasticity modulus of gel
Substantially do not change with frequency, show the property of a kind of " class solid ", and with the increase of α-CD and F127 concentration, supermolecule water
The elasticity modulus of gel also increases accordingly.As shown in fig. 7, for the embodiment 3-6 X-ray diffractogram obtained for carrying liquid medicine gel,
Since four kinds of load liquid medicine gels are poly pseudorotaxane structure, so being collectively referred to as hydrogel in figure.
Claims (9)
1. a kind of supramolecular hydrogel of the load adriamycin of targeting, which is characterized in that by alpha-cyclodextrin, Pluronic
F127, DOX-2N- β-CD and FA-2N- β-CD react to obtain.
2. the preparation method of the supramolecular hydrogel of the load adriamycin of targeting as described in claim 1, which is characterized in that
The following steps are included: weighing DOX-2N- β-CD, F127 and FA-2N- β-CD in reactor, deionized water is added, stirring is anti-
It answers；α-CD is added, continues to be stirred to react, after reaction, obtains the load Ah of targeting after so that reaction system is stood 10-15h
The supramolecular hydrogel of mycin.
3. the preparation method of the supramolecular hydrogel of the load adriamycin of targeting as claimed in claim 2, which is characterized in that
The ratio between described quality volume of F127, DOX-2N- β-CD and FA-2N- β-CD is respectively 5%, 2%-8%, 5%, and stirring is anti-
The temperature answered is 50-60 DEG C, time 4-5h, and continuing the temperature being stirred to react is 50-60 DEG C, time 4-5h, the α-of addition
The ratio between quality volume of CD is 10%-20%.
4. the preparation method of the supramolecular hydrogel of the load adriamycin of targeting as claimed in claim 2, which is characterized in that
The synthetic method of the DOX-2N- β-CD includes:
Step a: dry beta-cyclodextrin, paratoluensulfonyl chloride and sodium hydroxide are reacted in deionized water, are stopped anti-
Should after be filtered, after obtained filtrate is adjusted PH, set diel in 2-5 DEG C of low temperature so that white precipitate is precipitated, filtering
And intermediate compound list (6- oxygen-p-toluenesulfonyl)-beta-cyclodextrin can be obtained after recrystallizing；
Step b: taking list (6- oxygen-p-toluenesulfonyl)-beta-cyclodextrin and 1, and 3- propane diamine reacts in N-Methyl pyrrolidone,
Reaction is instilled after stopping is precipitated precipitating in acetone, be collected by filtration and precipitate up to the mono- 6- propane diamine-beta-cyclodextrin of product；
Step c: by drug adriamycin, mono- 6- propane diamine-beta-cyclodextrin and trifluoroacetic acid the in the mixed solvent of water and ethyl alcohol into
Row reaction is instilled precipitation precipitating in acetone after stopping reaction, is collected by filtration and precipitates and wash in acetone, before can be obtained
Medicine molecule DOX-2N- β-CD.
5. the preparation method of the supramolecular hydrogel of the load adriamycin of targeting as claimed in claim 4, which is characterized in that
Reaction temperature in the step a is 10-20 DEG C, the molar ratio of beta-cyclodextrin and paratoluensulfonyl chloride are as follows: 1:0.8-0.9, institute
It states solvent water consumption to determine according to every gram of beta-cyclodextrin 5-10mL, reaction time control is controlled in 2-2.5h, PH in 7-8.
6. the preparation method of the supramolecular hydrogel of the load adriamycin of targeting as claimed in claim 4, which is characterized in that
Reaction in the step b is carrying out under nitrogen atmosphere, reaction temperature be 70-80 DEG C, reaction time 10-12h, 1,3-
The molar ratio of propane diamine, 6-OTs- β-CD and NMP are as follows: 1:0.2-6:5-30.
7. the preparation method of the supramolecular hydrogel of the load adriamycin of targeting as claimed in claim 4, which is characterized in that
Reaction in the step c carries out under the conditions of being protected from light, and reaction temperature is room temperature, reaction time 48-60h, adriamycin with
The molar ratio of 2N- β-CD is 1.3-1.8:1.
8. the preparation method of the supramolecular hydrogel of the load adriamycin of targeting as claimed in claim 2, which is characterized in that
The synthetic method of the FA-2N- β-CD includes: to be protected from light folic acid, 2N- β-CD, DCC and NHS in DMSO solvent, is stopped
It is instilled after only reacting and precipitating is precipitated in acetone, be collected by filtration and wash in acetone, yellow solid FA-2N- can be obtained
β-CD。
9. the preparation method of the supramolecular hydrogel of the load adriamycin of targeting as claimed in claim 2, which is characterized in that
The molar ratio of the 2N- β-CD, folic acid, DCC, NHS are as follows: 1-1.1:1.1-1.8:4-4.6:4-4.6, reaction temperature are room
Temperature, reaction time 48-60h.
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| CN111728939A (en) * | 2020-06-02 | 2020-10-02 | 上海应用技术大学 | Heparin functionalized drug-loaded supramolecular hydrogel and preparation method thereof |
| CN114344247A (en) * | 2021-12-13 | 2022-04-15 | 上海应用技术大学 | Targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel and preparation method thereof |
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| CN108578707A (en) * | 2018-07-11 | 2018-09-28 | 上海应用技术大学 | A kind of supramolecular hydrogel and preparation method thereof of load Indomethacin |
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| CN108578707A (en) * | 2018-07-11 | 2018-09-28 | 上海应用技术大学 | A kind of supramolecular hydrogel and preparation method thereof of load Indomethacin |
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| CN111728939A (en) * | 2020-06-02 | 2020-10-02 | 上海应用技术大学 | Heparin functionalized drug-loaded supramolecular hydrogel and preparation method thereof |
| CN111728939B (en) * | 2020-06-02 | 2022-10-14 | 上海应用技术大学 | Heparin functionalized drug-loaded supramolecular hydrogel and preparation method thereof |
| CN114344247A (en) * | 2021-12-13 | 2022-04-15 | 上海应用技术大学 | Targeted hyaluronic acid-cyclodextrin drug-loaded supramolecular hydrogel and preparation method thereof |
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