CN110404069A - A kind of nanocomposite based on poly-dopamine@MOF-Al complex carries targeting-photo-thermal-light power synergistic treatment - Google Patents
A kind of nanocomposite based on poly-dopamine@MOF-Al complex carries targeting-photo-thermal-light power synergistic treatment Download PDFInfo
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Abstract
The present invention relates to field of medical materials, disclose a kind of nanocomposite based on poly-dopamine@MOF-Al complex carries targeting-photo-thermal-light power synergistic treatment, the present invention is using DTBA as organic ligand, its disulfide bond has reduction responsiveness to the glutathione being overexpressed in cancer cell, using Al ion as metal ion.1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride and n-hydroxysuccinimide are added simultaneously to activate DTBA, it reacts to obtain FA-MOF-Al with folic acid, then and poly-dopamine reaction synthesizes poly-dopamine@FA-MOF-Al, and last and hypericin, 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine react to obtain object.The polymer material can be achieved to targeted therapy, and the synergistic effect of tumor thermotherapy and chemotherapy increases the stability of polymer material, can be used for cancer cell treatment.
Description
Technical field
The present invention relates to field of medical materials, more particularly to one kind to be based on poly-dopamine@MOF-Al complex carries targeting-light
Heat-light power synergistic treatment nanocomposite.
Background technique
Cancer as threaten human life and health a kind of major disease, for a long time always cure rate it is low and recur,
The death rate is high.And in recent years due to the originals such as people's life stress is big, work and rest irregular eating, contact carcinogen chance are more
Cause.In recent years, the biomedical treatment for being combined into cancer with nanotechnology brings new opportunities.With unique optics, magnetic
The Nano medication of the physicochemical properties such as, electricity and acoustics brings new approaches for the prevention of major disease, diagnosing and treating.Its
In, polymer nano material has excellent biocompatibility and degradability, programmable size and surface property, higher load
Dose and drug delivery efficiency, good cyclical stability and EPR effect are realized high to improve the bioavilability of drug
The drug targeting of effect and control release.Therefore, nowadays polymer nano material is widely used in drug delivery system.Cause
This, this field research staff has been devoted to the exploitation of new, ideal medical nano composite material in recent years.
Summary of the invention
The present invention provides a kind of receiving based on poly-dopamine@MOF-Al complex carries targeting-photo-thermal-light power synergistic treatment
Nano composite material, the present invention with to 4,4 '-sensitive dithiodibenzoic acids (DTBA) of reducing environment be organic ligand, it is therein
Disulfide bond has reduction responsiveness to the glutathione (GSH) being overexpressed in cancer cell, using Al ion as metal ion.Add simultaneously
Enter 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride and n-hydroxysuccinimide activates DTBA, with
Folic acid reacts to obtain FA-MOF-Al, then synthesizes poly-dopamine@FA-MOF-Al by reaction between MOF-Al and poly-dopamine,
Last and hypericin, 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine reaction
Obtain final goal object.The polymer material of this method preparation will can realize targeted therapy in the later period, tumor thermotherapy and chemotherapy
Synergistic effect increases the stability of polymer material, can be used for cancer cell treatment；This method will not be in the experiment in later period simultaneously
Cell is made a significant impact in journey, does not influence the science of experimental result, experimental implementation process is simple, nontoxic, harmless, green
Environmental protection.
The specific technical proposal of the invention is: a kind of be based on poly-dopamine@MOF-Al complex carries targeting-photo-thermal-light power
The nanocomposite of synergistic treatment, in terms of mg and mL, comprising the following steps:
1) 20~25mL n,N-Dimethylformamide, 450~452.5mg Al (NO are sequentially added into container3)3·
9H24,4 '-dithiodibenzoic acid of O and 275~277.5mg, ultrasonic dissolution；Container is sequentially placed into 35-45 DEG C, 55-65
DEG C, 75-85 DEG C, 95-105 DEG C, reaction in 110-130 DEG C of baking oven, will be taken out after solution becomes cloudy in container, and be cooled to room
Temperature obtains suspension.
It is in order to which MOF-Al is more fully made using being reacted in different temperatures baking oven in step 1).And due to
The introducing of disulfide bond, so that MOF-Al is more sensitive to reducing environment.
2) suspension is centrifuged 10~15min to collect product, with N, N- dimethyl with the revolving speed of 12000~14000rpm
Formamide eccentric cleaning precipitates repeatedly to remove reactant remained on surface, then multiple with methanol eccentric cleaning, obtains MOF-
Al(DTBA)；It disperses MOF-Al (DTBA) in methanol, is stored for future use at 1-5 DEG C.
In step 2), centrifugation is repeatedly to wash MOF-Al reactant remained on surface.Metal organic framework
(MOFs) material is that metal ion and organic ligand assemble the polyporous materials to be formed by coordination.MOFs has size
Controllably, easily functionalization, drug loading be big, the advantages such as biodegradable, the coordinate bond pair between metal ion and organic ligand
Specific environment has the organic ligand of responsiveness or MOFs material to have responding ability.
3) 0.5~0.8g folic acid is added into step 2) acquired solution, ultrasonic disperse is uniform, addition 125 while stirring~
127mg 1- ethyl-(3- dimethylamino-propyl) carbodiimides and 182.5~184.5mg nitrogen-HOSu NHS, obtain
FA-MOF-Al nanoparticle.
In step 3), 1- ethyl-(3- dimethylamino-propyl) carbodiimides and nitrogen-HOSu NHS are as friendship
Join agent, acts on to activate MOF-Al, react it sufficiently with folic acid, by the way that folic acid is connected to the surface MOF, increase itself and receptor
Associativity, so that the polymer particles of carrying medicament is largely gathered in subject cell surface.
4) 8-12mg FA-MOF-Al nanoparticle is dispersed in the Dopamine hydrochloride methanol of 5~6mL 350-450 μ g/mL
In solution, it is ultrasonically treated 3~5min, it is spare.
5) the Tris buffer of 8-12mL pH=6.8-7.2 is added rapidly in step 4) acquired solution, and in room temperature
Under continuously stir 8-12h, then by centrifugation, washing, freeze-drying, obtain poly-dopamine mediation MOF-Al, i.e., poly- DOPA
Amine@FA-MOF-Al, it is spare.
6) 64.8~66.8mg poly-dopamine@FA-MOF-Al is taken, is scattered in 40-60mL deionization, is then added
6.05~6.25mg hypericin, 2.76~2.96mg 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride and
0.30~0.32mg 4-dimethylaminopyridine is stirred to react overnight.
7) product is collected by centrifugation, with the multiple eccentric cleaning of methanol until collecting product after supernatant is colourless and being dried in vacuo,
Obtain target product.
Preferably, the container is 50-70min in the baking oven standing time of each temperature in step 1).
Preferably, in step 2), centrifugal speed 12500rpm, centrifugation time 15min.
Preferably, in step 4), ultrasonic procedure are as follows: ultrasonic grinder is used, it is ultrasonic under 400-600W power
Handle 3~5min.
Preferably, in step 5), centrifugation, washing, freezing dry process are as follows: use high-speed refrigerated centrifuge, In
10~15min is centrifuged under conditions of 8000~10000r/min；Then it is washed with deionized repeatedly, then is placed in freeze drier
Middle freeze-drying.
It is compared with the prior art, the beneficial effects of the present invention are:
1. poly-dopamine, which has, improves its biocompatibility in step 2), itself toxicity is reduced, improves its medicine for power
The advantages that scholarship and moral conduct is and improves itself and cell-interacting capabilities.
2. by the way that folic acid is connected to surface of polymer material, increasing its associativity with receptor in step 4), making to bear
The polymer particles for carrying drug are largely gathered in subject cell surface, to increase the drug concentration of site of action, reduce to just
The toxic side effect of normal cell.
3. can be obtained after reacting hypericin with the poly-dopamine@MOF-Al of modified with folic acid a kind of poly- in step 6)
Object nano material is closed, wherein hypericin has photo-activity as a kind of photosensitizer, can be by destroying in tissue and cell
Organelle, finally cause the death of cancer cell, achieve the purpose that treating cancer.
4. in the present invention, can realize efficient tumor thermotherapy and chemotherapy collaboration effect by preparing polymer nano material
It answers, increases the stability of drug, realize active targeting, increase the binding ability with receptor, to greatly promote to cancer cell
Therapeutic effect.
5. the present invention is by constructing a kind of safety, non-toxic, and is capable of the pharmaceutical carrier of efficient transportation photosensitizer, can
The stability of drug is improved, convenient for storage.
Specific embodiment
The present invention will be further described with reference to the examples below.
Embodiment 1
1) 20mLN is added in the aluminium lid vial of 40mL, 450mg Al is added in dinethylformamide (DMF)
(NO3)3·9H24,4 '-dithiodibenzoic acid of O and 275mg, ultrasonic dissolution.By vial be respectively placed in warmed-up 40 DEG C,
60 DEG C, 80 DEG C, 100 DEG C, reaction (each baking oven time is 60min) in 120 DEG C of baking oven, after solution becomes cloudy in vial
It is drawn off and is cooled to room temperature.
2) by suspension with the revolving speed of 12500rpm centrifugation 15min to collect product, with DMF eccentric cleaning precipitating three times with
Its reactant remained on surface is removed, then three times with methanol eccentric cleaning.Finally by the MOF-Al of washes clean (DTBA) point
It dissipates in methanol, is stored in spare in 4 DEG C of refrigerators.
3) 0.5~0.8g folic acid is added in the solution obtained, ultrasonic disperse is uniform, while stirring to 125~127mg of addition
1- ethyl-(3- dimethylamino-propyl) carbodiimides and 182.5mg nitrogen-HOSu NHS.
4) 10mg FA-MOF-Al nanoparticle is dispersed in the Dopamine hydrochloride methanol solution of 400 μ g/mL of 5mL, is made
With ultrasonic grinder, 4min is ultrasonically treated under 500W power, it is spare.
5) the Tris buffer of 10mLpH=7 is added rapidly in the solution that step 4) obtains, and continuous at room temperature
12h is stirred, then by centrifugation, washing, freeze-drying: using high-speed refrigerated centrifuge, be centrifuged under conditions of 9000r/min
12min；Then it is washed with deionized repeatedly, then is placed in freeze drier and is freeze-dried, obtain poly-dopamine mediation
MOF-Al, i.e. poly-dopamine@FA-MOF-Al, it is spare.
6) 64.8mg poly-dopamine@FA-MOF-Al is taken, is dispersed in 50mL deionization, 6.05 spun golds is then added
Peach element, 2.76mg 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride and 0.32mg 4-dimethylaminopyridine,
It is stirred to react overnight.
7) product is collected by centrifugation, is collected by centrifugation after supernatant is colourless with the multiple eccentric cleaning of methanol and vacuum is done
It is dry.
Embodiment 2
1) 20mL n,N-Dimethylformamide (DMF) is added in the aluminium lid vial of 40mL, 451mg Al is added
(NO3)3·9H24,4 '-dithiodibenzoic acid of O and 275mg, ultrasonic dissolution.By vial be respectively placed in warmed-up 40 DEG C,
60 DEG C, 80 DEG C, 100 DEG C, reaction (each baking oven time is 50min) in 120 DEG C of baking oven, after solution becomes cloudy in vial
It is drawn off and is cooled to room temperature.
2) by suspension with the revolving speed of 12500rpm centrifugation 15min to collect product, with DMF eccentric cleaning precipitating three times with
Its reactant remained on surface is removed, then three times with methanol eccentric cleaning.Finally by the MOF-Al of washes clean (DTBA) point
It dissipates in methanol, is stored in spare in 4 DEG C of refrigerators.
3) 0.5~0.8g folic acid is added in the solution obtained, ultrasonic disperse is uniform, while stirring to 125~127mg of addition
1- ethyl-(3- dimethylamino-propyl) carbodiimides and 182.5mg nitrogen-HOSu NHS.
4) 10mg FA-MOF-Al nanoparticle is dispersed in the Dopamine hydrochloride methanol solution of 400 μ g/mL of 5mL, is made
With ultrasonic grinder, 5min is ultrasonically treated under 500W power, it is spare.
5) the Tris buffer of 10mLpH=7 is added rapidly in the solution that step 4) obtains, and continuous at room temperature
Stir 12h, then by centrifugation, washing, freeze-drying: use high-speed refrigerated centrifuge, under conditions of 10000r/min from
Heart 10min；Then it is washed with deionized repeatedly, then is placed in freeze drier and is freeze-dried.Obtain poly-dopamine mediation
MOF-Al, i.e. poly-dopamine@FA-MOF-Al, it is spare.
6) 64.8mg poly-dopamine@FA-MOF-Al is taken, is dispersed in 60mL deionization, 6.05 spun golds is then added
Peach element, 2.76mg 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride and 0.32mg 4-dimethylaminopyridine,
It is stirred to react overnight.
7) product is collected by centrifugation, is collected by centrifugation after supernatant is colourless with the multiple eccentric cleaning of methanol and vacuum is done
It is dry.
Embodiment 3
1) 20mL n,N-Dimethylformamide (DMF) is added in the aluminium lid vial of 40mL, 451.5mgAl is added
(NO3)3·9H24,4 '-dithiodibenzoic acid of O and 275mg, ultrasonic dissolution.By vial be respectively placed in warmed-up 40 DEG C,
60 DEG C, 80 DEG C, 100 DEG C, reaction (each baking oven time is 60min) in 120 DEG C of baking oven, after solution becomes cloudy in vial
It is drawn off and is cooled to room temperature.
2) by suspension with the revolving speed of 12500rpm centrifugation 15min to collect product, with DMF eccentric cleaning precipitating three times with
Its reactant remained on surface is removed, then three times with methanol eccentric cleaning.Finally by the MOF-Al of washes clean (DTBA) point
It dissipates in methanol, is stored in spare in 4 DEG C of refrigerators.
3) 0.5~0.8g folic acid is added in the solution obtained, ultrasonic disperse is uniform, while stirring to 125~127mg of addition
1- ethyl-(3- dimethylamino-propyl) carbodiimides and 182.5mg nitrogen-HOSu NHS.
4) 10mg FA-MOF-Al nanoparticle is dispersed in the Dopamine hydrochloride methanol solution of 400 μ g/mL of 5mL, is made
With ultrasonic grinder, 5min is ultrasonically treated under 500W power, it is spare.
5) the Tris buffer of 10mL pH=7 is added rapidly in the solution that step 4) obtains, and continuous at room temperature
Stir 12h, then by centrifugation, washing, freeze-drying: use high-speed refrigerated centrifuge, under conditions of 10000r/min from
Heart 10min；Then it is washed with deionized repeatedly, then is placed in freeze drier and is freeze-dried.Obtain poly-dopamine mediation
MOF-Al, i.e. poly-dopamine@FA-MOF-Al, it is spare.
6) 64.8mg poly-dopamine@FA-MOF-Al is taken, is dispersed in 50mL deionization, 6.05 spun golds is then added
Peach element, 2.76mg 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride and 0.32mg 4-dimethylaminopyridine,
It is stirred to react overnight.
7) product is collected by centrifugation, is collected by centrifugation after supernatant is colourless with the multiple eccentric cleaning of methanol and vacuum is done
It is dry.
Embodiment 4
1) 20mL n,N-Dimethylformamide (DMF) is added in the aluminium lid vial of 40mL, 452mg Al is added
(NO3)3·9H24,4 '-dithiodibenzoic acid of O and 275mg, ultrasonic dissolution.By vial be respectively placed in warmed-up 40 DEG C,
60 DEG C, 80 DEG C, 100 DEG C, reaction (each baking oven time is 60min) in 120 DEG C of baking oven, after solution becomes cloudy in vial
It is drawn off and is cooled to room temperature.
2) by suspension with the revolving speed of 12500rpm centrifugation 15min to collect product, with DMF eccentric cleaning precipitating three times with
Its reactant remained on surface is removed, then three times with methanol eccentric cleaning.Finally by the MOF-Al of washes clean (DTBA) point
It dissipates in methanol, is stored in spare in 4 DEG C of refrigerators.
3) 0.5~0.8g folic acid is added in the solution obtained, ultrasonic disperse is uniform, while stirring to 125~127mg of addition
1- ethyl-(3- dimethylamino-propyl) carbodiimides and 182.5mg nitrogen-HOSu NHS.
4) 10mg FA-MOF-Al nanoparticle is dispersed in the Dopamine hydrochloride methanol solution of 400 μ g/mL of 5mL, is made
With ultrasonic grinder, 5min is ultrasonically treated under 500W power, it is spare.
5) the Tris buffer of 10mLpH=7 is added rapidly in the solution that step 4) obtains, and continuous at room temperature
Stir 12h, then by centrifugation, washing, freeze-drying: use high-speed refrigerated centrifuge, under conditions of 10000r/min from
Heart 10min；Then it is washed with deionized repeatedly, then is placed in freeze drier and is freeze-dried.Obtain poly-dopamine mediation
MOF-Al, i.e. poly-dopamine@FA-MOF-Al, it is spare.
6) 64.8mg poly-dopamine@FA-MOF-Al is taken, is dispersed in 40-60mL deionization, 6.05 gold medals is then added
Silk peach element, 2.76mg 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride and 0.32mg 4- dimethylamino pyrrole
Pyridine is stirred to react overnight.
7) product is collected by centrifugation, is collected by centrifugation after supernatant is colourless with the multiple eccentric cleaning of methanol and vacuum is done
It is dry.
Raw materials used in the present invention, equipment is unless otherwise noted the common raw material, equipment of this field；In the present invention
Method therefor is unless otherwise noted the conventional method of this field.
The above is only presently preferred embodiments of the present invention, is not intended to limit the invention in any way, it is all according to the present invention
Technical spirit any simple modification, change and equivalent transformation to the above embodiments, still fall within the technology of the present invention side
The protection scope of case.
Claims (5)
1. a kind of nanocomposite based on poly-dopamine@MOF-Al complex carries targeting-photo-thermal-light power synergistic treatment,
Be characterized in that in terms of mg and mL, preparation method the following steps are included:
1) 20~25mL n,N-Dimethylformamide, 450~452.5mg Al (NO are sequentially added into container3)3·9H2O and
275~277.5mg, 4,4 '-dithiodibenzoic acid, ultrasonic dissolution；Container is sequentially placed into 35-45 DEG C, 55-65 DEG C, 75-85
DEG C, 95-105 DEG C, reaction in 110-130 DEG C of baking oven, will be taken out after solution becomes cloudy in container, and be cooled to room temperature, obtain
Suspension；
2) suspension is centrifuged 10~15min to collect product, with N, N- dimethyl formyl with the revolving speed of 12000~14000rpm
Amine eccentric cleaning precipitates repeatedly to remove reactant remained on surface, then multiple with methanol eccentric cleaning, obtains MOF-Al
(DTBA)；It disperses MOF-Al (DTBA) in methanol, is stored for future use at 1-5 DEG C；
3) 0.5~0.8g folic acid is added into step 2) acquired solution, ultrasonic disperse is uniform, and 125~127mg is added while stirring
1- ethyl-(3- dimethylamino-propyl) carbodiimides and 182.5~184.5mg nitrogen-HOSu NHS, obtain FA-
MOF-Al nanoparticle；
4) 8-12mg FA-MOF-Al nanoparticle is dispersed in the Dopamine hydrochloride methanol solution of 5~6mL 350-450 μ g/mL
In, it is ultrasonically treated 3~5min, it is spare；
5) the Tris buffer of 8-12mL pH=6.8-7.2 is added rapidly in step 4) acquired solution, and connected at room temperature
Continuous stirring 8-12h obtains the MOF-Al, i.e. poly-dopamine@of poly-dopamine mediation then by centrifugation, washing, freeze-drying
FA-MOF-Al, it is spare；
6) 64.8~66.8mg poly-dopamine@FA-MOF-Al is taken, is scattered in 40-60mL deionization, is then added 6.05
~6.25mg hypericin, 2.76~2.96mg 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride and 0.30
~0.32mg 4-dimethylaminopyridine is stirred to react overnight；
7) product is collected by centrifugation, with the multiple eccentric cleaning of methanol until collecting product after supernatant is colourless and being dried in vacuo, obtains
Target product.
2. nanocomposite as described in claim 1, which is characterized in that in step 1), the container is in each temperature
Baking oven standing time be 50-70min.
3. nanocomposite as described in claim 1, which is characterized in that in step 2), centrifugal speed 12500rpm,
Centrifugation time is 15min.
4. nanocomposite as described in claim 1, which is characterized in that in step 4), ultrasonic procedure are as follows: use ultrasound
Wave pulverizer is ultrasonically treated 3~5min under 400-600W power.
5. nanocomposite as described in claim 1, which is characterized in that in step 5), centrifugation, washing, freeze-drying
Process are as follows: use high-speed refrigerated centrifuge, 10~15min is centrifuged under conditions of 8000~10000r/min；Then spend from
Sub- water washing is multiple, then is placed in freeze drier and is freeze-dried.
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| CN112023060A (en) * | 2020-09-16 | 2020-12-04 | 上海市第一人民医院 | Double-drug loaded nano-microsphere with targeted cartilage having photothermal response characteristic and preparation method and application thereof |
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| CN109985247A (en) * | 2019-04-03 | 2019-07-09 | 河南科技学院 | A kind of preparation method of the hybridized metal organic framework compounds for drug release |
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