CN116747187B - Multifunctional iron-based photo-thermal controlled release agarose water gel system - Google Patents
Multifunctional iron-based photo-thermal controlled release agarose water gel system Download PDFInfo
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 title claims abstract description 134
- 229920000936 Agarose Polymers 0.000 title claims abstract description 87
- 229910052742 iron Inorganic materials 0.000 title claims abstract description 67
- 238000013270 controlled release Methods 0.000 title claims abstract description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 239000000499 gel Substances 0.000 claims abstract description 55
- 239000002135 nanosheet Substances 0.000 claims abstract description 47
- 239000011692 calcium ascorbate Substances 0.000 claims abstract description 38
- 235000010376 calcium ascorbate Nutrition 0.000 claims abstract description 38
- 229940047036 calcium ascorbate Drugs 0.000 claims abstract description 38
- BLORRZQTHNGFTI-ZZMNMWMASA-L calcium-L-ascorbate Chemical compound [Ca+2].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] BLORRZQTHNGFTI-ZZMNMWMASA-L 0.000 claims abstract description 38
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 35
- 239000000243 solution Substances 0.000 claims abstract description 34
- MBMLMWLHJBBADN-UHFFFAOYSA-N Ferrous sulfide Chemical compound [Fe]=S MBMLMWLHJBBADN-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000007864 aqueous solution Substances 0.000 claims abstract description 28
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 26
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 26
- 201000009273 Endometriosis Diseases 0.000 claims abstract description 21
- 238000001816 cooling Methods 0.000 claims abstract description 9
- IMBKASBLAKCLEM-UHFFFAOYSA-L ferrous ammonium sulfate (anhydrous) Chemical compound [NH4+].[NH4+].[Fe+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O IMBKASBLAKCLEM-UHFFFAOYSA-L 0.000 claims abstract description 8
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims abstract description 8
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 239000008049 TAE buffer Substances 0.000 claims abstract description 6
- HGEVZDLYZYVYHD-UHFFFAOYSA-N acetic acid;2-amino-2-(hydroxymethyl)propane-1,3-diol;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid Chemical compound CC(O)=O.OCC(N)(CO)CO.OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O HGEVZDLYZYVYHD-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 239000007788 liquid Substances 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 62
- -1 mercaptan modified ferrous sulfide Chemical class 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 20
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- 239000011543 agarose gel Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 5
- 239000001509 sodium citrate Substances 0.000 claims description 5
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 5
- 229940038773 trisodium citrate Drugs 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
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- 108700012813 7-aminoactinomycin D Proteins 0.000 description 3
- YXHLJMWYDTXDHS-IRFLANFNSA-N 7-aminoactinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=C(N)C=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 YXHLJMWYDTXDHS-IRFLANFNSA-N 0.000 description 3
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- 150000003573 thiols Chemical class 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
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- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 2
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- 229920001690 polydopamine Polymers 0.000 description 2
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- 108090000672 Annexin A5 Proteins 0.000 description 1
- 102000004121 Annexin A5 Human genes 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000035999 Recurrence Diseases 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
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- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000006701 autoxidation reaction Methods 0.000 description 1
- 230000022534 cell killing Effects 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
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- 229910001448 ferrous ion Inorganic materials 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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Abstract
The application discloses a multifunctional iron-based photo-thermal controlled release agarose water gel system. Using ferrous ammonium sulfate and thioacetamide as raw materials to prepare a ferrous sulfide two-dimensional nano sheet; and modifying the ferrous sulfide two-dimensional nano-sheet by methoxy polyethylene glycol mercaptan to obtain FeS-PEG. Dissolving agarose in TAE buffer solution, heating in water bath until the agarose is completely dissolved, and cooling to liquid state to obtain agarose solution; sequentially mixing agarose solution, calcium ascorbate aqueous solution and FeS-PEG aqueous solution, and standing at room temperature to form gel to obtain the multifunctional iron-based photo-thermal controlled release agarose aqueous gel system. The hydrogel system can degrade both the hydrogel and the iron-based nanosheets through the controlled release of the calcium ascorbate, and simultaneously realize the controllable degradation of the drug carrier and the photosensitizer, thereby being expected to obviously improve the clinical curative effect of endometriosis treatment.
Description
Technical Field
The application relates to the technical field of biological medicine, in particular to a multifunctional iron-based photo-thermal controlled release agarose water gel system.
Background
When the endometriosis disease is treated by the current means, normal tissues with larger range than the focus are generally resected by using a surgical mode with extremely high traumata so as to prevent the endometriosis from recrudescence, and the diseases which are scattered at the focus cannot be treated at the same time, so that the functions of the normal tissues are greatly damaged, and even the normal tissues cannot be grown; long-term medication can lead to physiological dysfunction of the body, causing a series of complications.
The hydrogel has good clinical application prospect in the field of nano biotechnology. Hydrogels have been widely used in the field of tumor therapy for drug carriers to carry clinical drugs, control drug release by different means, reduce toxic and side effects of the drugs, and improve the killing effect on tumor cells. Research shows that the iron-based material has low toxicity, high biocompatibility and high photo-thermal conversion efficiency, and the photo-thermal effect can cause cell death, so that the iron-based material has great application potential in the biomedical field. The patent with the application number of 202210860912.0 discloses a preparation method of photo-thermal controlled release polydopamine iron-loaded nanoparticle hydrogel, and the prepared polydopamine iron nanoparticle is not an ultrathin iron-based nanosheet, and the iron-based nanoparticle is difficult to degrade although an iron-based material is combined with the hydrogel. And hydrogel materials have not been widely used for other non-neoplastic diseases such as endometriosis. Therefore, it is necessary to develop a multifunctional iron-based photo-thermal controlled release agarose water gel system, which has good biocompatibility, controlled release property and degradability, synchronously realizes the combination treatment of various modes of the endometriosis, and fills the gap of the existing hydrogel system in the treatment of the endometriosis.
Disclosure of Invention
Aiming at the prior art, the application aims to provide a multifunctional iron-based photo-thermal controlled release agarose water gel system. The hydrogel system can degrade both the hydrogel and the iron-based nanosheets through the controlled release of the calcium ascorbate, and simultaneously realize the controllable degradation of the drug carrier and the photosensitizer, thereby being expected to obviously improve the clinical curative effect of endometriosis treatment.
In order to achieve the above purpose, the application adopts the following technical scheme:
in a first aspect of the application, a multifunctional iron-based photo-thermal controlled release agarose gel system is provided, comprising an agarose gel carrier, and calcium ascorbate and iron-based two-dimensional nano-sheets loaded in the agarose gel carrier.
The iron-based two-dimensional nano sheet is a methoxy polyethylene glycol mercaptan modified ferrous sulfide two-dimensional nano sheet.
Preferably, the methoxy polyethylene glycol mercaptan modified ferrous sulfide two-dimensional nano-sheet is prepared by the following method:
(1) Under the protection of nitrogen, dissolving ferrous ammonium sulfate and trisodium citrate in ethylene glycol to obtain a mixed solution, dropwise adding an ethylene glycol solution of polyethyleneimine into the mixed solution, carrying out a first stirring reaction, dropwise adding an ethylene glycol solution of thioacetamide, carrying out a second stirring reaction, dropwise adding triethanolamine, carrying out a third stirring reaction, carrying out solvothermal reaction on the obtained product, centrifuging and washing to obtain the ferrous sulfide two-dimensional nano-sheet.
(2) And (3) dissolving the ferrous sulfide two-dimensional nano-sheet obtained in the step (1) and methoxy polyethylene glycol mercaptan (mPEG-SH) in absolute ethyl alcohol, carrying out ice bath, stirring in a dark place, centrifuging and washing to obtain FeS-PEG.
Preferably, in the step (1), the ratio of the addition amount of the ferrous ammonium sulfate, the trisodium citrate and the ethylene glycol in the mixed solution is 0.6mmoL:0.2mmoL:15mL; the ratio of the adding amount of the polyethyleneimine to the adding amount of the ethylene glycol in the ethylene glycol solution of the polyethyleneimine is 500mg:5mL; the concentration of the ethylene glycol solution of the thioacetamide is 0.05M; the addition ratio of the ethylene glycol solution of the ferrous ammonium sulfate, the polyethyleneimine and the thioacetamide to the triethanolamine is 0.6mmoL:500mg:15mL:2mL.
Preferably, in the step (1), the time of the first stirring reaction is 2 hours, and the time of the second stirring reaction and the time of the third stirring reaction are both 5 minutes; the solvothermal reaction is carried out at 200 ℃ for 24 hours.
Preferably, in the step (2), the ratio of the addition amount of the ferrous sulfide two-dimensional nano-sheet, the methoxy polyethylene glycol thiol and the absolute ethyl alcohol is 1mg:1mg:1mL; the time of the light-shielding stirring is 6 hours.
Preferably, the multifunctional iron-based photo-thermal controlled release agarose water gel system is prepared by the following method:
dispersing FeS-PEG in water, and carrying out ultrasonic treatment to obtain FeS-PEG aqueous solution; dispersing calcium ascorbate in water, and performing rotary vibration to obtain calcium ascorbate aqueous solution; dissolving agarose in TAE buffer solution, heating in water bath until the agarose is completely dissolved, and cooling to liquid state to obtain agarose solution; sequentially mixing agarose solution, calcium ascorbate aqueous solution and FeS-PEG aqueous solution, and standing at room temperature to form gel to obtain the multifunctional iron-based photo-thermal controlled release agarose aqueous gel system.
Preferably, the concentration of the FeS-PEG aqueous solution is 2mg/mL; the concentration of the calcium ascorbate aqueous solution is 2mg/mL; the concentration of the agarose solution is 3.125mg/mL; the temperature of the water bath heating is 90-100 ℃; the agarose solution is cooled to 40-45 ℃ for use.
Preferably, the volume ratio of the FeS-PEG aqueous solution, the calcium ascorbate aqueous solution and the agarose solution is 1:1:8.
preferably, in the multifunctional iron-based photo-thermal controlled release agarose water gel system, the mass content of agarose is 0.25%, the content of FeS-PEG aqueous solution is 0.2mg/mL, and the content of calcium ascorbate aqueous solution is 0.2mg/mL.
In a second aspect of the application, there is provided the use of a multifunctional iron-based photothermal controlled release agarose hydrogel system for the manufacture of a medicament for the treatment of endometriosis.
The application has the beneficial effects that:
(1) The hydrogel system takes agarose as a hydrogel matrix, wraps a two-dimensional ferrous sulfide nano sheet, and is added with calcium ascorbate, so that the anti-inflammatory capability of the hydrogel system is provided, and the cell death can be directly caused by the photothermal effect of the system. The multifunctional hydrogel can show excellent photo-thermal killing effect under near infrared light irradiation, realizes synchronous release of calcium ascorbate, and enables the calcium ascorbate to have synergistic effect with photo-thermal, so that the multifunctional hydrogel is used for treating endometriosis. The ability to controllably release the drug can avoid local accumulation of the active drug, minimizing phototoxic side effects. The multifunctional iron-based photo-thermal controlled release agarose hydrogel is expected to realize the combined treatment of endometriosis frequently scattered on focus, and is widely applied to the fields of biology, medicine and tissue engineering.
(2) In the system of the application, the agarose hydrogel carrier consists of agarose and TAE buffer, and the mass content of the agarose is 0.25%. The content of the methoxypolyethylene glycol mercaptan modified ferrous sulfide two-dimensional nano-sheet is 0.2mg/mL, and the content of calcium ascorbate is 0.2mg/mL. The content of methoxy polyethylene glycol mercaptan modified ferrous sulfide two-dimensional nano sheet has the highest photo-thermal conversion efficiency, and is beneficial to improving the stability of a near infrared light controlled release system and the capability of controlling and releasing ascorbic acid. The ferrous sulfide two-dimensional nano sheet has a long diameter of 200nm-300nm and a thickness of about 2nm, and is an extremely thin sheet structure.
(3) The hydrogel system provided by the application has near infrared light (700 nm-1500 nm) responsiveness, plays the photo-thermal treatment effect of the photo-thermal material, and plays roles of focus cell death and multiple focus death caused by iron death, and has excellent clinical application value.
Drawings
Fig. 1: schematic diagram of a multifunctional iron-based photo-thermal controlled release agarose water gel system: (a) A structural schematic diagram of a multifunctional iron-based photo-thermal controlled release agarose water gel system, and (b) a schematic diagram of light-controlled release calcium ascorbate of the multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS) in endometriosis;
fig. 2: (a) a transmission electron microscope image of a methoxy polyethylene glycol mercaptan coated ferrous sulfide (FeS-PEG) two-dimensional nano sheet, (b) an atomic force microscope image thickness test image of a methoxy polyethylene glycol mercaptan coated ferrous sulfide (FeS-PEG) two-dimensional nano sheet, (c) an atomic force microscope image of a methoxy polyethylene glycol mercaptan coated ferrous sulfide (FeS-PEG) two-dimensional nano sheet and a thickness quantification image thereof;
fig. 3: (a) A single-period photo-thermal stability test result diagram of a methoxy polyethylene glycol mercaptan coated ferrous sulfide (FeS-PEG) two-dimensional nano sheet, (b) a cooling stage temperature change and cooling time negative natural logarithmic relation diagram of the single-period photo-thermal stability test;
fig. 4: schematic diagram of calcium ascorbate delayed ferrous sulfide nanosheet oxidation of multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS);
fig. 5: rheological behavior diagram of multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS);
fig. 6: the photo-thermal performance test result diagram of the multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS) under the irradiation of near infrared light with different powers;
fig. 7: the photo-thermal stability test result of the multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS) is shown in a schematic diagram;
fig. 8: the drug release performance test result of the multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS) prepared in the embodiment is shown in the schematic diagram under the condition of 808nm near infrared light irradiation;
fig. 9: the degradation test result of the multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS) is shown in a schematic diagram;
fig. 10: a dynamic volume change chart (a) and a dynamic volume change rate (b) of a multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS);
fig. 11: schematic diagram of the result of alive and dead staining of endometriosis cells of a multifunctional iron-based photothermal controlled release agarose water gel system (AG-VcCa-FeS);
fig. 12: schematic diagram of apoptosis results of endometriosis cells of a multifunctional iron-based photothermal controlled-release agarose water gel system (AG-VcCa-FeS);
fig. 13: examples and comparative examples 1 to 2 are schematic diagrams showing cytotoxicity test results on endometriosis cells.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
As described in the background, the use of hydrogel systems for endometriosis is currently in the blank phase. Based on the above, the application provides a multifunctional iron-based photo-thermal controlled release agarose water gel system. The multifunctional iron-based photo-thermal controlled release agarose gel system comprises an agarose gel carrier, and methoxy polyethylene glycol mercaptan modified ferrous sulfide two-dimensional nano-sheets and calcium ascorbate loaded in the agarose gel carrier. The preparation method has near infrared light response, can realize the transformation from a gelation state to a sol state through near infrared light irradiation, thereby realizing local photo-thermal controlled release of calcium ascorbate, providing abundant hydrogen peroxide raw materials for iron death through the autoxidation, and effectively killing the heterogenic cells in the focus part. Because the methoxy polyethylene glycol mercaptan modified ferrous sulfide two-dimensional nano-sheet has very high photo-thermal conversion efficiency, under the action of near infrared light, a large amount of heat is generated by ferrous sulfide to dissolve agarose water gel in a gel state into a sol state, so that the controllable release of calcium ascorbate is realized, the local administration of focus parts is realized, meanwhile, the methoxy polyethylene glycol mercaptan modified ferrous sulfide nano-sheet is degraded in the heating process generated by the near infrared light action, and the locally generated hydrogen sulfide gas can provide oxygen for the self-oxidation of calcium ascorbate, so that the controlled-release calcium ascorbate can simultaneously realize the controllable degradation of a drug carrier and a photosensitizer, and the clinical curative effect of endometriosis treatment is expected to be obviously improved.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present application, the technical scheme of the present application will be described in detail with reference to specific embodiments.
The test materials used in the examples of the present application are all conventional in the art and are commercially available.
Examples: a preparation method of a multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS) comprises the following steps:
(1) Synthesizing ferrous sulfide two-dimensional nano-sheet (FeS-PEI): first, 0.6mmoL of ferrous ammonium sulfate and 0.2mmoL of trisodium citrate were dissolved in 15mL of ethylene glycol under nitrogen atmosphere with stirring at 800rpm, and then 500mg of Polyethylenimine (PEI) ultrasonically dissolved in 5mL of ethylene glycol solution was dropped into the above room temperature solution and reacted for 120min under magnetic stirring at 800 rpm. Then, 0.05M thioacetamide dissolved in 15mL of ethylene glycol was added dropwise to the above mixed solution, and stirred at room temperature at 800rpm for 5 minutes, and finally 2mL of triethanolamine was added dropwise to the mixture, and stirred at 800rpm for 5 minutes. After the reaction was completed, the product was transferred to a stainless steel autoclave lined with teflon and reacted at 200 ℃ for 24 hours. Taking out the liquid in the reaction kettle, centrifuging at 14000rpm for 5min, discarding the supernatant, collecting the precipitate, washing with absolute ethanol for 3 times, and finally preserving in absolute ethanol at 4 ℃. All magnetic stirring was performed under nitrogen.
(2) Synthesizing methoxy polyethylene glycol mercaptan modified ferrous sulfide two-dimensional nano-sheet (FeS-PEG): 1mg of FeS-PEI was added to 1mg of mPEG-SH previously sonicated in 1mL of absolute ethanol, ice-bath, and stirred at 350rpm in the dark for 6h. The resulting product was centrifuged at 14000rpm for 5min, the supernatant was discarded, and the precipitate was collected, washed with absolute ethanol 1 time, and finally stored in absolute ethanol at 4 ℃.
(3) Dispersing 2mg of methoxy polyethylene glycol mercaptan modified ferrous sulfide two-dimensional nano-sheet (FeS-PEG) in 1mL of water, and performing ultrasonic treatment for 10s under the condition of nominal power of 1200W to obtain 2mg/mL of methoxy polyethylene glycol mercaptan modified ferrous sulfide aqueous solution; dispersing 2mg of calcium ascorbate in 1mL of water, and shaking for 5s to obtain 2mg/mL of calcium ascorbate aqueous solution; 62.5mg agarose was dissolved in 20mL TAE buffer, heated in a water bath to 100deg.C for sufficient dissolution, and used in liquid form when the temperature was reduced to 45deg.C.
(4) Sequentially mixing agarose solution, calcium ascorbate aqueous solution and methoxy polyethylene glycol mercaptan modified ferrous sulfide aqueous solution according to the volume ratio of 8:1:1, and standing at room temperature for 3min to form gel. The final concentration was 0.25% wt, 0.2mg/mL in this order.
Evaluation of performance:
FIG. 1a is a schematic diagram of a multifunctional iron-based photothermal controlled release agarose hydrogel system (AG-VcCa-FeS) prepared according to an embodiment of the application. Comprises an agarose water gel carrier, methoxy polyethylene glycol mercaptan modified ferrous sulfide nano-sheets uniformly distributed in the agarose water gel carrier and calcium ascorbate. In the system, the mass concentration of ferrous sulfide and calcium ascorbate is 0.2mg/mL, and the mass concentration of agarose in agarose gel carrier is 0.25%. Fig. 1b is a schematic diagram of a multifunctional iron-based photo-thermal controlled release agarose hydrogel system (AG-VcCa-FeS) for optically controlled release of calcium ascorbate in endometriosis prepared according to an embodiment of the application. Under the condition of near infrared light irradiation, the hydrogel system is heated rapidly to release calcium ascorbate, and the ferrous sulfide nanosheets release ferrous ions and hydrogen sulfide gas in a weak acid environment.
Fig. 2a is a transmission electron microscope image of a methoxypolyethylene glycol thiol-coated ferrous sulfide (FeS-PEG) two-dimensional nanosheet prepared in the example. As can be seen from FIG. 2a, the ferrous sulfide nanoparticles are in a two-dimensional flake shape, and have a long diameter of 100-200nm, and are relatively dispersed. Fig. 2b is an atomic force microscope of a methoxypolyethylene glycol thiol-coated ferrous sulfide (FeS-PEG) two-dimensional nanosheet prepared in the example. As can be seen from fig. 2b, the thickness of the ferrous sulfide nanoparticles is 2.3nm. Fig. 2c is an atomic force microscope image of a two-dimensional nano sheet of methoxy polyethylene glycol thiol coated ferrous sulfide (FeS-PEG) and a thickness quantization chart thereof, wherein the two-dimensional nano sheet of ferrous sulfide is in a two-dimensional lamellar shape, uniformly dispersed, and has a long diameter of 100-200nm, and the thickness of the nano sheet is about 2.3nm according to a transmission electron microscope image.
Fig. 3a is a schematic diagram showing a single-cycle photo-thermal stability test result of a methoxy polyethylene glycol thiol-coated ferrous sulfide (FeS-PEG) two-dimensional nanosheet prepared in example. The test conditions were cooling by irradiation/shut-down for one cycle with 808nm near infrared laser (1.5W/cm 2,5 min). FIG. 3b is a graph showing the relationship between the temperature change and the negative natural logarithm of the cooling time in the cooling stage of the single-cycle photo-thermal stability test. According to fig. 3a and 3b, the FeS-PEG two-dimensional nano-sheet can reach 74.7 ℃ within 5min, the requirement of eliminating the internal heterogenic disease focus by the photo-thermal effect is met, and the photo-thermal conversion efficiency is as high as 39.87%.
Fig. 4 is a schematic diagram of a multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS) for delaying oxidation of ferrous sulfide nanoplatelets. From the figure, the antioxidation capability of the calcium ascorbate can effectively overcome the defect that the methoxy polyethylene glycol mercaptan modified ferrous sulfide nano-sheet is extremely easy to oxidize by air, and prolong the action time of the hydrogel system (AG-VcCa-FeS) prepared in the embodiment.
FIG. 5 is a schematic representation of the rheological behavior of the hydrogel system (AG-VcCa-FeS) prepared in the examples. It can be seen that the storage modulus (G ') is greater than the loss modulus (G'), the hydrogel exhibits a solid state, and when the loss modulus (G ') is greater than the storage modulus (G') after reaching the temperature critical point (38 ℃ C.), the hydrogel exhibits a liquid state, indicating that the hydrogel of the present application has fluidity. The rheological behavior of hydrogels was tested using a rheometer in a temperature sweep mode.
FIG. 6 is a schematic diagram showing the results of photo-thermal performance test of the hydrogel system (AG-VcCa-FeS) prepared in the example under irradiation of near infrared light with different powers. The testing method comprises the following steps: placing hydrogel AG-VcCa-FeS in a cuvette, and testing different powers (1W/cm) with a thermal infrared imager under irradiation of 808nm (5 min) 2 、1.5W/cm 2 、2W/cm 2 ) The temperature change of the multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS) is as follows. As can be seen from fig. 6, the temperature increase increases with an increase in near infrared light power.
FIG. 7 is a schematic diagram showing the photo-thermal stability test results of the hydrogel system (AG-VcCa-FeS) prepared in the example. The test method comprises five 808nm (1.5W/cm) 2 ) The on/off periodic irradiation of near infrared light. As can be seen from fig. 7, the hydrogel can be rapidly heated up to 74.1 ℃ during the whole period by irradiation with near infrared light, and can be gradually cooled down to the initial temperature when the near infrared light is turned off, which means that the hydrogel system (AG-VcCa-FeS) of the present application has stable photo-thermal conversion performance.
FIG. 8 is a graph showing the results of drug release performance test of the hydrogel system (AG-VcCa-FeS) of the example under the irradiation condition of 808nm near infrared light. As can be seen from fig. 8, the methoxypolyethylene glycol thiol-modified ferrous sulfide two-dimensional nano-sheet will exert its super-strong photo-thermal conversion performance under near infrared illumination, provide a large amount of heat to soften gel-state agarose water gel, increase the diffusion coefficient of calcium ascorbate in the hydrogel, thereby rapidly releasing the drug, and exhibit the near infrared triggered "off-on" characteristic, indicating that the hydrogel system (AG-VcCa-FeS) of the present application has photo-thermal controllable drug release performance.
FIG. 9 is a schematic diagram showing the results of degradation test of the hydrogel system (AG-VcCa-FeS) prepared in the example. As can be seen from fig. 9, the hydrogel (AG-VcCa-FeS) of the present application was able to degrade to 25% in 6 days under near infrared light. The multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS) has higher degradation efficiency.
FIG. 10 is a graph showing the dynamic volume change rate of the hydrogel system (AG-VcCa-FeS) prepared in the example. Fig. 10a shows the influence of irradiation of near infrared light on the volume change of the hydrogel system under the condition of measuring the presence or absence of ferrous sulfide two-dimensional nano-sheets by a ruler, and the graph shows that the multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS) has higher dynamic volume change rate under the irradiation of near infrared light, which indicates that the multifunctional iron-based photo-thermal controlled release agarose water gel system is easier to release medicines in the system. Fig. 10b is a graph of the quantitative analysis of the data from the scale measurements (three sets of parallel experiments).
Comparative example 1
The difference from the examples is that:
in the step (4), sequentially mixing agarose solution and methoxy polyethylene glycol mercaptan modified ferrous sulfide aqueous solution according to a volume ratio of 8:1, and standing at room temperature for 3min to form gel. The final concentration was 0.25wt%, 0.2mg/mL in this order.
Comparative example 2
In the step (4), agarose solution and calcium ascorbate aqueous solution are mixed in sequence according to the volume ratio of 8:1, and the mixture is left at room temperature for 3min to form gel. The final concentration was 0.25wt%, 0.2mg/mL in this order.
FIG. 11 is a schematic representation of the results of live dead staining of endometriosis cells of the hydrogel system (AG-VcCa-FeS) prepared in the examples. The figure specifically shows the results of cell live-dead staining experiments of different groups of a multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS), wherein NC groups are blank controls (0.25 wt% agarose solution), NIR groups are only subjected to laser irradiation, AVN groups are hydrogels prepared in comparative example 2, AVFN groups are hydrogels prepared in examples, and AVFN+NIR groups are hydrogels prepared in examples and are subjected to laser irradiation. From the left to right groupings it is evident that the number of living cells gradually decreases while the number of dead cells gradually increases. The multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS) has extremely strong effect of killing focal cells.
FIG. 12 is a schematic representation of the results of apoptosis of endometriosis cells of the hydrogel system (AG-VcCa-FeS) prepared in the examples. Dyes used in the apoptosis experiments are Annexin-V FITC and 7-AAD, Q1 represents Annexin-VFITC-/7-AAD+, and indicates cell death; q2 represents Annexin-V FITC+/7-AAD+, which represents late apoptosis; q3 represents Annexin-V FITC+/7-AAD-, representing early apoptosis; q4 represents Annexin-V FITC-/7-AAD-, representing normal cells. The experimental results of apoptosis conditions of different groups of the multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS) are specifically shown in the figure, wherein NC group is blank control (0.25 wt% agarose solution), NIR group is only irradiated by laser, AVN group is hydrogel prepared in comparative example 2, AVFN group is hydrogel prepared in examples, and AVFN+NIR group is hydrogel prepared in examples and laser is added. From left to right, the proportion of apoptotic cells is gradually increased, and the apoptosis rate of the near infrared light irradiation group with 808nm is as high as 78.3%. The multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS) has extremely strong capability of promoting apoptosis.
FIG. 13 is a schematic diagram showing cytotoxicity detection results of endometriosis cells of the hydrogel systems prepared in examples and comparative examples 1 to 2 (and agarose solution prepared by dissolving agarose in TAE buffer using 0.25wt% agarose solution as a blank), which are divided into: blank, example, comparative example 1, comparative example 2, each with 808nm laser irradiation. The results of the experiments on the viability of the focal cells in different groups are shown in the figure, and it can be seen that the cell viability of the example group is obviously reduced compared with the cell viability of the other three groups, and the cell viability is 28%. The cell viability of the comparative example 1 group was 51% and the cell viability of the comparative example 2 group was 79%. The multifunctional iron-based photo-thermal controlled release agarose water gel system (AG-VcCa-FeS) has extremely strong focus cell killing effect under the NIR condition, and has a certain synergistic killing effect between FeS-PEG and VcCa in the hydrogel system.
The above description is only of the preferred embodiments of the present application and is not intended to limit the present application, but various modifications and variations can be made to the present application by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (9)
1. The multifunctional iron-based photo-thermal controlled release agarose gel system is characterized by comprising an agarose gel carrier, and calcium ascorbate and iron-based two-dimensional nano-sheets loaded in the agarose gel carrier;
the iron-based two-dimensional nano sheet is a methoxy polyethylene glycol mercaptan modified ferrous sulfide two-dimensional nano sheet;
the methoxy polyethylene glycol mercaptan modified ferrous sulfide two-dimensional nano-sheet is prepared by the following method:
(1) Under the protection of nitrogen, dissolving ferrous ammonium sulfate and trisodium citrate in ethylene glycol to obtain a mixed solution, dropwise adding an ethylene glycol solution of polyethyleneimine into the mixed solution, carrying out a first stirring reaction, dropwise adding an ethylene glycol solution of thioacetamide, carrying out a second stirring reaction, dropwise adding triethanolamine, carrying out a third stirring reaction, carrying out solvothermal reaction on the obtained product, centrifuging and washing to obtain the ferrous sulfide two-dimensional nano-sheet;
(2) Dissolving the ferrous sulfide two-dimensional nano-sheet and methoxy polyethylene glycol mercaptan obtained in the step (1) in absolute ethyl alcohol, carrying out ice bath, stirring in a dark place, and then centrifuging and washing to obtain the methoxy polyethylene glycol mercaptan modified ferrous sulfide two-dimensional nano-sheet FeS-PEG.
2. The multifunctional iron-based photo-thermal controlled release agarose water gel system according to claim 1, wherein in step (1), the ratio of the addition amount of ferrous ammonium sulfate, trisodium citrate and ethylene glycol in the mixed solution is 0.6mmoL:0.2mmoL:15mL; the ratio of the adding amount of the polyethyleneimine to the adding amount of the ethylene glycol in the ethylene glycol solution of the polyethyleneimine is 500mg:5mL; the concentration of the ethylene glycol solution of the thioacetamide is 0.05M; the addition ratio of the ethylene glycol solution of the ferrous ammonium sulfate, the polyethyleneimine and the thioacetamide to the triethanolamine is 0.6mmoL:500mg:15mL:2mL.
3. The multifunctional iron-based photo-thermal controlled release agarose water gel system according to claim 1, wherein in the step (1), the time of the first stirring reaction is 2 hours, and the time of the second stirring reaction and the time of the third stirring reaction are 5 minutes; the solvothermal reaction was at 200 ℃ for 24h.
4. The multifunctional iron-based photo-thermal controlled release agarose water gel system according to claim 1, wherein in step (2), the ratio of the addition amounts of the ferrous sulfide two-dimensional nano-sheet, methoxypolyethylene glycol thiol and absolute ethyl alcohol is 1mg:1mg:1mL; the time of the light-shielding stirring is 6 hours.
5. The multifunctional iron-based photo-thermal controlled release agarose water gel system according to claim 1, wherein the multifunctional iron-based photo-thermal controlled release agarose water gel system is prepared by the following method:
dispersing FeS-PEG in water, and carrying out ultrasonic treatment to obtain FeS-PEG aqueous solution; dispersing calcium ascorbate in water, and carrying out vortex oscillation to obtain a calcium ascorbate aqueous solution; dissolving agarose in TAE buffer solution, heating in water bath until the agarose is completely dissolved, and cooling to liquid state to obtain agarose solution; sequentially mixing agarose solution, calcium ascorbate aqueous solution and FeS-PEG aqueous solution, and standing at room temperature to form gel to obtain the multifunctional iron-based photo-thermal controlled release agarose aqueous gel system.
6. The multifunctional iron-based photothermal controlled release agarose water gel system according to claim 5, wherein the concentration of FeS-PEG aqueous solution is 2mg/mL; the concentration of the calcium ascorbate aqueous solution is 2mg/mL; the concentration of the agarose solution is 3.125mg/mL; the temperature of the water bath heating is 90-100 ℃; and cooling the agarose solution to 40-45 ℃ for use.
7. The multifunctional iron-based photo-thermal controlled release agarose water-gel system according to claim 5, wherein the volume ratio of FeS-PEG aqueous solution, calcium ascorbate aqueous solution and agarose solution is 1:1:8.
8. the multifunctional iron-based photo-thermal controlled release agarose water gel system according to claim 1, wherein the mass content of agarose in the multifunctional iron-based photo-thermal controlled release agarose water gel system is 0.25%, the content of FeS-PEG aqueous solution is 0.2mg/mL, and the content of calcium ascorbate aqueous solution is 0.2mg/mL.
9. Use of the multifunctional iron-based photo-thermal controlled release agarose water gel system according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of endometriosis.
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