CN115025248A - Iron-based ICG metal organic nano composite (MONs) and preparation method and application thereof - Google Patents
Iron-based ICG metal organic nano composite (MONs) and preparation method and application thereof Download PDFInfo
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- CN115025248A CN115025248A CN202110197570.4A CN202110197570A CN115025248A CN 115025248 A CN115025248 A CN 115025248A CN 202110197570 A CN202110197570 A CN 202110197570A CN 115025248 A CN115025248 A CN 115025248A
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- iron
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 title claims abstract description 121
- 239000002114 nanocomposite Substances 0.000 title claims abstract description 65
- 229910052742 iron Inorganic materials 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000002184 metal Substances 0.000 title claims abstract 13
- 229910052751 metal Inorganic materials 0.000 title claims abstract 13
- 239000007850 fluorescent dye Substances 0.000 claims abstract description 68
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 23
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 23
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 23
- 238000003745 diagnosis Methods 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 7
- 239000013082 iron-based metal-organic framework Substances 0.000 claims abstract description 5
- 229960004657 indocyanine green Drugs 0.000 claims description 61
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 claims description 58
- 229940014041 hyaluronate Drugs 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 claims description 12
- 239000013110 organic ligand Substances 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 239000002131 composite material Substances 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 150000002505 iron Chemical class 0.000 claims description 10
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 8
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 claims description 8
- QMKYBPDZANOJGF-UHFFFAOYSA-N benzene-1,3,5-tricarboxylic acid Chemical compound OC(=O)C1=CC(C(O)=O)=CC(C(O)=O)=C1 QMKYBPDZANOJGF-UHFFFAOYSA-N 0.000 claims description 8
- 239000013078 crystal Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000000975 dye Substances 0.000 claims description 5
- -1 iron ions Chemical class 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 3
- 238000003917 TEM image Methods 0.000 claims description 3
- 239000012467 final product Substances 0.000 claims description 3
- 229910021645 metal ion Inorganic materials 0.000 claims description 3
- 239000012621 metal-organic framework Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000013289 nano-metal-organic framework Substances 0.000 claims description 3
- 238000001878 scanning electron micrograph Methods 0.000 claims description 3
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 3
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 239000003446 ligand Substances 0.000 claims description 2
- 239000002086 nanomaterial Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000000717 retained effect Effects 0.000 claims description 2
- 230000001613 neoplastic effect Effects 0.000 claims 2
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 claims 1
- 229910000358 iron sulfate Inorganic materials 0.000 claims 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims 1
- MVFCKEFYUDZOCX-UHFFFAOYSA-N iron(2+);dinitrate Chemical compound [Fe+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MVFCKEFYUDZOCX-UHFFFAOYSA-N 0.000 claims 1
- 239000000463 material Substances 0.000 claims 1
- 150000002736 metal compounds Chemical class 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 238000009210 therapy by ultrasound Methods 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 13
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 2
- 238000011217 control strategy Methods 0.000 abstract 1
- 229920002125 Sokalan® Polymers 0.000 description 12
- 230000008685 targeting Effects 0.000 description 12
- 230000008569 process Effects 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 4
- 238000001000 micrograph Methods 0.000 description 4
- 230000008859 change Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000007626 photothermal therapy Methods 0.000 description 3
- 239000004584 polyacrylic acid Substances 0.000 description 3
- 238000009214 sonodynamic therapy Methods 0.000 description 3
- GPNNOCMCNFXRAO-UHFFFAOYSA-N 2-aminoterephthalic acid Chemical compound NC1=CC(C(O)=O)=CC=C1C(O)=O GPNNOCMCNFXRAO-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- 238000002428 photodynamic therapy Methods 0.000 description 2
- 238000001126 phototherapy Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010200 validation analysis Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QNVNLUSHGRBCLO-UHFFFAOYSA-N H2BDC Natural products OC(=O)C1=CC(O)=CC(C(O)=O)=C1 QNVNLUSHGRBCLO-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001095 inductively coupled plasma mass spectrometry Methods 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 1
- YHGPYBQVSJBGHH-UHFFFAOYSA-H iron(3+);trisulfate;pentahydrate Chemical compound O.O.O.O.O.[Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O YHGPYBQVSJBGHH-UHFFFAOYSA-H 0.000 description 1
- 229910000360 iron(III) sulfate Inorganic materials 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002905 metal composite material Substances 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 239000002539 nanocarrier Substances 0.000 description 1
- 108091008104 nucleic acid aptamers Proteins 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
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- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
- A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
-
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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Abstract
Description
技术领域technical field
本发明属于纳米药物技术领域及纳米制剂制备领域，具体涉及一种铁基ICG金属有机纳米复合物及其制备方法与应用。The invention belongs to the technical field of nano-medicine and the field of preparation of nano-formulations, and particularly relates to an iron-based ICG metal-organic nano-composite and a preparation method and application thereof.
背景技术Background technique
作为FDA批准的临床医用近红外荧光染料，吲哚菁绿(ICG)由于其优异的多功能性使其在肿瘤的精准诊疗方面得到了广泛的应用，除了作为成像分子进行荧光成像(NIR-FL)与光声成像(PA)，ICG还可以作为光敏剂与声敏剂进行光热治疗(PTT)，光动力治疗(PDT)与声动力治疗(SDT)。考虑到ICG自身代谢周期短、稳定性差等缺点，研究者在使用ICG进行肿瘤诊疗时通过纳米化的策略则可以有效延长ICG的血液循环时间，增加ICG诊疗性能的稳定性，从而提高其对肿瘤的诊疗效率。鉴于ICG自身优异的结构特点，设计利用ICG分子中磺酸根和金属离子的作用直接将ICG纳米化从而制备ICG金属有机纳米复合物(ICG@MON)的策略相比于利用纳米载体(脂质体、介孔二氧化硅、胶束等)运载ICG的方法具有更加显著的优势，例如运载递送效率更高、生物安全性更好、临床转化前景更广。因此，如何高效可控地制备ICG@MON成为ICG医用方面的研究热点。As an FDA-approved near-infrared fluorescent dye for clinical use, indocyanine green (ICG) has been widely used in the precise diagnosis and treatment of tumors due to its excellent versatility. ) and photoacoustic imaging (PA), ICG can also be used as photosensitizer and sonosensitizer for photothermal therapy (PTT), photodynamic therapy (PDT) and sonodynamic therapy (SDT). Considering the shortcomings of ICG's own short metabolic cycle and poor stability, researchers can effectively prolong the blood circulation time of ICG and increase the stability of ICG's diagnosis and treatment performance through the nanoscale strategy when using ICG for tumor diagnosis and treatment, thereby improving its ability to treat tumors. diagnostic efficiency. In view of the excellent structural characteristics of ICG itself, the strategy of using the effect of sulfonate and metal ions in ICG molecules to directly nanosize ICG to prepare ICG metal-organic nanocomposites (ICG@MON) was designed compared with the use of nanocarriers (liposomes). , mesoporous silica, micelles, etc.) methods for carrying ICG have more significant advantages, such as higher delivery efficiency, better biosafety, and broader prospects for clinical translation. Therefore, how to efficiently and controllably prepare ICG@MON has become a research hotspot in the field of ICG medicine.
发明内容SUMMARY OF THE INVENTION
为了克服现有技术的不足，本发明首先提供了一种铁基近红外荧光染料金属有机纳米复合物。In order to overcome the deficiencies of the prior art, the present invention first provides an iron-based near-infrared fluorescent dye metal-organic nanocomposite.
根据本发明的实施方案，所述铁基近红外荧光染料金属有机纳米复合物选自铁基ICG金属有机纳米复合物(Fe-ICG@MON)或铁基IR-820金属有机纳米复合物(Fe-IR-820@MON)。According to an embodiment of the present invention, the iron-based near-infrared fluorescent dye metal-organic nanocomposite is selected from iron-based ICG metal-organic nanocomposite (Fe-ICG@MON) or iron-based IR-820 metal-organic nanocomposite (Fe-ICG@MON) -IR-820@MON).
所述的铁基金属有机复合物以Fe3+为中心金属离子，近红外染料和有机配体为双配体，共配位成铁基近红外荧光染料金属复合物；所述有机配体可以选自邻氨基对苯二甲酸(H2BDC-NH2)、对苯二甲酸、均苯三甲酸和反丁烯二酸。The iron-based metal-organic composite takes Fe 3+ as the central metal ion, the near-infrared dye and the organic ligand are dual ligands, and co-coordinate to form the iron-based near-infrared fluorescent dye-metal composite; the organic ligand can be Selected from anthranilic acid ( H2BDC - NH2 ), terephthalic acid, trimesic acid and fumaric acid.
所述的铁基金属有机复合物的近红外荧光染料含量高于25wt％，当染料为ICG时，ICG的含量高达33wt％；The content of the near-infrared fluorescent dye of the iron-based metal-organic composite is higher than 25wt%, and when the dye is ICG, the content of ICG is as high as 33wt%;
所述近红外染料为吲哚菁绿(ICG)或新吲哚菁绿(IR-820)；所述复合物为纳米结构，尺寸为40-150nm；The near-infrared dye is indocyanine green (ICG) or neo-indocyanine green (IR-820); the composite is a nanostructure with a size of 40-150 nm;
所述的铁基金属有机复合物不再保留铁基金属有机骨架的结构，随着反应体系ICG浓度的增加，最终产物MOFs的晶型特征逐渐消失，晶型趋于无定型；The iron-based metal-organic composite no longer retains the structure of the iron-based metal-organic framework, and with the increase of the ICG concentration in the reaction system, the crystal characteristics of the final product MOFs gradually disappear, and the crystal form tends to be amorphous;
根据本发明的实施方案，所述铁基近红外荧光染料金属有机纳米复合物具有基本如图1a所示的扫描电镜图或图1b所示的透射电镜图。According to an embodiment of the present invention, the iron-based near-infrared fluorescent dye metal-organic nanocomposite has a scanning electron microscope image substantially as shown in FIG. 1a or a transmission electron microscope image as shown in FIG. 1b.
根据本发明的实施方案，所述铁基近红外荧光染料金属有机纳米复合物具有基本如图2所示的扫描电镜图。According to an embodiment of the present invention, the iron-based near-infrared fluorescent dye metal-organic nanocomposite has a scanning electron microscope image substantially as shown in FIG. 2 .
本发明还提供了所述近红外荧光染料金属有机纳米复合物的制备方法，包括以下步骤：将铁盐和有机配体溶于溶剂后，与近红外荧光染料溶液混合，反应得到所述近红外荧光染料金属有机纳米复合物。The present invention also provides a preparation method of the near-infrared fluorescent dye metal-organic nanocomposite, comprising the following steps: after dissolving the iron salt and the organic ligand in a solvent, mixing with the near-infrared fluorescent dye solution, and reacting to obtain the near-infrared fluorescent dye solution Fluorescent dye metal-organic nanocomposites.
根据本发明实施方案，所述铁盐可以选自硝酸铁、硫酸铁、氯化铁及其水合物中的至少一种，优选六水合三氯化铁。According to an embodiment of the present invention, the iron salt may be selected from at least one of ferric nitrate, ferric sulfate, ferric chloride and hydrates thereof, preferably ferric trichloride hexahydrate.
根据本发明实施方案，所述有机配体可以选自邻氨基对苯二甲酸(H2BDC-NH2)、对苯二甲酸、均苯三甲酸和反丁烯二酸。According to an embodiment of the present invention, the organic ligand may be selected from the group consisting of anthranilic acid (H 2 BDC-NH 2 ), terephthalic acid, trimesic acid and fumaric acid.
根据本发明实施方案，所述溶剂可以为有机溶剂，如醇类溶剂，例如甲醇、乙醇。According to an embodiment of the present invention, the solvent may be an organic solvent, such as an alcoholic solvent, such as methanol and ethanol.
根据本发明实施方案，所述近红外荧光染料可以为吲哚菁绿(ICG)或新吲哚菁绿(IR-820)。According to an embodiment of the present invention, the near-infrared fluorescent dye may be indocyanine green (ICG) or neo-indocyanine green (IR-820).
根据本发明实施方案，所述铁盐与所述有机配体的摩尔比可以为1:(0.2-5)，例如为1:(0.5-2)，示例性为1:1。According to an embodiment of the present invention, the molar ratio of the iron salt to the organic ligand may be 1:(0.2-5), for example, 1:(0.5-2), exemplarily 1:1.
根据本发明实施方案，所述铁盐与所述溶剂的质量体积比1:(20-200)g/mL，例如为1:(50-100)g/mL，示例性为1:74g/mL。According to an embodiment of the present invention, the mass volume ratio of the iron salt to the solvent is 1:(20-200) g/mL, for example, 1:(50-100) g/mL, exemplarily 1:74 g/mL .
根据本发明实施方案，所述铁盐与所述近红外荧光染料的质量比可以为1:(0.0001-0.001)，例如为1:(0.0003-0.0008)，示例性为1:0.00037、1:0.00074。According to an embodiment of the present invention, the mass ratio of the iron salt to the near-infrared fluorescent dye may be 1:(0.0001-0.001), for example, 1:(0.0003-0.0008), exemplarily 1:0.00037, 1:0.00074 .
根据本发明实施方案，所述近红外荧光染料溶液所用溶剂可以为有机溶剂或水，所述有机溶剂可以为二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺；According to an embodiment of the present invention, the solvent used in the near-infrared fluorescent dye solution may be an organic solvent or water, and the organic solvent may be dimethyl sulfoxide, dimethylformamide, and dimethylacetamide;
根据本发明实施方案，所述近红外荧光染料在反应体系中的浓度可以为10-200μgmL-1，例如为50-100μg mL-1。所述反应体系可以理解为总的反应混合液(包括将铁盐和有机配体溶于溶剂后，与近红外荧光染料溶液混合后形成的反应混合液)。According to an embodiment of the present invention, the concentration of the near-infrared fluorescent dye in the reaction system may be 10-200 μg mL −1 , for example, 50-100 μg mL −1 . The reaction system can be understood as the total reaction mixture (including the reaction mixture formed after dissolving the iron salt and the organic ligand in the solvent and mixing with the near-infrared fluorescent dye solution).
优选地，当所述近红外荧光染料为吲哚菁绿时，所述溶液的溶剂可以为二甲基亚砜，在反应体系中的浓度为100μg mL-1，其中ICG的浓度主要影响反应体系产物中Fe-NMOF向Fe-ICG@MON的转化效率；当所述近红外荧光染料为新吲哚菁绿时，所述溶液的溶剂可以为水，其浓度为50μg mL-1。Preferably, when the near-infrared fluorescent dye is indocyanine green, the solvent of the solution can be dimethyl sulfoxide, and the concentration in the reaction system is 100 μg mL -1 , wherein the concentration of ICG mainly affects the reaction system The conversion efficiency of Fe-NMOF in the product to Fe-ICG@MON; when the near-infrared fluorescent dye is neo-indocyanine green, the solvent of the solution can be water, and its concentration is 50 μg mL -1 .
根据本发明实施方案，所述反应的时间可以为0.5-4h，例如为0.8-2h，示例性为1h；所述反应的温度可以为20-60℃，例如为25-40℃，示例性为35℃，反应温度主要影响产物的尺寸，故可根据实际应用需求选择水浴温度。According to an embodiment of the present invention, the reaction time may be 0.5-4h, such as 0.8-2h, and the example is 1h; the temperature of the reaction may be 20-60°C, such as 25-40°C, and the example is 35℃, the reaction temperature mainly affects the size of the product, so the temperature of the water bath can be selected according to the actual application requirements.
根据本发明示例性的实施方案，所述制备方法包括以下步骤：According to an exemplary embodiment of the present invention, the preparation method includes the following steps:
(1)配制FeCl3·6H2O的醇溶液与H2BDC-NH2的醇溶液；(1) prepare the alcoholic solution of FeCl 3 ·6H 2 O and the alcoholic solution of H 2 BDC-NH 2 ;
(2)配制ICG的DMSO溶液或IR-820的水溶液；(2) Prepare the DMSO solution of ICG or the aqueous solution of IR-820;
(3)将步骤(1)中FeCl3·6H2O的醇溶液与H2BDC-NH2的醇溶液按比例混合均匀后，按比例加入步骤(2)中配制的ICG的DMSO溶液或IR-820的水溶液混合均匀；(3) After the alcoholic solution of FeCl 3 ·6H 2 O in step (1) and the alcoholic solution of H 2 BDC-NH 2 are uniformly mixed in proportion, the DMSO solution or IR of ICG prepared in step (2) is added in proportion The aqueous solution of -820 is evenly mixed;
(4)将步骤(3)中得到的反应体系在适当温度的水浴中反应合适时间后，通过离心洗涤得到Fe-ICG@MON或Fe-IR-820@MON；(4) after the reaction system obtained in step (3) is reacted for a suitable time in a water bath of appropriate temperature, Fe-ICG@MON or Fe-IR-820@MON is obtained by centrifugal washing;
本发明还提供所述的铁基近红外荧光染料金属有机纳米复合物在制备疾病诊断和治疗药物中的应用。The invention also provides the application of the iron-based near-infrared fluorescent dye metal-organic nanocomposite in the preparation of disease diagnosis and treatment drugs.
根据本发明的实施方案，所述疾病可以为肿瘤疾病或心血管疾病，所述心血管疾病可以为动脉粥状硬化。According to an embodiment of the present invention, the disease may be a tumor disease or a cardiovascular disease, and the cardiovascular disease may be atherosclerosis.
本发明还提供了一种透明质酸包覆的铁基近红外荧光染料金属有机纳米复合物。The invention also provides an iron-based near-infrared fluorescent dye metal-organic nanocomposite coated with hyaluronic acid.
根据本发明的实施方案，所述透明质酸包覆的铁基近红外荧光染料金属有机纳米复合物可以为透明质酸包覆的铁基ICG金属有机纳米复合物(Fe-ICG@MON@HA)或透明质酸包覆的铁基IR-820金属有机纳米复合物(Fe-IR-820@MON@HA)。According to an embodiment of the present invention, the hyaluronic acid-coated iron-based near-infrared fluorescent dye metal-organic nanocomposite may be a hyaluronic acid-coated iron-based ICG metal-organic nanocomposite (Fe-ICG@MON@HA ) or hyaluronic acid-coated iron-based IR-820 metal-organic nanocomposites (Fe-IR-820@MON@HA).
根据本发明的实施方案，所述透明质酸包覆的铁基近红外荧光染料金属有机纳米复合物是所述近红外荧光染料金属有机纳米复合物表面的铁离子与HA上的羧基配位得到的。According to an embodiment of the present invention, the hyaluronic acid-coated iron-based near-infrared fluorescent dye metal-organic nanocomposite is obtained by coordinating iron ions on the surface of the near-infrared fluorescent dye metal-organic nanocomposite with carboxyl groups on HA of.
根据本发明的实施方案，所述透明质酸包覆的铁基近红外荧光染料金属有机纳米复合物可以为肿瘤诊疗提供靶向性。According to an embodiment of the present invention, the hyaluronic acid-coated iron-based near-infrared fluorescent dye metal-organic nanocomposite can provide targeting for tumor diagnosis and treatment.
根据本发明的实施方案，所述透明质酸包覆的铁基近红外荧光染料金属有机纳米复合物可以进一步进行其他靶向修饰，例如可以通过靶向分子、靶向多肽、靶向蛋白、靶向核酸适配体等进行修饰。According to an embodiment of the present invention, the hyaluronic acid-coated iron-based near-infrared fluorescent dye metal-organic nanocomposite can be further modified by other targeting, such as targeting molecules, targeting polypeptides, targeting proteins, targeting Modifications are made to nucleic acid aptamers and the like.
本发明还提供所述透明质酸包覆的铁基近红外荧光染料金属有机纳米复合物的制备方法，包括以下步骤：将所述近红外荧光染料金属有机纳米复合物分散在透明质酸钠(HA)水溶液中室温超声反应，得到所述透明质酸包覆的铁基近红外荧光染料金属有机纳米复合物。The present invention also provides the preparation method of the hyaluronic acid-coated iron-based near-infrared fluorescent dye metal-organic nanocomposite, comprising the following steps: dispersing the near-infrared fluorescent dye metal-organic nanocomposite in sodium hyaluronate ( Ultrasonic reaction at room temperature in an aqueous solution of HA) to obtain the hyaluronic acid-coated iron-based near-infrared fluorescent dye metal-organic nanocomposite.
根据本发明的实施方案，所述近红外荧光染料金属有机纳米复合物为铁基ICG金属有机纳米复合物(Fe-ICG@MON)或铁基IR-820金属有机纳米复合物(Fe-IR-820@MON)。According to an embodiment of the present invention, the near-infrared fluorescent dye metal-organic nanocomposite is an iron-based ICG metal-organic nanocomposite (Fe-ICG@MON) or an iron-based IR-820 metal-organic nanocomposite (Fe-IR- 820@MON).
根据本发明的实施方案，所述近红外荧光染料金属有机纳米复合物与HA的质量比为1:0.5-10，例如为1:1-5，示例性为为1:2.5。According to an embodiment of the present invention, the mass ratio of the near-infrared fluorescent dye metal-organic nanocomposite to HA is 1:0.5-10, for example, 1:1-5, and exemplarily, 1:2.5.
根据本发明的实施方案，所述的HA水溶液浓度为0.5-3mg mL-1；进一步优选为1.2mg mL-1；According to an embodiment of the present invention, the concentration of the HA aqueous solution is 0.5-3 mg mL -1 ; more preferably 1.2 mg mL -1 ;
根据本发明的实施方案，所述超声功率为50-300W，优选为100W；超声时间为15-120min，优选为30min。According to the embodiment of the present invention, the ultrasonic power is 50-300W, preferably 100W; the ultrasonic time is 15-120min, preferably 30min.
根据本发明的实施方案，所述透明质酸包覆的铁基近红外荧光染料金属有机纳米复合物是通过近红外荧光染料金属有机纳米复合物表面的铁离子与HA上的羧基配位形成。According to an embodiment of the present invention, the hyaluronic acid-coated iron-based near-infrared fluorescent dye metal-organic nanocomposite is formed by the coordination of iron ions on the surface of the near-infrared fluorescent dye metal-organic nanocomposite with carboxyl groups on HA.
本发明还提供所述透明质酸包覆的铁基近红外荧光染料金属有机纳米复合物在制备疾病诊断和治疗药物中的应用。The invention also provides the application of the hyaluronic acid-coated iron-based near-infrared fluorescent dye metal-organic nanocomposite in the preparation of disease diagnosis and treatment medicines.
根据本发明的实施方案，所述疾病可以为肿瘤疾病或心血管疾病，所述心血管疾病可以为动脉粥状硬化。According to an embodiment of the present invention, the disease may be a tumor disease or a cardiovascular disease, and the cardiovascular disease may be atherosclerosis.
有益效果beneficial effect
本发明利用铁离子自身生物安全性较好与其纳米化后潜在的多功能性将铁基近红外荧光染料金属有机纳米复合物，如Fe-ICG@MON和Fe-IR-820@MON的合成体系引入到Fe-NMOF的合成体系中，通过调控反应体系中反应物的比例实现铁基近红外荧光染料金属有机纳米复合物可控合成，展现出更加优异的诊疗性能(例如额外增加的MRI性能，增强的PA成像性能，保留的NIR-FL成像性能，增强的光敏(PTT，PDT)与声敏(SDT)功能，延长的血液半衰期，增强的肿瘤EPR效应等)；进一步通过透明质酸进行包覆得到的透明质酸包覆的铁基近红外荧光染料金属有机纳米复合物具有更好的光热稳定性、肿瘤靶向性和光疗效率。In the invention, the iron-based near-infrared fluorescent dye metal-organic nanocomposite, such as the synthesis system of Fe-ICG@MON and Fe-IR-820@MON, utilizes the better biological safety of iron ion itself and its potential multifunctionality after nanometerization. Introduced into the synthesis system of Fe-NMOF, the controllable synthesis of iron-based near-infrared fluorescent dye metal-organic nanocomposites can be realized by adjusting the ratio of reactants in the reaction system, showing more excellent therapeutic performance (such as additional MRI performance, Enhanced PA imaging performance, retained NIR-FL imaging performance, enhanced photosensitivity (PTT, PDT) and sonosensitivity (SDT) functions, extended blood half-life, enhanced tumor EPR effect, etc.); further encapsulated by hyaluronic acid The obtained hyaluronic acid-coated iron-based near-infrared fluorescent dye metal-organic nanocomposite has better photothermal stability, tumor targeting and phototherapy efficiency.
本发明提供的铁基近红外荧光染料金属有机纳米复合物以及透明质酸包覆的铁基近红外荧光染料金属有机纳米复合物的可控合成策略工艺简单，操作方便，且为绿色合成，适用于大规模生产。The controllable synthesis strategy of the iron-based near-infrared fluorescent dye metal-organic nanocomposite and the iron-based near-infrared fluorescent dye metal-organic nanocomposite provided by the invention is simple in process, convenient in operation, green synthesis, and suitable for for mass production.
本发明提供的Fe-ICG@MON以及Fe-ICG@MON@HA相比于ICG分子，表现出更加优异的诊疗性能，能够有效推动ICG在肿瘤诊疗方面的发展。Compared with ICG molecules, the Fe-ICG@MON and Fe-ICG@MON@HA provided by the present invention show more excellent diagnosis and treatment performance, and can effectively promote the development of ICG in tumor diagnosis and treatment.
附图说明Description of drawings
图1是本发明实施例1中提供的Fe-ICG@MON的SEM与TEM图，SEM标尺为300nm，TEM标尺为25nm。FIG. 1 is the SEM and TEM images of Fe-ICG@MON provided in Example 1 of the present invention, the SEM scale is 300 nm, and the TEM scale is 25 nm.
图2是本发明实施例2中提供的随着ICG浓度变化产物XRD的变化图。FIG. 2 is a graph of the XRD change of the product provided in Example 2 of the present invention as the concentration of ICG changes.
图3是本发明实施例3中提供的Fe-IR-820@MON的TEM图，标尺为100nm。3 is a TEM image of Fe-IR-820@MON provided in Example 3 of the present invention, and the scale bar is 100 nm.
图4是本发明实施例3中提供的Fe-ICG@MON、Fe-ICG@MON@PAA和Fe-ICG@MON@HA的尺寸与电位变化图。FIG. 4 is a graph showing the size and potential changes of Fe-ICG@MON, Fe-ICG@MON@PAA and Fe-ICG@MON@HA provided in Example 3 of the present invention.
图5是Fe-ICG@MON@HA光热性能验证图。Figure 5 is the photothermal performance verification diagram of Fe-ICG@MON@HA.
图6是ICG分子、Fe-ICG@MON@PAA与Fe-ICG@MON@HA的4T1细胞共聚焦显微镜图。Figure 6 is a confocal microscope image of 4T1 cells of ICG molecules, Fe-ICG@MON@PAA and Fe-ICG@MON@HA.
图7是ICG分子、Fe-ICG@MON@PAA与Fe-ICG@MON@HA的4T1细胞光热治疗效果对比图。Figure 7 is a graph showing the comparison of photothermal treatment effects of ICG molecules, Fe-ICG@MON@PAA and Fe-ICG@MON@HA on 4T1 cells.
具体实施方式Detailed ways
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the intended protection scope of the present invention.
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise stated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.
实施例1：Fe-ICG@MON的合成Example 1: Synthesis of Fe-ICG@MON
称取13.5mg的FeCl3·6H2O溶解在1mL的无水乙醇中，称取9mg邻氨基对苯二甲酸(H2BDC-NH2)溶解在9mL乙醇中，加入50μL ICG的DMSO溶液，使其在反应体系中的浓度为100μg·mL-1，在35℃下反应1h，12000rpm，10min，离心超声再分散，用乙醇洗涤几次得到Fe-ICG@MON。Fe-ICG@MON最终形貌表征SEM与TEM如图1所示。Weigh 13.5 mg of FeCl 3 ·6H 2 O and dissolve it in 1 mL of absolute ethanol, weigh 9 mg of o-aminoterephthalic acid (H 2 BDC-NH 2 ) and dissolve it in 9 mL of ethanol, add 50 μL of ICG in DMSO, Its concentration in the reaction system was 100 μg·mL -1 , reacted at 35°C for 1 h, 12000 rpm, 10 min, redispersed by centrifugation and ultrasonic, washed several times with ethanol to obtain Fe-ICG@MON. The final morphological characterization of Fe-ICG@MON by SEM and TEM is shown in Fig. 1.
实施例2：Fe-ICG@MON的合成调控与表征Example 2: Synthetic regulation and characterization of Fe-ICG@MON
称取13.5mg的FeCl3·6H2O溶解在1mL的无水乙醇中，称取9mg邻氨基对苯二甲酸(H2BDC-NH2)溶解在9mL乙醇中，改变加入ICG的含量(使其在反应体系中的浓度梯度分别为0，25，50，75，100μg·mL-1)，35℃下反应1h，12000rpm，10min，离心超声再分散，用乙醇洗涤几次得到产物。通过XRD表征证明随着反应体系ICG浓度的增加，铁基金属有机复合物不再保留铁基金属有机骨架的结构，最终产物MOFs的晶型特征逐渐消失，晶型趋于无定型，XRD表征如图2所示；通过ICP-MS分析，随着随着反应体系ICG浓度的增加，铁基金属有机复合物中硫元素含量逐渐增加，根据计算可得当ICG浓度为100微克/ml时，ICG运载效率约为33wt％。Weigh 13.5 mg of FeCl 3 ·6H 2 O and dissolve it in 1 mL of absolute ethanol. Weigh 9 mg of o-aminoterephthalic acid (H 2 BDC-NH 2 ) and dissolve it in 9 mL of ethanol. Its concentration gradient in the reaction system was 0, 25, 50, 75, 100 μg·mL -1 ), reacted at 35°C for 1 h, 12000 rpm, 10 min, centrifuged and ultrasonicated for redispersion, and washed several times with ethanol to obtain the product. XRD characterization proves that with the increase of ICG concentration in the reaction system, the iron-based metal-organic composite no longer retains the structure of the iron-based metal-organic framework, and the crystal characteristics of the final product MOFs gradually disappear, and the crystal form tends to be amorphous. The XRD characterization is as follows: As shown in Figure 2; by ICP-MS analysis, with the increase of the ICG concentration in the reaction system, the content of sulfur in the iron-based metal-organic composite gradually increased. The efficiency is about 33 wt%.
实施例3：Fe-IR-820@MON的合成Example 3: Synthesis of Fe-IR-820@MON
称取13.5mg的FeCl3·6H2O溶解在1mL的无水乙醇中，称取9mg H2BDC-NH2溶解在9mL乙醇中，加入200μL IR-820的水溶液使其在反应体系中的浓度为50μg·mL-1，在40℃下反应1h，12000rpm，10min，离心超声再分散，用乙醇洗涤几次得到Fe-IR-820@MON。Fe-IR-820@MON最终形貌表征TEM如图2所示。Weigh 13.5 mg of FeCl 3 6H 2 O and dissolve it in 1 mL of absolute ethanol, weigh 9 mg of H 2 BDC-NH 2 and dissolve it in 9 mL of ethanol, add 200 μL of IR-820 aqueous solution to make the concentration in the reaction system 50 μg·mL -1 , reacted at 40°C for 1 h, 12000 rpm, 10 min, redispersed by centrifugation and ultrasonic, washed several times with ethanol to obtain Fe-IR-820@MON. The final morphological characterization of Fe-IR-820@MON is shown in Figure 2.
实施例4：Fe-ICG@MON@HA的合成Example 4: Synthesis of Fe-ICG@MON@HA
称取4mg实施实例1中合成的Fe-ICG@MON并将其分散在5mL透明质酸钠(HA)的水溶液(2mg mL-1)中，在超声功率为35W的条件下反应0.5h，12000rpm，10min，离心超声再分散，用去离子水洗涤几次得到Fe-ICG@MON@HA。为考察Fe-ICG@MON@HA的肿瘤靶向性能，选择聚丙烯酸(PAA)修饰的Fe-ICG@MON作为对照组并记为Fe-ICG@MON@PAA。Fe-ICG@MON@PAA的合成方法与Fe-ICG@MON@HA的合成方法相同，仅对合成过程使用的HA水溶液替换为相同浓度的PAA水溶液即可。其中合成过程中Fe-ICG@MON、Fe-ICG@MON@PAA、Fe-ICG@MON@HA的尺寸变化如图4a，电位变化如图4b所示。Weigh 4 mg Fe-ICG@MON synthesized in Example 1 and disperse it in an aqueous solution (2 mg mL -1 ) of 5 mL of sodium hyaluronate (HA), react for 0.5 h under the condition that ultrasonic power is 35 W, 12000 rpm , 10 min, centrifuged and ultrasonicated for redispersion, and washed with deionized water for several times to obtain Fe-ICG@MON@HA. To investigate the tumor targeting performance of Fe-ICG@MON@HA, polyacrylic acid (PAA)-modified Fe-ICG@MON was selected as the control group and denoted as Fe-ICG@MON@PAA. The synthesis method of Fe-ICG@MON@PAA is the same as that of Fe-ICG@MON@HA, except that the HA aqueous solution used in the synthesis process is replaced with the same concentration of PAA aqueous solution. The size changes of Fe-ICG@MON, Fe-ICG@MON@PAA, and Fe-ICG@MON@HA during the synthesis process are shown in Fig. 4a, and the potential changes are shown in Fig. 4b.
实施例5：Fe-ICG@MON@HA光热性能的研究Example 5: Study on Photothermal Properties of Fe-ICG@MON@HA
为考察Fe-ICG@MON@HA相比于ICG分子光热转换效率的提高，配制ICG浓度均为20μg/ml的ICG分子溶液和Fe-ICG@MON@HA溶液，分别用功率密度为1W/cm2的808激光器照射3min，然后关闭激光器，降温7min，在此过程中用近红外热像仪记录温度变化。如图5a所示，相同浓度时Fe-ICG@MON@HA的升温速度和升温效果显著高于ICG分子，且当ICG分子溶液的浓度增加至200μg/ml时与Fe-ICG@MON@HA展现出相同的光热效果。In order to investigate the improvement of the photothermal conversion efficiency of Fe-ICG@MON@HA compared with ICG molecules, ICG molecular solution and Fe-ICG@MON@HA solution with ICG concentration of 20 μg/ml were prepared, respectively, with a power density of 1 W/ml. The 808 laser of cm 2 was irradiated for 3 min, then the laser was turned off, and the temperature was lowered for 7 min. During this process, a near-infrared thermal imager was used to record the temperature change. As shown in Fig. 5a, the heating rate and heating effect of Fe-ICG@MON@HA were significantly higher than those of ICG molecules at the same concentration, and when the concentration of the ICG molecule solution increased to 200 μg/ml, it exhibited the same performance as Fe-ICG@MON@HA. produce the same thermal effect.
为考察Fe-ICG@MON@HA相比于ICG分子光热稳定性的增加，配制ICG浓度均为20μg/ml的ICG分子溶液和Fe-ICG@MON@HA溶液，分别用功率密度为1W/cm2的808激光器照射3min，然后关闭激光器，降温3min，重复四次，在此过程中用近红外热像仪记录温度变化。如图5b所示，相同浓度时Fe-ICG@MON@HA的光热稳定性显著高于ICG分子，不会在重复光热的过程中表现出显著的光热性能的衰减。In order to investigate the increase in photothermal stability of Fe-ICG@MON@HA compared with ICG molecules, ICG molecular solutions and Fe-ICG@MON@HA solutions with ICG concentration of 20 μg/ml were prepared, respectively, with a power density of 1 W/ml. The 808 laser of cm 2 was irradiated for 3 min, then the laser was turned off, and the temperature was lowered for 3 min, which was repeated four times. During this process, a near-infrared thermal imager was used to record the temperature change. As shown in Figure 5b, the photothermal stability of Fe-ICG@MON@HA is significantly higher than that of ICG molecules at the same concentration, and does not exhibit a significant attenuation of photothermal performance during repeated photothermal processes.
实施例6：Fe-ICG@MON@HA肿瘤靶向性能的研究Example 6: Study on tumor targeting performance of Fe-ICG@MON@HA
为考察Fe-ICG@MON@HA靶向肿瘤的效率，选择4T1乳腺癌细胞系作为模型细胞进行验证。将4T1细胞以1×105密度铺于经过处理的盖玻片的24孔培养板内，隔夜培养。第二天，弃去旧的培养液，将相同浓度的Fe-ICG@MON@PAA与Fe-ICG@MON@HA分别加入到培养板中，37℃孵育4h。然后用PBS清洗三次后，将细胞用于共聚焦显微镜检测。如图6所示，Fe-ICG@MON@HA靶向4T1的效率显著高于Fe-ICG@MON@PAA。To investigate the tumor targeting efficiency of Fe-ICG@MON@HA, 4T1 breast cancer cell line was selected as a model cell for validation. 4T1 cells were plated at a density of 1 x 105 in 24-well culture plates on treated coverslips and cultured overnight. The next day, the old culture medium was discarded, and Fe-ICG@MON@PAA and Fe-ICG@MON@HA with the same concentration were added to the culture plate respectively, and incubated at 37 °C for 4 h. Cells were then used for confocal microscopy after washing three times with PBS. As shown in Figure 6, the efficiency of Fe-ICG@MON@HA targeting 4T1 is significantly higher than that of Fe-ICG@MON@PAA.
实施例7：Fe-ICG@MON@HA光疗性能的研究Example 7: Study on phototherapeutic properties of Fe-ICG@MON@HA
为考察Fe-ICG@MON@HA的光疗性能，选择4T1乳腺癌细胞系作为模型细胞进行验证。按照1×104个/孔的密度接种到96孔板中，使细胞分散均匀，置于培养箱培养12h。将不同浓度的ICG分子，Fe-ICG@MON@PAA与Fe-ICG@MON@HA分别加入96孔板，将其分别培养12h后，移弃旧培养液，用功率密度为1W/cm2的808激光器照射5min后培养2h，移弃旧培养液，加入MTT溶液，将其放回培养箱继续培养4h，结束培养后，小心吸取上清，每孔加入0.15mLDMSO，在微量振荡器上振荡15min使甲瓒结晶充分溶解，随后在酶标仪上490nm处读出各孔的OD值，计算细胞存活率，结果如图7所示，由于光热性能和靶向性的提高，Fe-ICG@MON@HA展现出最高的光疗效率。To investigate the phototherapeutic properties of Fe-ICG@MON@HA, the 4T1 breast cancer cell line was selected as a model cell for validation. The cells were seeded into a 96-well plate at a density of 1×10 4 cells/well, and the cells were evenly dispersed, and cultured in an incubator for 12 h. Different concentrations of ICG molecules, Fe-ICG@MON@PAA and Fe-ICG@MON@HA were added to the 96-well plate, respectively, and after culturing them for 12 h, the old culture medium was discarded, and a power density of 1 W/cm After irradiating the 808 laser for 5 min, incubate for 2 h, discard the old culture medium, add MTT solution, put it back in the incubator to continue cultivation for 4 h, after the incubation, carefully aspirate the supernatant, add 0.15 mL of DMSO to each well, and shake on a micro shaker for 15 min The formazan crystals were fully dissolved, and then the OD value of each well was read at 490 nm on a microplate reader, and the cell viability was calculated. The results are shown in Figure 7. Due to the improvement of photothermal performance and targeting, Fe-ICG@ MON@HA exhibited the highest phototherapy rate.
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The embodiments of the present invention have been described above. However, the present invention is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.
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