CN112773899A - Drug delivery carrier based on biological metal organic framework material and preparation method and application thereof - Google Patents
Drug delivery carrier based on biological metal organic framework material and preparation method and application thereof Download PDFInfo
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- CN112773899A CN112773899A CN201911067010.6A CN201911067010A CN112773899A CN 112773899 A CN112773899 A CN 112773899A CN 201911067010 A CN201911067010 A CN 201911067010A CN 112773899 A CN112773899 A CN 112773899A
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- 239000012621 metal-organic framework Substances 0.000 title claims abstract description 34
- 239000000463 material Substances 0.000 title claims abstract description 30
- 238000012377 drug delivery Methods 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 210000004027 cell Anatomy 0.000 claims abstract description 53
- 239000003814 drug Substances 0.000 claims abstract description 43
- 229940079593 drug Drugs 0.000 claims abstract description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical class [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 claims abstract description 24
- 229960003067 cystine Drugs 0.000 claims abstract description 24
- 229910052751 metal Chemical class 0.000 claims abstract description 23
- 239000002184 metal Chemical class 0.000 claims abstract description 23
- 239000002244 precipitate Substances 0.000 claims abstract description 21
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 20
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 19
- 239000008367 deionised water Substances 0.000 claims abstract description 19
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 16
- 238000005406 washing Methods 0.000 claims abstract description 15
- 238000010253 intravenous injection Methods 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 229960002918 doxorubicin hydrochloride Drugs 0.000 claims description 71
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical group Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 33
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- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 12
- 229940109262 curcumin Drugs 0.000 claims description 12
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 claims description 12
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 11
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- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 6
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- 238000000034 method Methods 0.000 claims description 6
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- 229960002949 fluorouracil Drugs 0.000 claims description 4
- 229910017149 Fe(BF4)2 Inorganic materials 0.000 claims description 3
- 229910021576 Iron(III) bromide Inorganic materials 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
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- 159000000007 calcium salts Chemical class 0.000 claims description 3
- 159000000014 iron salts Chemical class 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- 159000000003 magnesium salts Chemical class 0.000 claims description 3
- 239000013354 porous framework Substances 0.000 claims description 3
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Inorganic materials [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 claims description 3
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 3
- 229910000368 zinc sulfate Inorganic materials 0.000 claims description 3
- 239000011686 zinc sulphate Substances 0.000 claims description 3
- 150000003754 zirconium Chemical class 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 2
- 229910007926 ZrCl Inorganic materials 0.000 claims description 2
- 229910007932 ZrCl4 Inorganic materials 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 2
- 229940127093 camptothecin Drugs 0.000 claims description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 2
- 229960003668 docetaxel Drugs 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 4
- 229910021529 ammonia Inorganic materials 0.000 claims 2
- WGEFECGEFUFIQW-UHFFFAOYSA-L calcium dibromide Chemical compound [Ca+2].[Br-].[Br-] WGEFECGEFUFIQW-UHFFFAOYSA-L 0.000 claims 1
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 12
- 206010028980 Neoplasm Diseases 0.000 abstract description 10
- 239000000047 product Substances 0.000 abstract description 10
- 230000004043 responsiveness Effects 0.000 abstract description 9
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- 239000011701 zinc Substances 0.000 description 53
- 239000002609 medium Substances 0.000 description 14
- 238000012360 testing method Methods 0.000 description 12
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- 238000011534 incubation Methods 0.000 description 9
- 238000011068 loading method Methods 0.000 description 9
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- 239000013110 organic ligand Substances 0.000 description 8
- 239000003937 drug carrier Substances 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
- 239000008363 phosphate buffer Substances 0.000 description 6
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 4
- 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 4
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- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
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- 229910021645 metal ion Inorganic materials 0.000 description 3
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- 239000012498 ultrapure water Substances 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
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- MFLKDEMTKSVIBK-UHFFFAOYSA-N zinc;2-methylimidazol-3-ide Chemical compound [Zn+2].CC1=NC=C[N-]1.CC1=NC=C[N-]1 MFLKDEMTKSVIBK-UHFFFAOYSA-N 0.000 description 2
- DLLMHEDYJQACRM-UHFFFAOYSA-N 2-(carboxymethyldisulfanyl)acetic acid Chemical compound OC(=O)CSSCC(O)=O DLLMHEDYJQACRM-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
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- AALUCPRYHRPMAG-UHFFFAOYSA-N Glycerol 1-propanoate Chemical compound CCC(=O)OCC(O)CO AALUCPRYHRPMAG-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
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- 229910052782 aluminium Inorganic materials 0.000 description 1
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- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 229910000422 cerium(IV) oxide Inorganic materials 0.000 description 1
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- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
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- 238000005580 one pot reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
- 238000007626 photothermal therapy Methods 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 229920001690 polydopamine Polymers 0.000 description 1
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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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a drug delivery carrier based on a biological metal organic framework material and a preparation method and application thereof, cystine and metal salt are dissolved in deionized water, and a reaction is carried out after pH is adjusted by alkali liquor to obtain a product; mixing anticancer drug with water, stirring at room temperature in dark place, centrifuging to obtain precipitate, and washing with water to obtain nanometer compound for intravenous injection for treating tumor. The drug delivery carrier prepared by the technical scheme of the invention has good reduction responsiveness, can be quickly cracked in tumor cells and releases anticancer drugs; can keep stable in normal cells, limit the release of the drug and reduce the damage to the normal cells.
Description
Technical Field
The invention relates to the technical field of nano materials and the field of biomedical materials, in particular to preparation of a biological metal organic framework material (bioMOF-M (Cys)) which has redox responsiveness to a tumor microenvironment and good biocompatibility and application of the material loaded with an anti-cancer drug as a drug delivery carrier.
Background
The Metal Organic Framework (MOF) is a porous material assembled by metal ions and organic ligands, and the porous material with different structures and functions can be obtained by selecting different metal ions and organic ligands. The porous characteristic of the carrier can be used for loading a large amount of drugs, and the carrier is a good drug delivery carrier.
The microenvironment of the tumor cells is different from that of normal cells, such as more acidic pH, higher temperature, higher level of reduced glutathione and the like. The characteristics are utilized to develop a drug delivery carrier with responsiveness to a tumor microenvironment, so that the release efficiency of the drug in tumor cells can be improved, the curative effect can be enhanced, and the damage of the anti-cancer drug to normal cells can be reduced. In the case of MOF materials, coordination bonds between metals and ligands are easily broken under acidic conditions, so that the MOF materials can be used as pH-responsive drug carriers. Such as: zheng et al synthesized ZIF-8 nanoparticles loaded with the anticancer drug doxorubicin by a "one-pot" method, which drug carrier rapidly decomposed to release the drug under acidic pH (5.0-6.5) conditions, and thus could achieve responsive release in the slightly acidic environment of tumor cells (Journal of the American Chemical Society, 2015, 138(3), 962). Zhang et al discloses a one-step method for in-situ polymerization, which realizes the synthesis of ZIF-8 and the loading of Polydopamine (PDA) and adriamycin (DOX), and the prepared ZIF-8-PDA-DOX hybrid metal organic framework compound realizes the drug release of pH and near infrared dual response and the combination of chemotherapy and photothermal therapy (Chinese patent application No. 201910267043.9). Furthermore, the responsiveness of the MOF carrier to the tumor microenvironment can also be achieved by introducing responsive groups onto the organic ligands. Such as: zhao et al developed a complex of manganese ions (Mn)2+) A metal-organic framework coordinated with dithiodiethanolic acid, the disulfide bond (S-S) in dithiodiglycolic acid can be cleaved in the presence of high concentration of glutathione, thereby releasing drugs (ACS Applied Materials)&Interfaces,2017,9(28), 23555-23563). Zhuchunling et al disclose a method for preparing zirconium tetrachlorideIs metal salt and 4, 4-dithiodibenzoic acid as organic ligand, and is used as the carrier for synthesizing the medicine with redox stimulation response (Chinese patent application No. 201610198876.0). In addition, reactive groups can also be attached to the MOF surface by post-synthesis modification. Such as: wang et al modified the surface of MOF with a pH-responsive phenylimide linkage and a reduction-responsive disulfide linkage to achieve a dual-responsive release of drug from the MOF carrier (Nanoscale,2015,7, 16061-16070). Zhuchunling et al discloses a drug carrier with dual responsiveness of pH and glucose, which is prepared by modifying a metal organic framework material Uio66# NH with phenylboronic acid2Uio66# CBA is prepared, and then CeO is modified by cyclodextrin2Preparing alpha # CD # CeO by nano particles2Uio66# CBA and alpha # CD # CeO2The assembly is carried out through a borate ester bond, and RGD target molecules are modified on the surface of the assembled material (Chinese invention patent, application No. 201610400817.7). Yao Propionin et al prepared a pH responsive drug carrier by grafting a pH responsive segment onto an organic ligand of a MOF material, wherein the pH responsive segment can be a pH responsive polymer, a segment containing carboxylic acid groups, or a segment containing pyridine groups (Chinese patent application No. 201710121563. X).
The metal forming the MOF material by the method is usually transition metal such as Al, Mn, Cu and the like, most of organic ligands are artificially synthesized compounds, and organic solvents are often introduced in the synthesis reaction, so that the biocompatibility is difficult to guarantee, therefore, the MOF material generates toxicity to tumor cells and normal cells, and degradation products of the MOF material also generate toxic and side effects to human bodies, and the application of the MOF material in actual drug delivery is limited.
Disclosure of Invention
The invention aims to overcome the defects of the technology and provide a drug delivery carrier (bioMOF-M (Cys)) with reduction responsiveness and good biocompatibility for a biological metal organic framework material and a preparation method thereof. The MOF is synthesized in a green color in an aqueous solution by taking endogenous metal ions as coordination nodes (M) and natural biomolecule cystine (Cys) as a ligand. The prepared bioMOF-M (Cys) is used as a carrier to load anticancer drugs, and after the anticancer drugs enter tumor cells through intravenous injection, over-expressed glutathione in the cells interacts with S-S in cystine ligands, so that S-S bonds are broken, a porous framework structure is damaged, and the anticancer drugs are rapidly released. In normal cells, the S-S bond is not broken, and the drug is still limited in the carrier, so that the damage and toxic and side effects of the drug on normal tissues are reduced.
The technical purpose of the invention is realized by the following technical scheme.
A drug delivery carrier based on a biological metal organic framework material and a preparation method thereof are carried out according to the following steps: uniformly dispersing cystine and metal salt in deionized water, adjusting pH to be alkaline by using alkali liquor, cooling and centrifuging after reaction, collecting precipitate, and washing to obtain the drug delivery carrier bioMOF-M (Cys).
The alkali solution is sodium hydroxide aqueous solution, potassium hydroxide aqueous solution or ammonia aqueous solution, the concentration is 0.1-1 mol/L, and the pH is adjusted to 10-13 by using the alkali solution.
Moreover, the reaction temperature is 40-180 ℃, the reaction time is 4-12 h, the preferable reaction temperature is 80-120 ℃, and the reaction time is 6-10 h.
And uniformly dispersing cystine and metal salt in deionized water, wherein the concentration of the cystine is 1-20 mmol/L, preferably 8-15 mmol/L.
And uniformly dispersing cystine and metal salt in deionized water, wherein the concentration of the metal salt is 1-20 mmol/L, preferably 8-15 mmol/L.
Furthermore, the metal salt is a zinc salt (e.g., ZnCl)2、ZnSO4、Zn(NO3)2Etc.), or iron salts (e.g.: FeCl3、Fe(BF4)2·6H2O、FeBr3Etc.), or zirconium salts (e.g.: ZrCl4Etc.), or magnesium salts (e.g.: MgSO (MgSO)4、MgCl2Etc.), or calcium salts (e.g.: CaCl2、CaBr2Etc.).
The drug delivery carrier bioMOF-M (Cys) prepared by the invention is mixed with an anticancer drug in water, the mixture reacts under the conditions of room temperature, light shielding and stirring, then the precipitate is obtained by centrifugation, and the nano-composite is obtained after water washing and can be used for treating tumors through intravenous injection.
Moreover, the anticancer drug is doxorubicin hydrochloride, or curcumin, or docetaxel, or 5-fluorouracil, or camptothecin, etc.; the concentration is 100-1000 mg/L.
Furthermore, the drug delivery vehicle bioMOF-M (Cys) concentration was 1000-5000 mg/L.
And the anticancer drug and the drug delivery carrier bioMOF-M (Cys) are stirred in water at room temperature of 20-25 ℃ in the dark (such as 100-300 r/min) for 12-72 h.
Compared with the prior art, the invention has the following beneficial effects: (1) the drug delivery carrier bioMOF-M (Cys) of the biological metal organic framework material has good reduction responsiveness, and can be quickly cracked in tumor cells to release anticancer drugs; can keep stable in normal cells, limit the release of the drug and reduce the damage to the normal cells. (2) The metal used in the invention is endogenous metal, the toxicity is low, the organic ligand is natural biomolecule cystine, the synthetic reaction solvent is water, the reaction condition is green and environment-friendly, the product bioMOF-M (Cys) has good biological safety, and the in vivo metabolite has no toxic or side effect. (3) The raw materials for synthesizing the bioMOF-M (Cys) have low cost and simple preparation process.
Drawings
FIG. 1 shows the particle size results of the drug carrier prepared in example 1 measured by transmission electron microscopy images and dynamic light scattering of the drug carrier before (bioMOF-Zn (Cys)) and after (DOX @ bioMOF-Zn (Cys)) being responsible for doxorubicin hydrochloride (DOX).
FIG. 2 is a UV-VISIBLE absorption spectrum of an aqueous solution of doxorubicin hydrochloride (DOX), bioMOF-Zn (Cys), DOX @ bioMOF-Zn (Cys).
FIG. 3 is a graph of the effect of DOX @ bioMOF-Zn (Cys) nanoparticle release in buffer solutions of different GSH concentrations.
FIGS. 4a and 4B show the viability of A549 cells and BEAS-2B cells, respectively, after incubation in media containing different concentrations of bioMOF-Zn (Cys).
FIG. 5 is a graph showing the survival of A549 cells after incubation in media containing varying concentrations of doxorubicin hydrochloride (DOX) and DOX @ bioMOF-Zn (Cys).
FIG. 6 is a graph showing the viability of BEAS-2B cells after incubation in media containing varying concentrations of doxorubicin hydrochloride (DOX) and DOX @ bioMOF-Zn (Cys).
FIG. 7a is a fluorescent photograph of A549 cells cultured in free DOX and DOX @ bioMOF-Zn (Cys) nanomedicines.
FIG. 7B is a fluorescent photograph of BEAS-2B cells cultured in free DOX and DOX @ bioMOF-Zn (Cys) nanomedicines.
Detailed Description
In order to clearly understand the technical scheme of the invention, the technical scheme of the invention is further described in detail by the following examples and figures, wherein the stirring speed is 150 r/min, and the reaction temperature is 20-25 ℃ in the dark.
Example 1
1) Cystine with the concentration of 16mmol/L and ZnCl with the concentration of 16mmol/L2Adding the mixture into deionized water, adding a sodium hydroxide solution with the concentration of 0.1mol/L, and adjusting the pH value of the solution to 13;
2) placing the reaction solution obtained in the step 1) at 100 ℃ for reacting for 8h, and stopping the reaction;
3) after cooling, centrifuging the reaction solution, collecting the precipitate, and washing the precipitate with deionized water for multiple times to obtain a product bioMOF-Zn (Cys);
4) doxorubicin hydrochloride (DOX) and bioMOF-Zn (Cys) are mixed in water, wherein the concentration of the doxorubicin hydrochloride is 400mg/L, the concentration of the bioMOF-Zn (Cys) is 2000mg/L, the mixture is stirred for 24 hours in a dark place, precipitates are obtained by centrifugation, and the nanometer compound DOX @ bioMOF-Zn (Cys) is obtained after washing, and can be used for treating tumors through intravenous injection.
Example 2
1) Cystine with the concentration of 20mmol/L and FeCl with the concentration of 20mmol/L3Adding the mixture into deionized water, adding a sodium hydroxide solution with the concentration of 0.5mol/L, and adjusting the pH value of the solution to 11;
2) placing the reaction solution obtained in the step 1) at 180 ℃ for reaction for 3h, and stopping the reaction;
3) after cooling, centrifuging the reaction solution, collecting the precipitate, and washing the precipitate with deionized water for multiple times to obtain a product bioMOF-Fe (Cys);
4) mixing curcumin (CCM) and bioMOF-Zn (Cys) in water, wherein the concentration of the curcumin is 100mg/L, the concentration of the bioMOF-Fe (Cys) is 1000mg/L, stirring for 72h in a dark place, centrifuging to obtain a precipitate, washing with water to obtain a nano compound CCM @ bioMOF-Fe (Cys), and the nano compound CCM @ bioMOF-Fe (Cys) can be used for treating tumors through intravenous injection.
Example 3
1) Cystine with the concentration of 1mmol/L and ZrCl with the concentration of 1mmol/L4Adding the mixture into deionized water, adding a potassium hydroxide solution with the concentration of 1mol/L, and adjusting the pH value of the solution to 12;
2) placing the reaction solution obtained in the step 1) at 40 ℃ for reaction for 12h, and stopping the reaction;
3) after cooling, centrifuging the reaction solution, collecting the precipitate, and washing the precipitate with deionized water for multiple times to obtain a product bioMOF-Zr (Cys);
4) mixing 5-fluorouracil (5-Fu) and bioMOF-Zr (Cys) in water, wherein the concentration of the 5-fluorouracil is 1000mg/L, the concentration of the bioMOF-Zr (Cys) is 5000mg/L, stirring for 12h in a dark place, centrifuging to take out precipitate, washing with water to obtain the nano compound 5-Fu @ bioMOF-Zr (Cys), and the nano compound can be used for treating tumors through intravenous injection.
Example 4
1) Cystine with the concentration of 16mmol/L and MgCl with the concentration of 8mmol/L2Adding the mixture into deionized water, adding a potassium hydroxide solution with the concentration of 0.75mol/L, and adjusting the pH value of the solution to 12;
2) placing the reaction solution obtained in the step 1) at 100 ℃ for reaction for 10h, and stopping the reaction;
3) after cooling, centrifuging the reaction solution, collecting the precipitate, and washing the precipitate with deionized water for multiple times to obtain a product bioMOF-Mg (Cys);
4) doxorubicin hydrochloride (DOX) and bioMOF-Mg (Cys) are mixed in water, wherein the concentration of the doxorubicin hydrochloride is 1000mg/L, the concentration of the bioMOF-Mg (Cys) is 1000mg/L, the mixture is stirred for 48 hours in a dark place, precipitates are obtained by centrifugation, and the nanometer compound DOX @ bioMOF-Mg (Cys) is obtained after washing, and can be used for treating tumors through intravenous injection.
Example 5
1) Cystine with the concentration of 5mmol/L and CaCl with the concentration of 5mmol/L2Adding into deionized water, adding 0.1mol/L ammonia water solution, adjusting solutionThe pH of the solution is 11;
2) placing the reaction solution obtained in the step 1) at 80 ℃ for reaction for 12h, and stopping the reaction;
3) after cooling, centrifuging the reaction solution, collecting precipitate, and washing with deionized water for multiple times to obtain a product bioMOF-Ca (Cys);
4) mixing curcumin (CCM) and bioMOF-Ca (Cys) in water, wherein the concentration of curcumin is 200mg/L, the concentration of bioMOF-Ca (Cys) is 3000mg/L, stirring for 72h in a dark place, centrifuging to obtain a precipitate, washing with water to obtain a nano compound CCM @ bioMOF-Ca (Cys), and the nano compound CCM @ bioMOF-Ca (Cys) can be used for treating tumors through intravenous injection.
Test examples and test results
The product performance of the invention is described in detail by taking the bio-metal organic framework material bioMOF-Zn (Cys) prepared in the embodiment 1 and the nano-composite DOX @ bioMOF-Zn (Cys) loaded with doxorubicin hydrochloride as test examples.
1) Testing of shape and particle size before and after loading with drug
Transmission electron microscope test: diluting 100 μ L of bioMOF-Zn (Cys) and DOX @ bioMOF-Zn (Cys) suspension by 20 times, and subjecting to ultrasonic treatment for 20min to uniformly disperse the sample in ultrapure water. 10 mu L of sample is absorbed and dropped on the surface of a 300-mesh copper net, the solvent is evaporated at room temperature, and then the appearance of the sample is observed by using a transmission electron microscope (accelerating voltage: 200 kV).
Dynamic light scattering test: taking 200 mu L of the suspension of bioMOF-Zn (Cys) and DOX @ bioMOF-Zn (Cys) in ultrapure water, dispersing the suspension in 5mL of ultrapure water, carrying out ultrasonic treatment for 20min to uniformly disperse the sample, and then carrying out dynamic light scattering test on the sample.
The morphology of the bioMOF-Zn (Cys) before loading the drug is shown as a in the attached figure 1, the morphology of the bioMOF-Zn (Cys) is nano-granular, and the dynamic light scattering result shows that the average particle size is 189.1nm and the particle sizes are uniform. The morphology of DOX @ bioMOF-Zn (Cys) after the anticancer drug adriamycin is loaded still maintains the nano-particle shape, as shown in b in figure 1, the average particle size is 195.4nm, the particle size is uniform, and the requirement of intravenous injection on the particle size of the drug (200 nm) is met.
2) Drug load testing
Respectively measuring the absorption spectrum of the water solution of the free doxorubicin hydrochloride (DOX), the bioMOF-Zn (Cys), the DOX @ bioMOF-Zn (Cys) by using an ultraviolet-visible spectrophotometer, wherein the wavelength scanning range is 190nm-600nm, so as to analyze the load of the medicament in the MOF-Zn (Cys). As shown in FIG. 2, free DOX has characteristic absorption peaks at 233nm, 256nm and 480nm, which are simultaneously present in DOX @ bioMOF-Zn (Cys), but are not shown in bioMOF-Zn (Cys), indicating that DOX is successfully loaded in bioMOF-Zn (Cys).
And (3) calculating the drug loading rate: 20mg of the bioMOF-Zn (Cys) nanoparticles obtained in example 1 are added into 400 mu g/mL doxorubicin hydrochloride aqueous solution for full mixing, the mixture is stirred at room temperature for 24 hours in the dark, centrifuged, washed with water for 3 times, the combined supernatant is collected, and the amount of the unloaded doxorubicin hydrochloride in the supernatant is determined. The drug loading rate calculation formula is as follows: drug loading (mg/g) ([ total drug mass in solution before loading (mg) — drug mass not loaded in supernatant (mg) ]/mass of added bioMOF-zn (cys)) (g). Finally, the drug loading was 138.0 mg/g.
3) In vitro drug responsive release test
The release of the nanocomposite DOX @ bioMOF-zn (cys) in buffers containing different concentrations of Glutathione (GSH) was tested: 1mg of DOX @ bioMOF-Zn (Cys) solid powder was ultrasonically dispersed in 8mL of phosphate buffer (10mM, pH 7.4) containing GSH (0, 1, 5, 10mM) at various concentrations, and stirred at 37 ℃ in the absence of light. Centrifuging at 12000rpm for 10min at regular intervals, and collecting supernatant to determine the amount of free doxorubicin hydrochloride.
The results are shown in figure 3, where the drug release rate and cumulative release increase rapidly with increasing GSH concentration. After 48h, DOX @ bioMOF-Zn (Cys) released 80% of the accumulated DOX in phosphate buffer with 10mM GSH, while DOX @ bioMOF-Zn (Cys) released only 8.25% of the DOX in phosphate buffer without GSH, demonstrating good redox responsiveness of the drug carrier.
4) biocompatibility testing of bioMOF-Zn (Cys) materials
Toxicity of bioMOF-zn (cys) was determined by MTT assay for human lung cancer cells (a549) and normal human lung (bronchial) epithelial cells (BEAS-2B) to assess their biocompatibility: a549 cells and BEAS-2B cells which reach logarithmic growth phase after passage are taken and respectively connectedPlanted in a 96-well plate with the concentration of 105cells/mL, 5% CO at 37 ℃2The culture box is used for culturing for 24 hours to make the culture box grow adherently. The old medium was then aspirated off, and replaced with DMEM-H medium containing bioMOF-Zn (Cys) at different concentrations (0, 20, 50, 80, 100, 200. mu.g/mL), 5 wells per group, 90. mu.L of the above medium was added to each well, and the culture was carried out for 24 hours. Then, the culture solution was aspirated, a new 90. mu.L of the culture medium was added, 10. mu.L of 5mg/mL MTT solution was added to each well, and after 4 hours of incubation, the solution was aspirated with a pipette gun, and 100. mu.L of DMSO was added thereto and shaken to dissolve formazan crystals (mitochondria in living cells can reduce MTT to water-insoluble blue-purple formazan). The cell viability was calculated by measuring the absorbance at 490nm using a microplate reader.
The results are shown in figure 4a and figure 4B, the bioMOF-Zn (Cys) has no obvious inhibition effect on the growth of A549 cells and BEAS-2B cells within the concentration range of 0-200 mug/mL, the cell survival rate is above 90%, and the results show that the bioMOF-Zn (Cys) has low toxicity and good biocompatibility.
5) DOX @ bioMOF-Zn (Cys) lethality test for tumor cells
Cytotoxicity of DOX @ bioMOF-zn (cys) against human lung cancer cells (a549) was determined by MTT assay: a549 cells which reach logarithmic growth phase after passage are taken and inoculated in a 96-well plate with the concentration of 105cells/mL, 5% CO at 37 ℃2The culture box is used for culturing for 24 hours to make the culture box grow adherently. The old medium was aspirated, DMEM medium containing free doxorubicin hydrochloride (DOX) and DOX @ bioMOF-Zn (Cys) (wherein the concentrations of DOX were 0, 0.01, 0.05, 0.1, 0.5, 1/2.5. mu.g/mL), 5 wells per group, 200. mu.L of the above medium per well, was added, and the mixture was cultured for 48 hours. Subsequently, 10. mu.L of 5mg/mL MTT solution was added to each well, and after 4 hours of incubation, the solution was aspirated with a pipette, and 150. mu.L of DMSO was added thereto and shaken to dissolve formazan produced from living cells. The cell viability was calculated by measuring the absorbance at 490nm using a microplate reader. Cells treated with DMEM medium without drug served as a control.
FIG. 5 shows that DOX @ bioMOF-Zn (Cys) treated tumor cells survived only 40% when the drug was added at a concentration of 2.5. mu.g/mL, while the survived free DOX treated tumor cells still reached 80%, indicating that DOX @ bioMOF-Zn (Cys) had a higher tumor cell lethality than the free drug.
6) DOX @ bioMOF-Zn (Cys) toxic side effect test on normal cells
Cytotoxicity of DOX @ bioMOF-Zn (Cys) on normal human lung (bronchial) epithelial cells (BEAS-2B) was determined by MTT assay: a549 cells which reach logarithmic growth phase after passage are taken and inoculated in a 96-well plate with the concentration of 105cells/mL, 5% CO at 37 ℃2The culture box is used for culturing for 24 hours to make the culture box grow adherently. The old medium was aspirated, DMEM medium containing free doxorubicin hydrochloride (DOX) and DOX @ bioMOF-Zn (Cys) (wherein the concentrations of DOX were 0, 0.01, 0.05, 0.1, 0.5, 1/2.5. mu.g/mL), 5 wells per group, 200. mu.L of the above medium per well, was added, and the mixture was cultured for 48 hours. Subsequently, 10. mu.L of 5mg/mL MTT solution was added to each well, and after 4 hours of incubation, the solution was aspirated with a pipette, and 150. mu.L of DMSO was added thereto and shaken to dissolve formazan produced from living cells. The cell viability was calculated by measuring the absorbance at 490nm using a microplate reader. Cells treated with DMEM medium without drug served as a control.
FIG. 6 shows that the survival rate of normal cells treated with DOX @ bioMOF-Zn (Cys) is still above 90% when the drug is added at a concentration of 2.5. mu.g/mL, while the survival rate of normal cells treated with free DOX is only around 60%, indicating that DOX @ bioMOF-Zn (Cys) has lower toxic side effects on normal cells than free drug.
7) Efficiency of uptake of DOX @ bioMOF-Zn (Cys) by tumor cells and normal cells
Inoculating human lung cancer cell (A549) and normal human lung (bronchus) epithelial cell (BEAS-2B) in 6-well plate with 10 cells per well5The cells were cultured at 37 ℃ in an incubator containing 5% CO2 for 24 hours to grow adherently. The old medium was aspirated off the clean bench, 1.5mL of medium with drug (DOX or DOX @ MOF-Zn (Cys) with a DOX concentration of 1. mu.g/mL) was added, and the mixture was placed in a cell incubator for culture. After culturing the cells for 0.5h, 1h, and 4h, the drug-containing medium was aspirated, and each well was washed three times with 2mL of phosphate buffer (10mM, pH 7.4), and washedAfter removing the residual drug on the cell surface, 1mL of 4% paraformaldehyde was added to fix the cells at room temperature for 20min, and then the paraformaldehyde was aspirated and the cells were washed three times with phosphate buffer. 1mL of 1. mu.g/mL DAPI stain was added to each well, nuclei were stained at room temperature for 10min, and then the DAPI stain was aspirated and washed three times with phosphate buffer. Cells were observed on the UV channel of DAPI and the TxRed channel of DOX using an inverted fluorescence microscope of type TI-S-EJOY from Nikon, Japan.
FIG. 7a shows that the red fluorescence intensity increases with the time of incubation of A549 cells in DOX @ bioMOF-Zn (Cys) nano-drug, and the drug is distributed relatively uniformly throughout the cells at 4h of incubation, indicating that the loaded DOX has been released and is able to act on the nucleus. The red fluorescence of the free DOX group was weaker, indicating that the cells took less drug and that the drug was mainly distributed in the cytoplasm. FIG. 7B shows that as the incubation time of BEAS-2B cells in free DOX and DOX @ bioMOF-Zn (Cys) nanomedicines was increased, there was no significant increase in the red fluorescence intensity, and the red fluorescence intensity was stronger in the free DOX group than in the DOX @ bioMOF-Zn (Cys) group. The result shows that the DOX @ bioMOF-Zn (Cys) nano-drug can quickly release the anticancer drug in tumor cells, after entering the tumor cells through intravenous injection, the over-expressed glutathione in the cells interacts with S-S in cystine ligand, so that S-S bonds are broken, the porous framework structure is damaged, and the anticancer drug is quickly released. In normal cells, the S-S bond is not broken, and the drug is still limited in the carrier, so that the damage and toxic and side effects of the drug on normal tissues are reduced.
The preparation method can realize the preparation of the drug delivery carrier based on the biological metal organic framework material by utilizing the content of the invention to adjust the process parameters, shows the performance basically consistent with the invention, has good reduction responsiveness, can be quickly cracked in tumor cells and releases anticancer drugs; the compound can be kept stable in normal cells, drug release is limited, damage to the normal cells is reduced, the used metal is endogenous metal and low in toxicity, the organic ligand is natural biomolecule cystine, the synthetic reaction solvent is water, the reaction conditions are green and environment-friendly, the product bioMOF-M (Cys) is good in biological safety, and the in-vivo metabolic product has no toxic or side effect.
The invention has been described in an illustrative manner, and it is to be understood that any simple variations, modifications or other equivalent changes which can be made by one skilled in the art without departing from the spirit of the invention fall within the scope of the invention.
Claims (10)
1. A drug delivery carrier based on a bio-metal organic framework material, which is characterized by comprising the following steps: and uniformly dispersing cystine and metal salt in deionized water, adjusting the pH to be alkaline by using alkali liquor, cooling and centrifuging after reaction, collecting precipitate, and washing to obtain the drug delivery carrier.
2. The drug delivery carrier based on the bio-metal organic framework material as claimed in claim 1, wherein the alkali solution is an aqueous solution of sodium hydroxide, or an aqueous solution of potassium hydroxide, or an aqueous solution of ammonia, the concentration is 0.1-1 mol/L, and the pH is adjusted to 10-13 by using the alkali solution.
3. The drug delivery carrier based on the biological metal organic framework material as claimed in claim 1, wherein the reaction temperature is 40 ℃ to 180 ℃ and the reaction time is 4 to 12 hours, preferably the reaction temperature is 80 ℃ to 120 ℃ and the reaction time is 6 to 10 hours.
4. The drug delivery vehicle based on the bio-metal organic framework material according to claim 1, wherein the cystine and the metal salt are uniformly dispersed in deionized water, and the concentration of the cystine is 1-20 mmol/L, preferably 8-15 mmol/L.
5. The drug delivery carrier based on the bio-metal organic framework material as claimed in claim 1, wherein cystine and metal salt are uniformly dispersed in deionized water, the concentration of the metal salt is 1-20 mmol/L, preferably 8-15 mmol/L, and the metal salt is zinc salt (such as ZnCl)2、ZnSO4、Zn(NO3)2) Or iron salts (e.g.: FeCl3、Fe(BF4)2·6H2O、FeBr3) Or a zirconium salt (e.g. ZrCl)4) Or magnesium salts (e.g.: MgSO (MgSO)4、MgCl2) Or a calcium salt (e.g. CaCl)2、CaBr2)。
6. A preparation method of a drug delivery carrier based on a biological metal organic framework material is characterized by comprising the following steps: uniformly dispersing cystine and metal salt in deionized water, adjusting pH to be alkaline by using alkali liquor, cooling and centrifuging after reaction, collecting precipitate, and washing to obtain the drug delivery carrier, wherein: uniformly dispersing cystine and metal salt in deionized water, wherein the concentration of cystine is 1-20 mmol/L, the concentration of metal salt is 1-20 mmol/L, and the metal salt is zinc salt (such as ZnCl)2、ZnSO4、Zn(NO3)2Etc.), or iron salts (e.g.: FeCl3、Fe(BF4)2·6H2O、FeBr3Etc.), or zirconium salts (e.g.: ZrCl4Etc.), or magnesium salts (e.g.: MgSO (MgSO)4、MgCl2Etc.), or calcium salts (e.g.: CaCl2、CaBr2Etc.); the reaction temperature is 40-180 ℃, and the reaction time is 4-12 h.
7. The method for preparing a drug delivery carrier based on a bio-metal organic framework material as claimed in claim 6, wherein the alkali solution is an aqueous solution of sodium hydroxide, or an aqueous solution of potassium hydroxide, or an aqueous solution of ammonia, the concentration is 0.1-1 mol/L, and the pH is adjusted to 10-13 by using the alkali solution; the reaction temperature is 80-120 ℃, and the reaction time is 6-10 h; the concentration of cystine is 8-15 mmol/L; the concentration of the metal salt is 8-15 mmol/L.
8. Use of a drug delivery vehicle based on a bio-metal organic framework material according to any one of claims 1 to 5 for the delivery of an anticancer drug, wherein after entering tumor cells by intravenous injection, glutathione overexpressed in the cells interacts with S-S in cystine ligands, so that S-S bonds are broken and the porous framework structure is destroyed, thereby rapidly releasing the anticancer drug; in normal cells, the S-S bond is not broken, and the drug is still confined in the carrier, thereby reducing the damage and toxic and side effects of the drug on normal tissues.
9. The use of claim 8, wherein the drug delivery vehicle is mixed with the anticancer drug in water, the mixture is reacted under the conditions of room temperature, light-shielding and stirring, the precipitate is centrifuged, and the precipitate is washed with water to obtain the nanocomposite, and the nanocomposite is stirred at room temperature of 20-25 ℃ for 12-72 hours under light-shielding conditions (such as 100-300 rpm).
10. The use of claim 8, wherein the anticancer agent is doxorubicin hydrochloride, or curcumin, or docetaxel, or 5-fluorouracil, or camptothecin, etc.; the concentration is 100-1000 mg/L; the concentration of the drug delivery carrier is 1000-5000 mg/L.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115581777A (en) * | 2022-10-18 | 2023-01-10 | 无锡学院 | Preparation method and application of AuNC @ ZIF-8 drug carrier |
| CN115737838A (en) * | 2022-11-11 | 2023-03-07 | 上海交通大学医学院附属第九人民医院 | Curcumin-containing polymer and application thereof in promoting healing of burn |
| CN116271097A (en) * | 2023-04-07 | 2023-06-23 | 四川大学 | Engineering exosome based on metal organic framework and preparation method and application thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114099706A (en) * | 2021-11-30 | 2022-03-01 | 江南大学 | MOF drug carrier for treating breast cancer and preparation method thereof |
| CN114099706B (en) * | 2021-11-30 | 2024-10-01 | 江南大学 | MOF (metal oxide semiconductor field) drug carrier for breast cancer treatment and preparation method thereof |
| CN115581777A (en) * | 2022-10-18 | 2023-01-10 | 无锡学院 | Preparation method and application of AuNC @ ZIF-8 drug carrier |
| CN115581777B (en) * | 2022-10-18 | 2024-05-28 | 无锡学院 | Preparation method and application of AuNC@ZIF-8 drug carrier |
| CN115737838A (en) * | 2022-11-11 | 2023-03-07 | 上海交通大学医学院附属第九人民医院 | Curcumin-containing polymer and application thereof in promoting healing of burn |
| CN116271097A (en) * | 2023-04-07 | 2023-06-23 | 四川大学 | Engineering exosome based on metal organic framework and preparation method and application thereof |
| CN116271097B (en) * | 2023-04-07 | 2024-01-26 | 四川大学 | Engineering exosome based on metal organic framework and preparation method and application thereof |
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