CN112294751B - Preparation method and application of calcium peroxide-loaded metal-organic framework pharmaceutical composition - Google Patents
Preparation method and application of calcium peroxide-loaded metal-organic framework pharmaceutical composition Download PDFInfo
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- CN112294751B CN112294751B CN202011195208.5A CN202011195208A CN112294751B CN 112294751 B CN112294751 B CN 112294751B CN 202011195208 A CN202011195208 A CN 202011195208A CN 112294751 B CN112294751 B CN 112294751B
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- LHJQIRIGXXHNLA-UHFFFAOYSA-N calcium peroxide Chemical compound [Ca+2].[O-][O-] LHJQIRIGXXHNLA-UHFFFAOYSA-N 0.000 title claims abstract description 98
- 235000019402 calcium peroxide Nutrition 0.000 title claims abstract description 98
- 239000012621 metal-organic framework Substances 0.000 title claims abstract description 76
- 239000004343 Calcium peroxide Substances 0.000 title claims abstract description 66
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 229910052684 Cerium Inorganic materials 0.000 claims abstract description 43
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000003814 drug Substances 0.000 claims abstract description 29
- 239000002245 particle Substances 0.000 claims abstract description 24
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 18
- 229940079593 drug Drugs 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims abstract description 16
- 229910052751 metal Inorganic materials 0.000 claims abstract description 14
- 239000002184 metal Substances 0.000 claims abstract description 14
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 12
- 150000002500 ions Chemical class 0.000 claims abstract description 12
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 9
- 238000011068 loading method Methods 0.000 claims abstract description 6
- 229940044683 chemotherapy drug Drugs 0.000 claims abstract description 5
- 238000003837 high-temperature calcination Methods 0.000 claims abstract description 4
- 238000001179 sorption measurement Methods 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract description 3
- 239000002244 precipitate Substances 0.000 claims description 129
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 72
- 238000003756 stirring Methods 0.000 claims description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 50
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 claims description 48
- 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 claims description 46
- 238000005406 washing Methods 0.000 claims description 41
- 239000000243 solution Substances 0.000 claims description 34
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 claims description 32
- 239000006228 supernatant Substances 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000011259 mixed solution Substances 0.000 claims description 24
- 238000001291 vacuum drying Methods 0.000 claims description 20
- 239000000843 powder Substances 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 238000001354 calcination Methods 0.000 claims description 16
- 238000000227 grinding Methods 0.000 claims description 16
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 16
- 239000012498 ultrapure water Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 235000019441 ethanol Nutrition 0.000 claims description 14
- 229960004679 doxorubicin Drugs 0.000 claims description 13
- 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 10
- 229930012538 Paclitaxel Natural products 0.000 claims description 10
- 229960003668 docetaxel Drugs 0.000 claims description 10
- 229960001592 paclitaxel Drugs 0.000 claims description 10
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 8
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 8
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 claims description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 8
- 239000001110 calcium chloride Substances 0.000 claims description 8
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 229940113115 polyethylene glycol 200 Drugs 0.000 claims description 8
- 238000007789 sealing Methods 0.000 claims description 8
- 238000002512 chemotherapy Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 239000011148 porous material Substances 0.000 claims description 5
- 150000003384 small molecules Chemical class 0.000 claims description 5
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 claims description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 230000002452 interceptive effect Effects 0.000 claims description 4
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 4
- 229960001156 mitoxantrone Drugs 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 230000000973 chemotherapeutic effect Effects 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229940126586 small molecule drug Drugs 0.000 claims description 3
- 239000013384 organic framework Substances 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 4
- 239000007943 implant Substances 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 abstract description 9
- 210000004881 tumor cell Anatomy 0.000 abstract description 4
- 230000006907 apoptotic process Effects 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 20
- 239000008055 phosphate buffer solution Substances 0.000 description 12
- 239000011575 calcium Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 206010006187 Breast cancer Diseases 0.000 description 6
- 208000026310 Breast neoplasm Diseases 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- -1 DOX modified CaO Chemical class 0.000 description 2
- 229930064664 L-arginine Natural products 0.000 description 2
- 235000014852 L-arginine Nutrition 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 208000004434 Calcinosis Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 102000003952 Caspase 3 Human genes 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 125000002059 L-arginyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 238000010000 carbonizing Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229910000420 cerium oxide Inorganic materials 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000004146 energy storage Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002539 nanocarrier Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- MSLRPWGRFCKNIZ-UHFFFAOYSA-J tetrasodium;hydrogen peroxide;dicarbonate Chemical compound [Na+].[Na+].[Na+].[Na+].OO.OO.OO.[O-]C([O-])=O.[O-]C([O-])=O MSLRPWGRFCKNIZ-UHFFFAOYSA-J 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to a preparation method and application of a metal organic framework pharmaceutical composition loaded with calcium peroxide, which can effectively solve the preparation of the metal organic framework pharmaceutical composition loaded with calcium peroxide, and realize cascade catalysis for treating tumors and ion interference for tumor cells, and promote apoptosis of tumor cells. The metal organic frame is a cerium-based synthesized organic frame, and is carbonized into the cerium-based metal organic frame with the grain diameter of 80-180nm and the aperture of 6-8nm under high-temperature calcination, and then the micromolecular chemotherapeutic drug is connected to CaO through chemical bonds 2 Surface to be loaded with CaO 2 The small particles are adhered to the holes of the cerium-based metal organic framework through physical adsorption, so that the metal organic framework pharmaceutical composition with the particle size of 100-200nm and loaded with calcium peroxide is obtained, the drug loading weight is 20% -60%, the preparation method is stable and reliable, the cost is low, and the prepared metal organic framework pharmaceutical composition loaded with calcium peroxide is used for preparing antitumor drugsIn the aspect, the effects of cascade catalysis and ion interference can be exerted, and the anti-tumor effect is enhanced.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to a preparation method and application of a metal organic framework pharmaceutical composition loaded with calcium peroxide.
Background
The hot metal-on-metal frameworks (MOFs) are emerging nano-carriers which have the advantages of large pore size, high load and high catalysis and are widely applied to the fields of catalysis, energy storage, separation, medicine and the like. In addition, cerium-based metal organic frameworks (CeMOFs) contain large numbers of small particles of cerium oxide with strong peroxidase activity inside, which can interact with H in acidic tumor environments 2 O 2 Fenton-like reactions occur to produce Reactive Oxygen Species (ROS) with high toxicity. But the reaction is limited by the low intracellular concentration of H 2 O 2 If exogenous H is provided 2 O 2 It is clear that the antitumor efficacy can be improved.
Interestingly, peroxides can react catalytically in the acidic environment of tumors to produce H 2 O 2 Solves the problem that the CeMOF performs Fenton-like reaction. Wherein the calcium peroxide nanoparticles are producing H 2 O 2 Is also disintegrated to generate a large amount of Ca 2+ . As is generally known, ca 2+ As cellular second messengers are involved in apoptosis signaling, calcium-based ion-interference therapies have become a focus of attention for researchers. Studies have shown that extracellular Ca 2+ The release of the inner flow or the intracellular calcium reservoir leads to the overload of intracellular calcium, so as to activate a Caspase-3 pathway to induce apoptosis; in addition, ca 2+ Also promotes calcification development in the focal zone of the tumor. Thus (2)Small particles of CaO with high activity 2 The particles are loaded into a cerium-based metal organic framework, and then an anti-tumor small molecule drug is added, so that the effect of triple striking interactive comprehensive treatment of Fenton-like catalytic oxidation effect, ion interference therapy and chemotherapy can be achieved.
Disclosure of Invention
Aiming at the situation, the invention aims to solve the defects in the prior art, and provides a preparation method and application of a metal organic framework pharmaceutical composition loaded with calcium peroxide, which can effectively solve the preparation of the metal organic framework pharmaceutical composition loaded with calcium peroxide, and realize cascade catalysis for treating tumors and ion interference for tumor cells, and promote apoptosis of tumor cells.
The technical scheme of the invention is that the preparation method of the calcium peroxide-loaded metal-organic framework pharmaceutical composition comprises the steps of carbonizing a cerium-based synthesized organic framework into a cerium-based metal-organic framework with the particle size of 80-180nm and the pore diameter of 6-8nm under high-temperature calcination, and then connecting a micromolecular chemotherapeutic drug to CaO through a chemical bond 2 Surface, finally, caO loaded with medicine 2 The small particles are adhered to the holes of the cerium-based metal organic framework through physical adsorption, so that the metal organic framework pharmaceutical composition with the particle size of 100-200nm and loaded with calcium peroxide is obtained, and the drug loading weight is 20% -60%, and the specific steps are as follows:
(1) Dissolving 450-470mg of ceric ammonium nitrate in 2-4mL of ultrapure water to form ceric ammonium nitrate aqueous solution, dissolving 130-150mg of terephthalic acid in 2-4mL of N, N-dimethylformamide, mixing and sealing the N, N-dimethylformamide solution of terephthalic acid and the ceric ammonium nitrate aqueous solution, stirring for 20-40min in an oil bath at 95-115 ℃, centrifuging for 10min at 8000-12000rpm, taking precipitate, washing the precipitate with N, N-dimethylformamide for 3 times, wherein each time is 2-3 times of the volume of the precipitate by weight, washing with acetone for 3 times, each time is 2-3 times of the volume of the precipitate by weight, wherein the volume by weight is calculated in mL of liquid, the solid is calculated in g (the same below), and grinding into white powder which passes through a 100-120 mesh sieve after vacuum drying to obtain a cerium-based metal organic frame (CeMOF); calcining the prepared cerium-based metal organic framework (CeMOF) in a muffle furnace, heating to 350-400 ℃ at 5-10 ℃/min, calcining for 3-5h, and cooling to below 20 ℃ to obtain a carbonized cerium-based metal organic framework (CeMOF);
(2) Dissolving 0.4-0.6mg of calcium chloride particles in 4-6mL of ultrapure water, stirring at 2000-2400rpm to dissolve completely, adding 2-3mL of 0.5-1.5M ammonia water under stirring at room temperature, then adding 30-50mL of polyethylene glycol 200 (PEG 200), continuously stirring to mix completely into a uniform solution, adding 2-3mL of hydrogen peroxide with the mass concentration of 30%, continuously stirring for 5-7h, then gradually adjusting the pH to 11.5 with sodium hydroxide solution, centrifuging at 8000-12000rpm for 10min, discarding the supernatant to obtain white precipitate, washing the white precipitate with anhydrous ethanol for 3 times, each time being 2-3 times the weight volume of the white precipitate, and vacuum drying to obtain calcium dioxide (CaO) 2 )；
(3) 1-3mg of calcium dioxide (CaO) 2 ) Dispersing the precipitate with 1mg of small molecule chemotherapeutic drug in 3-5mL of mixed solution with equal volume ratio of ethanol and water, stirring at room temperature at 2000-2400rpm in the dark for 48h, centrifuging at 8000-12000rpm for 10min, discarding supernatant to obtain precipitate, washing the precipitate with mixed solution of ethanol-water with equal volume ratio for three times, wherein each dosage is 2-3 times of weight volume of white precipitate to obtain calcium peroxide loaded with small molecule drug;
the small molecule chemotherapeutic medicine is L-arginine, doxorubicin, taxol, docetaxel, hydroxycamptothecin or mitoxantrone;
(4) Dissolving 5-10mg of the calcined carbonized cerium-based metal organic framework (CeMOF) prepared in the step (2) in 5-10mL of a solvent, uniformly dispersing by utilizing ultrasonic, and dissolving 3-5mg of the calcium peroxide loaded with the micromolecule drug prepared in the step (3) in 3-5mL of the solvent; adding the two solutions into a round bottom flask together, stirring at 2000-2400rpm for reaction for 20-40min at dark room temperature, centrifuging at 8000-12000rpm for 10min, discarding supernatant to obtain precipitate, washing the precipitate with PBS (phosphate buffer solution) with pH of 7.2-7.4 for 3 times, each time with 2-3 times of the weight volume of the precipitate, vacuum drying, and grinding into 100-120 mesh powder to obtain metal organic frame pharmaceutical composition loaded with calcium peroxide;
the solvent is one of PBS or MES with the pH of 7.2-7.4 and a mixed solution of ethanol and water in an equal volume ratio.
The application of the metal organic framework pharmaceutical composition loaded with the calcium peroxide in preparing an antitumor drug combined with pharmaceutically active or pharmacologically active molecules, wherein the pharmaceutically active or pharmacologically active molecules are L-arginine, doxorubicin, paclitaxel, docetaxel, hydroxycamptothecin or mitoxantrone.
The metal organic framework pharmaceutical composition loaded with the calcium peroxide, prepared by the method, is applied to preparation of anti-tumor injection, oral preparation or implantation administration preparation.
The metal organic framework pharmaceutical composition loaded with the calcium peroxide, prepared by the method, is applied to the preparation of drugs for the triple striking interactive comprehensive treatment of tumors, wherein the drugs have Fenton-like catalytic oxidation effect, ion interference therapy and chemotherapy.
The preparation method of the invention is stable and reliable, has low cost, and the prepared metal organic framework pharmaceutical composition loaded with the calcium peroxide can play roles of cascade catalysis and ion interference in the aspect of preparing the anti-tumor drugs, thereby enhancing the anti-tumor effect, being an innovation in the tumor treatment drugs and having huge economic and social benefits.
Detailed Description
The following describes specific embodiments of the present invention in detail with reference to examples and specific cases.
The invention is illustrated in the following examples in the practice.
Example 1:
in the specific implementation of the invention, the preparation method of the metal organic framework pharmaceutical composition loaded with the calcium peroxide comprises the following steps:
(1) Dissolving 460mg of ceric ammonium nitrate in 3mL of ultrapure water to form ceric ammonium nitrate aqueous solution, dissolving 140mg of terephthalic acid in 3mL of N, N-dimethylformamide at the same time, mixing and sealing the N, N-dimethylformamide solution of terephthalic acid and the ceric ammonium nitrate aqueous solution, stirring for 30min at 100 ℃ in an oil bath, centrifuging for 10min at 10000rpm, taking precipitate, washing the precipitate with N, N-dimethylformamide for 3 times, wherein the amount of the precipitate is 2-3 times of the weight volume of the precipitate, washing the precipitate with acetone for 3 times, wherein the amount of the precipitate is 2-3 times of the weight volume of the precipitate, and grinding the precipitate into white powder which passes through a 110-mesh sieve after vacuum drying to obtain a cerium-based metal organic frame (CeMOF); calcining the prepared cerium-based metal organic framework (CeMOF) in a muffle furnace, heating to 370 ℃ at 7 ℃/min, calcining for 4 hours, and cooling to below 20 ℃ to obtain a carbonized cerium-based metal organic framework (CeMOF);
(2) Dissolving 0.5mg of calcium chloride particles in 5mL of ultrapure water, stirring at 2200rpm to dissolve completely, adding 2.5mL of 1M ammonia water under stirring at room temperature, then adding 40mL of polyethylene glycol 200 (PEG 200), continuously stirring to mix completely into a uniform solution, further adding 2.5mL of hydrogen peroxide with the mass concentration of 30%, continuously stirring for 6 hours, then gradually adjusting the pH to 11.5 with sodium hydroxide solution, centrifuging at 10000rpm for 10 minutes, discarding the supernatant, obtaining white precipitate, washing the white precipitate with absolute ethyl alcohol for 3 times, each time with the amount being 2-3 times the weight volume of the white precipitate, and vacuum drying to obtain calcium dioxide (CaO) 2 )；
(3) 2mg of calcium dioxide (CaO) 2 ) Dispersing 1mg of doxorubicin in 4mL of mixed solution with equal volume ratio of ethanol and water, stirring at room temperature at 2200rpm in the dark for 48h, centrifuging at 10000rpm for 10min, discarding supernatant to obtain precipitate, washing the precipitate with the mixed solution with equal volume ratio of ethanol-water for three times, wherein the dosage is 2-3 times of the weight volume of the white precipitate each time to obtain doxorubicin-loaded calcium peroxide;
(4) Dissolving 7.5mg of the calcined carbonized cerium-based metal organic framework (CeMOF) prepared in the step (2) in 7.5mL of an ethanol-water mixed solution with an equal volume ratio, uniformly dispersing by utilizing ultrasonic, and dissolving 4mg of the doxorubicin-loaded calcium peroxide prepared in the step (3) in 4mL of the ethanol-water mixed solution with an equal volume ratio; adding the two solutions into a round bottom flask together, stirring and reacting for 30min at a dark room temperature at 2200rpm, centrifuging at 10000rpm for 10min, discarding supernatant to obtain precipitate, washing the precipitate with PBS with pH of 7.3 for 3 times, each time with 2-3 times of the weight volume of the precipitate, vacuum drying, and grinding into powder with 110 mesh sieve to obtain the metal organic frame pharmaceutical composition loaded with calcium peroxide.
Example 2:
in the specific implementation of the invention, the preparation method of the metal organic framework pharmaceutical composition loaded with the calcium peroxide comprises the following steps:
(1) Dissolving 452mg of ceric ammonium nitrate in 2mL of ultrapure water to form ceric ammonium nitrate aqueous solution, dissolving 132mg of terephthalic acid in 2mL of N, N-dimethylformamide at the same time, mixing and sealing the N, N-dimethylformamide solution of terephthalic acid and the ceric ammonium nitrate aqueous solution, stirring for 38min at an oil bath of 97 ℃, centrifuging for 10min at 9000rpm, taking precipitate, washing the precipitate with N, N-dimethylformamide for 3 times, wherein the amount of the precipitate is 2-3 times of the weight volume of the precipitate, washing the precipitate with acetone for 3 times, wherein the amount of the precipitate is 2-3 times of the weight volume of the precipitate, and grinding the precipitate into white powder which passes through a 100-mesh sieve after vacuum drying to obtain a cerium-based metal organic framework (CeMOF); calcining the prepared cerium-based metal organic framework (CeMOF) in a muffle furnace, heating to 355 ℃ at a speed of 6 ℃/min, calcining for 4.5 hours, and cooling to below 20 ℃ to obtain a carbonized cerium-based metal organic framework (CeMOF);
(2) Dissolving 0.4mg of calcium chloride particles in 4mL of ultrapure water, stirring at 2000rpm to dissolve completely, adding 2mL of 1.5M ammonia water under stirring at room temperature, then adding 30mL of polyethylene glycol 200 (PEG 200), continuously stirring to mix completely into a uniform solution, further adding 2mL of hydrogen peroxide with mass concentration of 30%, continuously stirring for 5 hours, gradually adjusting pH to 11.5 with sodium hydroxide solution, centrifuging at 9000rpm for 10min, discarding the supernatant to obtain white precipitate, washing the white precipitate with absolute ethyl alcohol for 3 times, each time with 2-3 times the weight volume of the white precipitate, and vacuum drying to obtain calcium dioxide (CaO) 2 )；
(3) 1mg of calcium dioxide (CaO) 2 ) Dispersing paclitaxel with 1mg in 3mL mixed solution with equal volume ratio of ethanol and water, stirring at room temperature at 2000rpm for 48 hr in the absence of light, centrifuging at 9000rpm for 10min, discarding supernatant to obtain precipitate, washing the precipitate with mixed solution of ethanol and water with equal volume ratio for three times, each time with 2-3 times of the weight volume of white precipitate, and obtaining paclitaxel-loaded calcium peroxide;
(4) Dissolving 6mg of the calcined carbonized cerium-based metal organic framework (CeMOF) prepared in the step (2) in 6mL of PBS with the pH of 7.2-7.4, uniformly dispersing by utilizing ultrasonic, and dissolving 3mg of the taxol-loaded calcium peroxide prepared in the step (3) in 3mL of PBS with the pH of 7.2-7.4; adding the two solutions into a round bottom flask together, stirring and reacting for 38min at 2000rpm at room temperature in the absence of light, centrifuging for 10min at 9000rpm, discarding supernatant to obtain precipitate, washing the precipitate with PBS with pH of 7.2 for 3 times, each time with 2-3 times of the weight volume of the precipitate, vacuum drying, and grinding into powder passing through a 100-mesh sieve to obtain the metal organic frame pharmaceutical composition loaded with calcium peroxide.
Example 3:
in the specific implementation of the invention, the preparation method of the metal organic framework pharmaceutical composition loaded with the calcium peroxide comprises the following steps:
(1) Dissolving 468mg of ceric ammonium nitrate in 4mL of ultrapure water to form ceric ammonium nitrate aqueous solution, dissolving 148mg of terephthalic acid in 4mL of N, N-dimethylformamide at the same time, mixing and sealing the N, N-dimethylformamide solution of terephthalic acid and the ceric ammonium nitrate aqueous solution, stirring for 22min at 115 ℃ under an oil bath, centrifuging for 10min at 11000rpm, taking precipitate, washing the precipitate with N, N-dimethylformamide for 3 times, wherein the amount of the precipitate is 2-3 times of the weight volume of the precipitate, washing the precipitate with acetone for 3 times, wherein the amount of the precipitate is 2-3 times of the weight volume of the precipitate, and grinding the precipitate into white powder which passes through a 120-mesh sieve after vacuum drying to obtain a cerium-based metal organic framework (CeMOF); calcining the prepared cerium-based metal organic framework (CeMOF) in a muffle furnace, heating to 390 ℃ at 9 ℃/min, calcining for 3 hours, and cooling to below 20 ℃ to obtain a carbonized cerium-based metal organic framework (CeMOF);
(2) Dissolving 0.6mg of calcium chloride particles in 6mL of ultrapure water, stirring at 2400rpm to dissolve completely, adding 3mL of 0.5M ammonia water under stirring at room temperature, then adding 50mL of polyethylene glycol 200 (PEG 200), continuously stirring to mix completely into a uniform solution, further adding 3mL of hydrogen peroxide with the mass concentration of 30%, continuously stirring for 7h, gradually adjusting the pH to 11.5 with sodium hydroxide solution, centrifuging at 11000rpm for 10min, discarding the supernatant to obtain white precipitate, washing the white precipitate with absolute ethyl alcohol for 3 times, each time with the amount being 2-3 times the weight volume of the white precipitate, and vacuum drying to obtain calcium dioxide (CaO) 2 )；
(3) 3mg of dioxygenCalcium carbide (CaO) 2 ) Dispersing docetaxel with 1mg of ethanol and water in the mixed solution with equal volume ratio, stirring at 2400rpm at room temperature for 48h in the absence of light, centrifuging at 11000rpm for 10min, discarding supernatant to obtain precipitate, washing the precipitate with the mixed solution with equal volume ratio of ethanol-water for three times, wherein the dosage is 2-3 times of the weight volume of the white precipitate, and obtaining calcium peroxide loaded with docetaxel;
(4) Dissolving 10mg of the calcined carbonized cerium-based metal organic framework (CeMOF) prepared in the step (2) in 10mL of MES with the pH of 7.2-7.4, uniformly dispersing by utilizing ultrasonic, and dissolving 5mg of calcium peroxide of the loaded docetaxel prepared in the step (3) in 5mL of MES with the pH of 7.2-7.4; adding the two solutions into a round bottom flask together, stirring and reacting at 2400rpm at a dark room temperature for 22min, centrifuging at 11000rpm for 10min, discarding supernatant to obtain precipitate, washing the precipitate with PBS with pH of 7.4 for 3 times, each time with 2-3 times of the weight volume of the precipitate, vacuum drying, and grinding into powder passing through a 120-mesh sieve to obtain the metal organic frame pharmaceutical composition loaded with calcium peroxide.
It should be noted that the foregoing embodiments of the present invention are merely illustrative of specific embodiments of the present invention, and are not intended to limit the scope of the invention, and any equivalent modifications and substitutions made within the spirit and principles of the present invention are essentially the same as the technical solutions of the present invention and are included in the scope of the present invention.
The preparation method is scientific and reasonable, the raw materials are easy to obtain, the production and the preparation are easy, the method is stable and reliable, the product quality is good, and the scientific test shows that the metal organic framework pharmaceutical composition loaded with the calcium peroxide is prepared, and the H provided by the calcium peroxide 2 O 2 Enhancing Fenton-like reaction to generate active oxygen and simultaneously increasing intracellular Ca 2+ And the addition of the small molecule chemotherapeutic greatly enhances the anti-tumor effect. The preparation of the antitumor drug can exert the antitumor effect of cascade catalysis and ion interference, has the advantages of high efficiency and small toxic and side effects compared with the traditional chemotherapy, and the related experimental data are as follows (taking example 1):
1. characterization experiment of calcium peroxide-loaded metal organic framework pharmaceutical composition
1. Determination of doxorubicin content in calcium peroxide-loaded metal organic framework pharmaceutical compositions:
the content of doxorubicin was measured at 482nm wavelength by ultraviolet spectrophotometry, and the drug loading of the sample was calculated as 50% by formula (1).
2. Determination of particle size and potential of calcium peroxide-loaded metal organic framework pharmaceutical composition:
dispersing a proper amount of doxorubicin-loaded calcium peroxide metal organic framework pharmaceutical composition in water, and measuring CeMOF and CeMOF-CaO by using a Nano-ZS90 laser nanometer particle size analyzer 2 The particle size and the potential of the DOX were 116nm, 132nm and-20.1.+ -. 1.1mV and-24.7.+ -. 2.0mV, respectively.
3、H 2 O 2 Self-supplying Ca 2+ Pore size determination of generator pharmaceutical composition:
and (3) uniformly dispersing a proper amount of CeMOF powder in water, and measuring the pore diameter of the powder to be 7.3nm by using an ASAP 2020 type full-automatic specific surface and porosity analyzer and a BJH algorithm.
2. In vitro active oxygen generation experiment of metal organic framework pharmaceutical composition loaded with calcium peroxide
Selecting MCF-7 human breast cancer cells in logarithmic growth phase, and adjusting cell number to 3×10 5 Inoculating/ml into 6-hole culture plate, adding 2ml per hole, and adding medicine after cell wall-adhering growth for 24 hr, wherein the cell wall-adhering growth is blank group, ceMOF-CaO group in sequence 2 Group, ceMOF-CaO 2 DOX group, wherein the final concentration of CeMOF was set to 150. Mu.g/ml, after culturing for 24 hours, the old culture solution was discarded, each well was washed 2-3 times with fresh PBS, 1ml of DCFH-DA-containing active oxygen probe medium was added to each well, after culturing for 30 minutes at 37℃and washing 2-3 times with fresh PBS, and as a result, it was found that the other groups except the blank group and CeMOF group detected green DCFH-DA fluorescent signals, consistent with the literature report that CeMOF was compatible with H produced by calcium peroxide 2 O 2 Fenton-like reaction occurs to produce a large amount of active oxygen.
3. Cell uptake experiments of calcium peroxide-loaded metal organic framework pharmaceutical compositions
Selecting MCF-7 human breast cancer cells in logarithmic growth phase, and adjusting cell number to 3×10 5 Inoculating/ml into 6-hole culture plate, adding 2ml per hole, and adding medicine after wall-attached growth for 24 hr, wherein the medicine is DOX group and CeMOF-CaO in sequence 2 In DOX group, the final concentration of the drug is 5 mug/ml, the incubation time is 0.5h,1h,2h, and the temperature is 37 ℃ after the drug addition, 5% CO 2 After culturing under the condition, the medicine-contained culture medium in the hole is discarded, each hole is washed by 1ml PBS for 2-3 times, 500 mu l of pancreatin digestive cells without EDTA are added, 1ml of fresh culture medium is added to stop digestion until the cells are separated from the wall, the cell suspension is transferred into a 10ml centrifuge tube, the supernatant is removed by centrifugation, PBS is added for resuspension, and the measurement by a flow cytometry shows that MCF-7 human breast cancer cells are subjected to DOX and CeMOF-CaO for 0.5h 2 The uptake per DOX was: 47.1 percent and 24.1 percent; the intake at 1h was respectively: 83.8%, 54.4%; the intake at 2h was respectively: 99.0% and 98.4%. The result shows that DOX cells of the water-soluble small molecular raw material medicine take the fastest, and the intake of the DOX cells is nearly saturated in 1 h; whereas CeMOF-CaO 2 The molecular weight of the DOX nano preparation is larger, the cellular uptake is slower, and the MCF-7 human breast cancer cells have the effects on DOX and CeMOF-CaO at 2 hours 2 the/DOX uptake was essentially the same.
4. Cell proliferation inhibition assay for calcium peroxide loaded metal organic framework pharmaceutical compositions
Selecting MCF-7 human breast cancer cells in logarithmic phase by MTT method, and adjusting cell number to 5×10 4 Inoculating/ml into 96-well culture plate, and adding medicine after cell wall-attached growth for 24 hr, wherein the cell wall-attached growth comprises blank group, ceMOF group and CaO in sequence 2 Group, DOX group, ceMOF-CaO 2 Group, ceMOF-CaO 2 A DOX group in which the final concentration of the drug was set at 70. Mu.g/ml; medicated cells were incubated at 37℃with 5% CO 2 After 24h incubation in the environment of (2) 25 μl of freshly prepared and filtered 5mg/mL MTT was added to each well, incubated in an incubator protected from light for 4h and removed, all liquid was spun dry in the wells, 150 μl of DMSO was added to each well, and the wells were subjected to shaking by shaking in a shaker at 37deg.CAfter 100rpm micro-shaking for 10min, OD value of each small hole is measured at 490nm wavelength of an enzyme-labeled instrument, tumor cell growth inhibition rate (%) = (1-experimental group OD value/control group OD value) ×100% is calculated, and CeMOF group and CaO are calculated 2 Group, DOX group, ceMOF-CaO 2 Group, ceMOF-CaO 2 The inhibition rate of cell growth of the DOX group is respectively as follows: 16.5%,21.3%,32.5%,72.8%,82.1%. The results show that CeMOF and CaO 2 The DOX group has certain toxicity to cells, but carries DOX modified CaO in CeMOF 2 After that, the anti-tumor effect is increased, and the experiment shows that the CeMOF-CaO 2 The DOX group plays an anti-tumor effect greatly, and is a synergistic treatment result of cascade catalysis, ion interference and chemotherapy.
5. Pharmacodynamic research experiment of metal organic framework pharmaceutical composition loaded with calcium peroxide
Purchasing female nude mice of 4-6 weeks old, subcutaneously inoculating MCF-7 human breast cancer cells on the back of right upper limb of the mice, measuring tumor volume after 7 days, and taking tumor volume not less than 100mm 3 Mice with similar tumor volumes and weights were randomly divided into 6 groups of 6 mice each, with the following specific groupings: physiological saline group, ceMOF group, caO 2 Group, DOX group, ceMOF-CaO 2 Group, ceMOF-CaO 2 group/DOX; the mice of each group are administrated by tail vein injection once every two days, and are administrated for 7 times, the normal daily diet of the mice is ensured in the whole experimental process, the weight of each mouse is weighed every two days, the long diameter (A) and the short diameter (B) of the sarcoma of the tumor-bearing mice are measured by using a digital vernier caliper, and the tumor volume V=A×B is calculated according to the formula 2 Tumor volume was calculated. The recorded data show that CeMOF group, caO 2 Group, DOX group, ceMOF-CaO 2 Group, ceMOF-CaO 2 The tumor inhibition rates of the/DOX group were 25.32%,26.71%,24.18%,71.32% and 85.91%, respectively. The results show that CeMOF-CaO 2 The medicine effect of the DOX group is obvious, and the DOX group can greatly inhibit the growth of tumors. The experiment proves that the tumor targeting drug delivery system has synergistic treatment effect based on combination of cascade catalysis, ion interference and chemotherapy.
Experiments were performed in accordance with the above-described methods in examples 2-3 of the present invention, all of which gave the same or similar results, and are not shown here.
The above can clearly show that the method of the invention is stable and reliable, has good product quality, and the drug loading amount is up to 35%, compared with the prior art, the method has the following outstanding beneficial technical effects:
1. the metal organic framework pharmaceutical composition loaded with the calcium peroxide provided by the invention is carbonized by high-temperature calcination, so that the activity of CeMOF is improved, the product quality is good, the drug loading capacity is up to about 35%, the particle size is small, and the particle size is only 100-200nm (nanometers), thereby being beneficial to drug absorption and improving the utilization rate and the curative effect;
2. the metal organic framework pharmaceutical composition loaded with the calcium peroxide provided by the invention has the advantage that the metal organic framework is selected to be favorable for fixing CaO 2 Hold CaO 2 And with CaO 2 H produced 2 O 2 Fenton-like reaction occurs to increase the content of active oxygen, and meanwhile, calcium ions generated by calcium peroxide are subjected to ion interference therapy;
3. the metal organic framework pharmaceutical composition loaded with the calcium peroxide provided by the invention has the Fenton-like catalytic oxidation effect of CeMOF and CaO 2 The ion interference therapy and the chemotherapy are integrated together, the triple striking interactive comprehensive treatment is carried out on the tumor, the anti-tumor treatment effect is enhanced, and the method is innovation in tumor treatment medicines and has huge economic and social benefits.
Claims (7)
1. A preparation method of a calcium peroxide-loaded metal-organic framework pharmaceutical composition is characterized in that the metal-organic framework is a cerium-based synthesized organic framework, the cerium-based metal-organic framework with the particle size of 80-180nm and the pore diameter of 6-8nm is carbonized under high-temperature calcination, and then a small molecular chemotherapeutic drug is connected to CaO through a chemical bond 2 Surface, finally, caO loaded with medicine 2 The small particles are adhered to the holes of the cerium-based metal organic framework through physical adsorption, so that the metal organic framework pharmaceutical composition with the particle size of 100-200nm and loaded with calcium peroxide is obtained, and the drug loading weight is 20% -60%, and the specific steps are as follows:
(1) Dissolving 450-470mg of ceric ammonium nitrate in 2-4mL of ultrapure water to form ceric ammonium nitrate aqueous solution, dissolving 130-150mg of terephthalic acid in 2-4mL of N, N-dimethylformamide, mixing and sealing the N, N-dimethylformamide solution of terephthalic acid and the ceric ammonium nitrate aqueous solution, stirring for 20-40min in an oil bath at 95-115 ℃, centrifuging for 10min at 8000-12000rpm, taking precipitate, washing the precipitate with N, N-dimethylformamide for 3 times, wherein each time is 2-3 times of the volume of the precipitate by weight, washing with acetone for 3 times, each time is 2-3 times of the volume of the precipitate by weight, wherein the volume by weight is calculated as mL of liquid, the solid is calculated as g, and grinding into white powder which passes through a 100-120 mesh sieve after vacuum drying to obtain a cerium-based metal organic framework (CeMOF); calcining the prepared cerium-based metal organic framework (CeMOF) in a muffle furnace, heating to 350-400 ℃ at 5-10 ℃/min, calcining for 3-5h, and cooling to below 20 ℃ to obtain a carbonized cerium-based metal organic framework (CeMOF);
(2) Dissolving 0.4-0.6mg of calcium chloride particles in 4-6mL of ultrapure water, stirring at 2000-2400rpm to dissolve completely, adding 2-3mL of 0.5-1.5M ammonia water under stirring at room temperature, then adding 30-50mL of polyethylene glycol 200 (PEG 200), continuing stirring to mix completely into a uniform solution, adding 2-3mL of hydrogen peroxide with the mass concentration of 30%, continuing stirring for 5-7h, then gradually adjusting the pH to 11.5 with sodium hydroxide solution, centrifuging at 8000-12000rpm for 10min, discarding the supernatant to obtain white precipitate, washing the white precipitate with absolute ethyl alcohol for 3 times, wherein the dosage of each time is 2-3 times of the weight volume of the white precipitate, and drying in vacuum to obtain calcium dioxide;
(3) Dispersing 1-3mg of calcium dioxide and 1mg of small molecule chemotherapeutic drugs in a mixed solution with the equal volume ratio of 3-5mL of ethanol and water, stirring at room temperature at 2000-2400rpm in the dark for 48h, centrifuging at 8000-12000rpm for 10min, discarding supernatant to obtain a precipitate, washing the precipitate with the mixed solution with the equal volume ratio of ethanol-water for three times, wherein the dosage is 2-3 times of the weight volume of the white precipitate, and obtaining the calcium peroxide loaded with the small molecule drugs;
the small molecule chemotherapeutic medicine is doxorubicin, paclitaxel, docetaxel, hydroxycamptothecin or mitoxantrone;
(4) Dissolving 5-10mg of the calcined carbonized cerium-based metal organic framework (CeMOF) prepared in the step (1) in 5-10mL of a solvent, uniformly dispersing by utilizing ultrasonic, and dissolving 3-5mg of the calcium peroxide loaded with the micromolecule drug prepared in the step (3) in 3-5mL of the solvent; adding the two solutions into a round bottom flask together, stirring at 2000-2400rpm at dark room temperature for reaction for 20-40min, centrifuging at 8000-12000rpm for 10min, discarding supernatant to obtain precipitate, washing the precipitate with PBS with pH of 7.2-7.4 for 3 times, each time with 2-3 times of the weight volume of the precipitate, vacuum drying, and grinding into 100-120 mesh powder to obtain metal organic frame pharmaceutical composition loaded with calcium peroxide;
the solvent is one of PBS or MES with the pH of 7.2-7.4 and a mixed solution of ethanol and water in an equal volume ratio.
2. The method for preparing a calcium peroxide-loaded metal-organic framework pharmaceutical composition according to claim 1, comprising the steps of:
(1) Dissolving 460mg of ceric ammonium nitrate in 3mL of ultrapure water to form ceric ammonium nitrate aqueous solution, dissolving 140mg of terephthalic acid in 3mL of N, N-dimethylformamide at the same time, mixing and sealing the N, N-dimethylformamide solution of terephthalic acid and the ceric ammonium nitrate aqueous solution, stirring for 30min at 100 ℃ in an oil bath, centrifuging for 10min at 10000rpm, taking precipitate, washing the precipitate with N, N-dimethylformamide for 3 times, wherein the amount of the precipitate is 2-3 times of the weight volume of the precipitate, washing the precipitate with acetone for 3 times, wherein the amount of the precipitate is 2-3 times of the weight volume of the precipitate, and grinding the precipitate into white powder which passes through a 110-mesh sieve after vacuum drying to obtain a cerium-based metal organic frame (CeMOF); calcining the prepared cerium-based metal organic framework (CeMOF) in a muffle furnace, heating to 370 ℃ at 7 ℃/min, calcining for 4 hours, and cooling to below 20 ℃ to obtain a carbonized cerium-based metal organic framework (CeMOF);
(2) Dissolving 0.5mg of calcium chloride particles in 5mL of ultrapure water, stirring at 2200rpm to dissolve completely, adding 2.5mL of 1M ammonia water under stirring at room temperature, then adding 40mL of polyethylene glycol 200 (PEG 200), continuing stirring to mix completely to form a uniform solution, adding 2.5mL of hydrogen peroxide with the mass concentration of 30%, continuing stirring for 6 hours, then gradually adjusting the pH to 11.5 by using a sodium hydroxide solution, centrifuging at 10000rpm for 10 minutes, discarding the supernatant to obtain white precipitate, washing the white precipitate with absolute ethyl alcohol for 3 times, wherein the dosage of each time is 2-3 times the weight volume of the white precipitate, and drying in vacuum to obtain calcium dioxide;
(3) Dispersing 2mg of calcium dioxide and 1mg of doxorubicin in 4mL of mixed solution with equal volume ratio of ethanol and water, stirring at room temperature at 2200rpm in the dark for 48h, centrifuging at 10000rpm for 10min, discarding supernatant to obtain precipitate, washing the precipitate with the mixed solution of ethanol and water with equal volume ratio for three times, wherein the dosage is 2-3 times of the weight volume of the white precipitate, and obtaining doxorubicin-loaded calcium peroxide;
(4) Dissolving 7.5mg of the calcined carbonized cerium-based metal organic framework (CeMOF) prepared in the step (1) in 7.5mL of an ethanol-water mixed solution with an equal volume ratio, uniformly dispersing by utilizing ultrasonic, and dissolving 4mg of the doxorubicin-loaded calcium peroxide prepared in the step (3) in 4mL of the ethanol-water mixed solution with an equal volume ratio; adding the two solutions into a round bottom flask together, stirring and reacting for 30min at room temperature under dark condition at 2200rpm, centrifuging at 10000rpm for 10min, discarding supernatant to obtain precipitate, washing the precipitate with PBS with pH of 7.3 for 3 times, each time with 2-3 times of the weight volume of the precipitate, vacuum drying, and grinding into powder with 110 mesh sieve to obtain the metal organic frame pharmaceutical composition loaded with calcium peroxide.
3. The method for preparing a calcium peroxide-loaded metal-organic framework pharmaceutical composition according to claim 1, comprising the steps of:
(1) Dissolving 452mg of ceric ammonium nitrate in 2mL of ultrapure water to form ceric ammonium nitrate aqueous solution, dissolving 132mg of terephthalic acid in 2mL of N, N-dimethylformamide at the same time, mixing and sealing the N, N-dimethylformamide solution of terephthalic acid and the ceric ammonium nitrate aqueous solution, stirring for 38min at an oil bath of 97 ℃, centrifuging for 10min at 9000rpm, taking precipitate, washing the precipitate with N, N-dimethylformamide for 3 times, wherein the amount of the precipitate is 2-3 times of the weight volume of the precipitate, washing the precipitate with acetone for 3 times, wherein the amount of the precipitate is 2-3 times of the weight volume of the precipitate, and grinding the precipitate into white powder which passes through a 100-mesh sieve after vacuum drying to obtain a cerium-based metal organic framework (CeMOF); calcining the prepared cerium-based metal organic framework (CeMOF) in a muffle furnace, heating to 355 ℃ at a speed of 6 ℃/min, calcining for 4.5 hours, and cooling to below 20 ℃ to obtain a carbonized cerium-based metal organic framework (CeMOF);
(2) Dissolving 0.4mg of calcium chloride particles in 4mL of ultrapure water, stirring at 2000rpm to dissolve completely, adding 2mL of 1.5M ammonia water under stirring at room temperature, then adding 30mL of polyethylene glycol 200 (PEG 200), continuing stirring to mix completely to form a uniform solution, adding 2mL of hydrogen peroxide with the mass concentration of 30%, continuing stirring for 5 hours, then gradually adjusting the pH to 11.5 by using a sodium hydroxide solution, centrifuging at 9000rpm for 10 minutes, discarding the supernatant to obtain white precipitate, washing the white precipitate with absolute ethyl alcohol for 3 times, wherein the dosage of each time is 2-3 times the weight volume of the white precipitate, and drying in vacuum to obtain calcium dioxide;
(3) Dispersing 1mg of calcium dioxide and 1mg of taxol in 3mL of mixed solution with equal volume ratio of ethanol and water, stirring at 2000rpm at room temperature for 48 hours in a dark place, centrifuging at 9000rpm for 10min, discarding supernatant to obtain precipitate, washing the precipitate with the mixed solution of ethanol and water with equal volume ratio for three times, wherein the dosage of the mixed solution is 2-3 times of the weight volume of the white precipitate to obtain taxol-loaded calcium peroxide;
(4) Dissolving 6mg of the calcined carbonized cerium-based metal organic framework (CeMOF) prepared in the step (1) in 6mL of PBS with the pH of 7.2-7.4, uniformly dispersing by utilizing ultrasonic, and dissolving 3mg of the taxol-loaded calcium peroxide prepared in the step (3) in 3mL of PBS with the pH of 7.2-7.4; adding the two solutions into a round bottom flask together, stirring and reacting for 38min at 2000rpm at room temperature in the absence of light, centrifuging for 10min at 9000rpm, discarding supernatant to obtain precipitate, washing the precipitate with PBS with pH of 7.2 for 3 times, each time with 2-3 times of the weight volume of the precipitate, vacuum drying, and grinding into powder passing through a 100-mesh sieve to obtain the metal organic frame pharmaceutical composition loaded with calcium peroxide.
4. The method for preparing a calcium peroxide-loaded metal-organic framework pharmaceutical composition according to claim 1, comprising the steps of:
(1) Dissolving 468mg of ceric ammonium nitrate in 4mL of ultrapure water to form ceric ammonium nitrate aqueous solution, dissolving 148mg of terephthalic acid in 4mL of N, N-dimethylformamide at the same time, mixing and sealing the N, N-dimethylformamide solution of terephthalic acid and the ceric ammonium nitrate aqueous solution, stirring for 22min at 115 ℃ under an oil bath, centrifuging for 10min at 11000rpm, taking precipitate, washing the precipitate with N, N-dimethylformamide for 3 times, wherein the amount of the precipitate is 2-3 times of the weight volume of the precipitate, washing the precipitate with acetone for 3 times, wherein the amount of the precipitate is 2-3 times of the weight volume of the precipitate, and grinding the precipitate into white powder which passes through a 120-mesh sieve after vacuum drying to obtain a cerium-based metal organic framework (CeMOF); calcining the prepared cerium-based metal organic framework (CeMOF) in a muffle furnace, heating to 390 ℃ at 9 ℃/min, calcining for 3 hours, and cooling to below 20 ℃ to obtain a carbonized cerium-based metal organic framework (CeMOF);
(2) Dissolving 0.6mg of calcium chloride particles in 6mL of ultrapure water, stirring at 2400rpm to dissolve completely, adding 3mL of 0.5M ammonia water under stirring at room temperature, then adding 50mL of polyethylene glycol 200 (PEG 200), continuously stirring to mix completely into a uniform solution, then adding 3mL of hydrogen peroxide with the mass concentration of 30%, continuously stirring for 7h, then gradually adjusting the pH to 11.5 by using a sodium hydroxide solution, centrifuging at 11000rpm for 10min, discarding the supernatant to obtain white precipitate, washing the white precipitate with absolute ethyl alcohol for 3 times, wherein the dosage of each time is 2-3 times the weight volume of the white precipitate, and drying in vacuum to obtain calcium dioxide;
(3) Dispersing 3mg of calcium dioxide and 1mg of docetaxel in 5mL of mixed solution with equal volume ratio of ethanol and water, stirring at 2400rpm at room temperature for 48 hours in a dark place, centrifuging at 11000rpm for 10min, discarding supernatant to obtain precipitate, washing the precipitate with the mixed solution of ethanol and water with equal volume ratio for three times, wherein the dosage of the mixed solution is 2-3 times of the weight volume of the white precipitate to obtain calcium peroxide loaded with docetaxel;
(4) Dissolving 10mg of the calcined carbonized cerium-based metal organic framework (CeMOF) prepared in the step (1) in 10mL of MES with the pH of 7.2-7.4, uniformly dispersing by utilizing ultrasonic, and dissolving 5mg of calcium peroxide of the loaded docetaxel prepared in the step (3) in 5mL of MES with the pH of 7.2-7.4; adding the two solutions into a round bottom flask together, stirring at 2400rpm at dark room temperature for reaction for 22min, centrifuging at 11000rpm for 10min, discarding supernatant to obtain precipitate, washing the precipitate with PBS with pH of 7.4 for 3 times, each time 2-3 times of the weight volume of the precipitate, vacuum drying, and grinding into powder passing through 120 mesh sieve to obtain the metal organic frame pharmaceutical composition loaded with calcium peroxide.
5. Use of a calcium peroxide-loaded metal organic framework pharmaceutical composition prepared by the method of any one of claims 1-4 for the preparation of an antitumor drug in combination with a pharmaceutically or pharmacologically active molecule, said pharmaceutically or pharmacologically active molecule being doxorubicin, paclitaxel, docetaxel, hydroxycamptothecin or mitoxantrone.
6. Use of a calcium peroxide-loaded metal organic framework pharmaceutical composition prepared by the method of any one of claims 1-4 in the preparation of an anti-tumor injection, oral or implant.
7. Use of a calcium peroxide-loaded metal-organic framework pharmaceutical composition prepared by the method of any one of claims 1-4 in the preparation of a drug for the triple impact interactive comprehensive treatment of tumors like Fenton catalytic oxidation effect, ion interference therapy and chemotherapy.
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