GB2615705A - Use of artemisinin and derivative thereof in preparation of sensitizer for thermodynamic therapy - Google Patents
Use of artemisinin and derivative thereof in preparation of sensitizer for thermodynamic therapy Download PDFInfo
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- GB2615705A GB2615705A GB2307236.6A GB202307236A GB2615705A GB 2615705 A GB2615705 A GB 2615705A GB 202307236 A GB202307236 A GB 202307236A GB 2615705 A GB2615705 A GB 2615705A
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- United Kingdom
- Prior art keywords
- icg
- artemisinin
- artesunate
- liposome
- derivative
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- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 title claims abstract description 40
- 229960004191 artemisinin Drugs 0.000 title claims abstract description 29
- 229930101531 artemisinin Natural products 0.000 title claims abstract description 29
- 238000002560 therapeutic procedure Methods 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims description 18
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 claims abstract description 69
- 229960004657 indocyanine green Drugs 0.000 claims abstract description 67
- 239000002502 liposome Substances 0.000 claims abstract description 48
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 41
- 229960004991 artesunate Drugs 0.000 claims description 56
- FIHJKUPKCHIPAT-AHIGJZGOSA-N artesunate Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@@H](OC(=O)CCC(O)=O)[C@@H]4C FIHJKUPKCHIPAT-AHIGJZGOSA-N 0.000 claims description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- WLNARFZDISHUGS-MIXBDBMTSA-N cholesteryl hemisuccinate Chemical compound C1C=C2C[C@@H](OC(=O)CCC(O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 WLNARFZDISHUGS-MIXBDBMTSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 7
- 238000000502 dialysis Methods 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 6
- 229960002521 artenimol Drugs 0.000 claims description 4
- BJDCWCLMFKKGEE-ISOSDAIHSA-N artenimol Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-ISOSDAIHSA-N 0.000 claims description 4
- 229930016266 dihydroartemisinin Natural products 0.000 claims description 4
- SXYIRMFQILZOAM-HVNFFKDJSA-N dihydroartemisinin methyl ether Chemical compound C1C[C@H]2[C@H](C)CC[C@H]3[C@@H](C)[C@@H](OC)O[C@H]4[C@]32OO[C@@]1(C)O4 SXYIRMFQILZOAM-HVNFFKDJSA-N 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 4
- 238000002390 rotary evaporation Methods 0.000 claims description 4
- 238000009210 therapy by ultrasound Methods 0.000 claims description 4
- 229960000981 artemether Drugs 0.000 claims description 3
- 230000036571 hydration Effects 0.000 claims description 3
- 238000006703 hydration reaction Methods 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- IPSYLHZJPVDMHR-LDLOPFEMSA-N [(2r)-3-[ethoxy(hydroxy)phosphoryl]oxy-2-octadecanoyloxypropyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC)OC(=O)CCCCCCCCCCCCCCCCC IPSYLHZJPVDMHR-LDLOPFEMSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000007626 photothermal therapy Methods 0.000 abstract description 13
- 230000000259 anti-tumor effect Effects 0.000 abstract description 5
- 239000012221 photothermal agent Substances 0.000 abstract description 4
- 230000002195 synergetic effect Effects 0.000 abstract description 3
- 239000002114 nanocomposite Substances 0.000 abstract 2
- 239000003814 drug Substances 0.000 description 25
- 229940079593 drug Drugs 0.000 description 24
- 239000003642 reactive oxygen metabolite Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 238000002428 photodynamic therapy Methods 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 7
- XDFNWJDGWJVGGN-UHFFFAOYSA-N 2-(2,7-dichloro-3,6-dihydroxy-9h-xanthen-9-yl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1C2=CC(Cl)=C(O)C=C2OC2=CC(O)=C(Cl)C=C21 XDFNWJDGWJVGGN-UHFFFAOYSA-N 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010021143 Hypoxia Diseases 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- -1 artemisinin peroxide Chemical class 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000001146 hypoxic effect Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000002086 nanomaterial Substances 0.000 description 3
- 238000011275 oncology therapy Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003430 antimalarial agent Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 2
- 125000002133 (4-hydroxy-3-iodo-5-nitrophenyl)acetyl group Chemical group OC1=C(C=C(C=C1I)CC(=O)*)[N+](=O)[O-] 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical class N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- PXEZTIWVRVSYOK-UHFFFAOYSA-N 2-(3,6-diacetyloxy-2,7-dichloro-9h-xanthen-9-yl)benzoic acid Chemical compound C1=2C=C(Cl)C(OC(=O)C)=CC=2OC2=CC(OC(C)=O)=C(Cl)C=C2C1C1=CC=CC=C1C(O)=O PXEZTIWVRVSYOK-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- HATRDXDCPOXQJX-UHFFFAOYSA-N Thapsigargin Natural products CCCCCCCC(=O)OC1C(OC(O)C(=C/C)C)C(=C2C3OC(=O)C(C)(O)C3(O)C(CC(C)(OC(=O)C)C12)OC(=O)CCC)C HATRDXDCPOXQJX-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000001994 activation Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000000385 dialysis solution Substances 0.000 description 1
- BJDCWCLMFKKGEE-HVDUHBCDSA-N dihydroartemisinin group Chemical group C[C@@]12OO[C@]34[C@@H](CC1)[C@@H](CC[C@H]3[C@H](C(O[C@@H]4O2)O)C)C BJDCWCLMFKKGEE-HVDUHBCDSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001663 electronic absorption spectrum Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 238000003333 near-infrared imaging Methods 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 238000006552 photochemical reaction Methods 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 229930009674 sesquiterpene lactone Natural products 0.000 description 1
- 150000002107 sesquiterpene lactone derivatives Chemical class 0.000 description 1
- 238000009958 sewing Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000007725 thermal activation Methods 0.000 description 1
- 238000001931 thermography Methods 0.000 description 1
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 1
- NVLRFXKSQQPKAD-UHFFFAOYSA-N tricarbon Chemical compound [C]=C=[C] NVLRFXKSQQPKAD-UHFFFAOYSA-N 0.000 description 1
- 230000001875 tumorinhibitory effect Effects 0.000 description 1
Classifications
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- 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
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
- A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
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- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- 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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- General Chemical & Material Sciences (AREA)
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Abstract
A new use of artemisinin and a derivative thereof. The artemisinin or the derivative thereof is directly used as a sensitizer for thermodynamic therapy, and is used for thermodynamic therapy of tumors; or a liposome nanocomposite prepared from the artemisinin or the derivative thereof, and indocyanine green is used as a sensitizer for thermodynamic therapy or a photothermal agent for photothermal therapy, and is used for thermodynamic therapy and/or photothermal therapy of tumors. The artemisinin or the derivative thereof and the liposome nanocomposite show an excellent tumor-targeting capability and anti-tumor activity of synergistic photothermal therapy and thermodynamic therapy.
Description
USE OF ARTEMISININ AND DERIVATIVE THEREOF IN PREPARATION OF
SENSITIZER FOR THERMODYNAMIC THERAPY
CROSS REFERENCE TO RELATED APPLICATION
[0001] The present application claims priority to the Chinese Patent Application No. CN202011111545.1 filed to the China National Intellectual Property Administration (CNIPA) on Friday, October 16, 2020 and entitled "USE OF ARTEMISININ AND DERIVATIVE THEREOF IN PREPARATION OF SENSITIZER FOR THERMODYNAMIC THERAPY", which is incorporated herein by reference in its entirety.
TECHNICAL FIELD
[0002] The present disclosure belongs to the field of functional materials and medicines, and specifically relates to use of an artemisinin derivative and a liposome nanomaterial prepared by the artemisinin derivative with indocyanine green (ICG) in preparation of a sensitizer for thermodynamic therapy (TDT) of a tumor.
BACKGROUND
[0003] Photodynamic therapy (PDT) is adopted to treat cancers. In the PDT, photosensitizers are excited with light, and photochemical reactions occur in the presence of oxygen to generate reactive oxygen species (ROS), which induces the damage on cancer cells and cancer tissues. PDT has been widely used due to its minimal invasiveness and non-drug resistance. However, the PDT has a limited therapeutic effect on hypoxic tumors. Recently, a new approach, thermodynamic therapy (TDT), emerged. The TDT activates sensitizers using heat as an energy source, and then generates ROS or other free radicals for cancer treatment. Compared with PDT, the TDT can provide heat through more ways, such as chemical reactions, light, ultrasonic, radiation, and microwave. Accordingly, TDT is a novel and promising approach for cancer therapy. Furthermore, in TDT, active species can be obtained directly from a thermodynamic sensitizer after heating without oxygen dependence. Therefore, the TDT can overcome a limited efficacy of the PDT on hypoxic tumors. However, there are still rare TDT-related reports. A small number of thermally-unstable azobisisobutyronitrile derivatives can be decomposed upon thermal activation, and lead to the generation of free radicals, thus sewing as chemothennosensitizers for cancer therapy.
[0004] lndocyanine green (ICG) is currently the only near-infrared imaging reagent approved by the Food and Drug Administration (FDA) for clinical use. The ICG, as a tri-carbon cyanine dye, has a maximum emission wavelength of 795 nm to 845 nm, and is a drug molecule with an amphiphilic structure. ICG is capable of absorbing and converting light energy into heat or generating singlet oxygen, which is used in photothermal therapy (PTT) or PDT. However, ICG is easily decomposed in a light environment, bringing difficulties to the preservation and subsequent application of drugs. Moreover, the ICG exhibits instability in an aqueous solution, and has a relatively-high clearance rate (with a half-life of 2 min to 4 min) in biological tissues, such as plasma. This limits the application of ICG in diagnosis and treatment. Nano-scale modification can effectively enhance the photostability and thermal stability of ICG, and can also effectively improve the water stability of ICG.
[0005] Artemisinin, a sesquiterpene lactone containing an endoperoxide bridge, is a well-known antimalarial drug. As an antimalarial drug, the artemisinin has shown high safety. Due to unique structures, the artemisinin and derivatives thereof have various other functions besides the antimalarial properties. It was recently reported that the peroxide bridge of an artemisinin peroxide can be activated by Fe2+ ions to generate reactive free radicals for cancer therapy. Unlike the ROS produced during PDT, ROS produced by the artemisinin does not depend on an oxygen content of the surrounding environment. This is particularly advantageous for the treatment of hypoxic tumor tissues. It is well known that blood has a relatively high storage of Fe2+ ions due to the presence of hemoglobin. However, the Fe2-ions do not show a specific distribution in tumor tissues, and can hardly activate the artemisinin due to an extremely-low content level in the tumor tissues. This limits the development of artemisinin in clinical use. At present, there is no report on use of artemisinin thermosensitivity in generating active substances for tumor therapy. It has also not been reported that artesunate and ICG are entrapped in liposomes to prepare a nanomaterial for the PTT and TDT of tumors.
SUMMARY
[0006] An objective of the present disclosure is to provide use of artemisinin and a derivative thereof in preparation of a sensitizer for TDT of a tumor. In the present disclosure, the artemisinin and the derivative thereof have an extremely high anti-tumor activity synergistically with PTT and TDT, and show an excellent tumor-targeting ability. Therefore, the artemisinin and the derivative thereof have significant advantages as anticancer drugs.
[0007] To achieve the above objective, the present disclosure adopts the following technical solutions: [0008] The present disclosure provides use of artemisinin and a derivative thereof in preparation of a sensitizer for TDT of a tumor, where since the artemisinin and the derivative thereof are thermosensitive and can generate ROS under a thermal effect, the artemisinin or the derivative thereof is directly used as the sensitizer for the TDT of the tumor; alternatively, a liposome nanocomplex prepared by the artemisinin or the derivative thereof with ICG is used as the sensitizer for the TDT or a photothermal agent for PTT in the TDT and/or the PTT of the tumor; [0009] the artemisinin derivative is any one selected from the group consisting of artemether, dihydroartemisinin, and artesunate; and [0010] a thermal effect is implemented by raising a temperature to not less than 48°C by a direct or indirect heating technique, and the heating technique includes heating, laser, ultrasonic, or microwave.
[0011] Specifically, when the artesunate is used as the artemisinin derivative, the artesunate and the ICG are encapsulated into a lipoid bilayer to form a liposome nanocomplex of microvesicles, and a preparation method of the liposome nanocomplex includes the following steps: [0012] 1) adding dipalmitoylphosphati dyl choline (DEW), 1,2-di stearoyl -sn-glycero-3-ph osph °ethanol am i ne-N -[m ethoxy(polyethyl en e glycol)-2000] (DSPE-PEG 2000), cholesteryl hemisuccinate (CHEMS), artesunate, and ICG in a molar ratio of 12:1.5:9:3:13 to a mixed solvent of chloroform and methanol at a volume ratio of 1:1, completely dissolving, and then conducting an ultrasonic treatment for 1 min to 5 min; [0013] 2) subjecting an obtained solution to rotary evaporation to dryness, and conducting hydration with redistilled water (DI) to form a liposome suspension; and [0014] 3) crushing the liposome suspension with an ultrasonic cell disruptor at 0°C to 20°C for 5 min to 10 min, and then conducting dialysis with redistilled water using a filter membrane with a molecular weight cut-off (MWCO) of 10,000 at 4°C to 25°C for 12 h to 48 h to remove free ICG and artesunate to obtain the liposome nanocomplex having an average particle size of 100 nm to 200 nm.
[0015] In the present disclosure, the liposome nanocomplex of ICG-artesunate is used as a sensitizer or a photothermal agent in antitumor therapy, and adopts laser with a wavelength of 808 nm and an intensity of 0.3 W * cm-2 to 0.8 W * cm-2.
[0016] Beneficial effects and outstanding advantages of the present disclosure are as follows: [0017] (I) Artemisinin derivatives are main drugs for the clinical treatment of malaria, with high safety. The human safety and pharmacokinetic properties have been extensively evaluated. The present disclosure provides new use of the artemisinin derivative as a sensitizer or a photothermal agent (where artesunate has a significant thermosensitive activity). The artemisinin derivative is a relatively safe drug for clinical use, which is more conducive to the clinical use and promotion.
[0018] (2) ICG is a reagent approved by the FDA for clinical use, with high safety, strong PDT and PTT effects. The present disclosure further provides a liposome nanocomplex prepared by the artemisinin derivative and the ICG. The liposome nanocomplex directly provides an lit-situ heat source for artesunate by a photothermal effect of the ICG, without requiring an external heat source, which has an ingenious overall design.
[0019] (3) In the present disclosure, when the liposome nanocomplex of ICG-artesunate is irradiated by 808-nm laser, the ICG can produce a desirable photothermal effect, while the artesunate can produce significant ROS. Therefore, the nanomaterial has excellent photothermal and thermodynamic effects, can be used as a new type of antitumor drug for the TDT and PTT, and shows desirable biocompatibility and higher human safety. Moreover, since liposomes have excellent biocompatibility (degradability, non-toxicity, and non-immunogenicity), there are liposome preparations of various drugs that are marketed at home and abroad so far.
[0020] (4) In the present disclosure, the liposome nanocomplex of ICG-artesunate has an excellent tumor-targeting ability. After intravenous administration to the tumors of tumor-bearing mice, obvious fluorescent signals and photoacoustic signals are observed only in tumor parts of the mice. Therefore, this liposome nanocomplex can also be used for multimodal diagnosis of tumors.
[0021] (5) In the present disclosure, the liposome nanocomplex of ICG-artesunate has an excellent synergistic anti-tumor effect of the PTT and TDT. On day 10 of treatment, the tumors basically disappeared, showing a tumor inhibition rate reaching 100%. Moreover, no recurrence occurred until day 14. This shows that the liposome nanocomplex has an excellent antitumor efficacy and is a highly promising antitumor drug.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 shows a fluorescence spectrum of 2',7-dichlorodihydrofluorescein (DCFH) in mixed solutions of artesunate (ARS) and ICG with different ratios (where ICG is fixed at 100 [TM) under 808-nm laser (at an intensity of 0.3 W* cm-2 for 10 min); [0023] FIG. 2 shows a comparison of cytotoxicity on human liver cancer cells HepG2 treated with different nanomedicines under laser irradiation (where 1CG@NP5 and 1CG-ARS@NP5 are based on a content of the TCG as an indicator; while ARSONPs is based on a content of the ARS as an indicator); arid [0024] FIG. 3 shows a comparison of tumor growth curves of tumor-bearing H22 mice subjected to different treatments within 14 d.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0025] To make the content of the present disclosure easier to understand, the technical solutions of the present disclosure will be further described below in conjunction with specific examples. However, it should be noted that the present disclosure is not limited to these
examples.
[0026] In the examples, ICG, artemisinin derivatives, and raw materials for preparing liposomes are all commercially available.
[0027] Example 1 Use of artemisinin derivatives as a TDT sensitizer [0028] A hydrolysis product 2',7'-di chl orodihydrofluorescein (DCFH) of 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) was used as a probe for ROS. The probe had an excitation wavelength of 488 nm and an emission detection wavelength of 500 nm to 600 nm. A preparation method of a DCFH-DA hydrolyzed aqueous solution was conducted with reference to existing papers (".1. 1771171111701. Methods" 1993, 159 (1-2), 131-138). By observing the fluorescence of DCFH (at about 524 nm) in a solution containing a sample to be tested with a laser irradiation time, an ability of the sample to generate ROS by thermosensitivity was determined. A higher fluorescence intensity produced by DCFH meant a stronger ability of ROS generated by thermosensitivity.
[0029] The artesunate (ARS) was taken as an example for determination. An appropriate amount of the artesunate was dissolved in DMF to obtain a 2 mM stock solution. In the test, 100 p.L. of the 2',7'-dichlorodihydrofluorescein and 100 (LL of the artesunate were added to 1.8 mL of redistilled water to obtain a mixed solution (where a final concentration of the artesunate was 100 (tM, and a final concentration of the 2',7'-dichlorodihydrofluorescein was 10 uM). The mixed solution was heated in a water bath at 60°C for 30 min. During this period, the mixed solution was taken out every 5 min, and its fluorescence intensity at 500 nm to 600 nm was tested. According to the fluorescence intensity, the ability of the artesunate to generate ROS under heat was explored to determine its thermal sensitization performance.
[0030] By a same method, the ROS generation of dihydroartemisinin, artemether, and artemisinin was measured separately.
[0031] Through the analysis results, it was found that: compared with the fluorescence intensity of a control group with simple probes, the fluorescence intensity of an artesunate group was 6.475 times that of the control group; the fluorescence intensity of an dihydroartemisinin group was 2.813 times that of the control group; the fluorescence intensity of an artemether group was 0.773 times that of the control group; and the fluorescence intensity of an artemisinin group was 1.164 times that of the control group. From the above results, it was found that the artesunate and dihydroartemisinin had obvious thennosensitization effects, and could be used in the preparation and research of thennosensitizer nano-drugs.
[0032] Example 2
[0033] Through research literature and experiments, it was found that when the concentration of ICG reached 100 gM, the temperature of an ICG aqueous solution could be raised to 50°C, which met the requirements of artesunate to generate ROS by heating. By exploring a ratio of artesunate and ICG, it was found that the ratio of artesunate and ICG might show different properties within a certain range. As shown in FIG. 1, the artesunate and ICG with a molar ratio of 1:1 and the artesunate and ICG with a molar ratio of 2:1 both had the strongest ability to generate ROS with a comparable intensity. Therefore, the ICG was selected as a heat source for laser irradiation of drugs, and a molar ratio of the artesunate and ICG at 1:1 was regarded as an optimal drug ratio.
100341 Example 3 Liposome nano-drug entrapped with ICG and artesunate 100351 DPPC, DSPE-PEG 2000, CHEMS, artesunate, and ICG were weighed at a molar ratio of 12:1.5:9:3:13, and dissolved in a mixed solvent of chloroform (10 mL) and methanol (10 mL), and then subjected to ultrasonic treatment for 5 min. An obtained solution was subjected to rotary evaporation to dryness, and wall removal was conducted with redistilled water (DI) to form a liposome suspension. The liposome suspension was crushed with an ultrasonic cell disruptor at 10°C for 10 min, and then dialysis was conducted with redistilled water using a filter membrane with an MWCO of 10,000 at 25°C for 48 h to remove free ICG and artesunate to obtain the liposome nanocomplex ICG-ARS@NPs, where the artesunate and the ICG in the nanocomplex were at a molar ratio of 1:1 [0036] Electron microscope analysis showed that the liposome nanocomplex was relatively-uniform spherical or near-spherical vesicles with a particle size of about 150 nm. The nanoparticle size analyzer also showed that the liposome nanocomplex of ICG and artesunate had a particle size of about 90 nm to 160 nm. The encapsulation efficiency of ICG and artesunate in the liposome nanocomplex was separately analyzed by HPLC, showing that the ICG and artesunate had encapsulation efficiencies of 81.4% and 69.0%, respectively.
100371 Comparative Example 1 Liposome nano-drug entrapped with ICG [0038] A liposome nano-drug ICG@NPs (with a particle size of about 90 nm to 160 nm) with only ICG added was prepared according to the method in Example 3.
[0039] Comparative Example 2 Liposome nano-drug entrapped with artesunate 100401 A liposome nano-drug ARS@NPs (with a particle size of about 90 nm to 160 nm) with only artesunate added was prepared according to the method in Example 3.
[0041] Example 4
100421 The ICG-ARS@NPs of Example 3 was placed in a dialysis bag (Mw=10,000), and stirred at 120 rpm in PBS solutions (pH=6.5 and pH=7.4) separately in a shaker incubator at a room temperature. Dialysates were withdrawn at different time points (0 h, 6 h, 12 h, 24 h, 48 h, and 72 h) for UV-Vis spectroscopy measurements. A released ICG concentration was calculated by comparing the absorbance at 780 nm with a calibration curve. The drug release was calculated using the following formula: 100431 Drug release (%) = released ICG/total ICG in nano-dmg.
[0044] The pH-sensitive efficiency of the ICG-ARS@NPs was evaluated in the PBS solutions with different pH values by detecting a release percentage of ICG using UV-Vis spectroscopy. The results showed that in the PBS solution with a pH value of 6.5, the ICG was rapidly released within 24 h and reached a steady level at 48 h, showing a release percentage of about 80%. However, in the PBS solution at a pH value of 7.4, the ICG was only released in a small amount of about 20% within 48 h.
100451 Example 5
[0046] In the present disclosure, the liposome nanocomplex of artesunate and ICG could effectively produce a thermal effect under laser irradiation. In an aqueous solution, the 808-nm laser was irradiated for 10 min (with a laser intensity of 0.3 W.cm-2 to 0.8 W.cm-2), and the solution could reach 50°C.
[0047] The thermal effect of laser could induce the artesunate to produce ROS. The liposome nanocomplex of artesunate and ICG was irradiated with laser at a laser wavelength of 808 nm and a laser intensity of 0.3 W.cm-2. An electronic absorption spectrum of the sample was measured every 1 min of laser irradiation at a scanning range of 500 nm to 600 nm. The experimental results showed that the liposome nanocomplex of artesunate and ICG could effectively generate fluorescence under laser activation.
100481 Example 6
[0049] The nanocomplex ICG-ARS @NPs of Example 3, the liposome nano-drug ICG@NPs of Comparative Example 1, and the liposome nano-drug ARS@NPs of Comparative Example 2 were diluted with water, or normal saline, or PBS solution to obtain I mM solutions, respectively. The three solutions were mixed, and a resulting mixed solution was diluted with a medium to obtain a 100 MVI drug-containing medium. In a 96-well plate, the drug administration was conducted when a spreading area of the growing cells accounted for not less than 75% of a culture medium area. The old medium was removed by aspiration, 60 pL, 50 pL, 40 [IL, and 30 pi, of the drug-containing medium were added to each well, and the medium was supplemented to a final volume of 100 pL per well, and a blank control group was set up (no drug + laser and no drug + no laser), each group was cultured for 2 h. The 96-well plate was placed under 808-nm laser (at 0.3W.cm-2), and each well was illuminated for 5 min. After exposure to laser, the medicine was removed by aspiration and then replaced with a fresh medium. After culturing for 24 h, 10 pL of 5 g/L MTT was added to each well, and the culture was continued for another 4 h. The medium in the plate was poured, 150 j.LL of a DMSO solution was added to each well, and shaken for 10 min to fully dissolve the crystals. An absorbance (A) value of each well was measured with a microplate reader (at a wavelength of 492 nm), and an average A value of n wells in each group was taken as an average A value of each group. An inhibition rate was calculated according to the following formula: [0050] Inhibition rate (%) = (1-experimental group A/control group A)x 100%.
[0051] The experimental results were shown in FIG. 2. The experimental results showed that the laser irradiation alone or the nano-drug alone both had no obvious killing effect on cancer cells. However, under the action of laser, when the liposome nanocomplex ICG-ARS@NPs had the ICG at a concentration of 40 RM, the nanocomplex had an inhibition rate on the cancer cells of 75%. This indicated that the nanocomplex had a significant thermodynamic anticancer effect. [0052] Example 7 [0053] H22 tumor-bearing ICR mice were randomly divided into 7 groups: (I) blank (normal saline), (II) laser alone, (III) ARS@NPs+laser, (IV) ICG-ARS@NPs, (V) free ICG+laser, (VI) ICG@NPs+laser, and (VII) ICG-ARS@NPs+laser. The mice were injected with normal saline intravenously, where the free ICG, the ICG@NPs, the ICG-ARS@NPs, and the ARS@NPs had a dose of 10 mg-kg-1 of ICG or 7.5 mg*kg+ of ARS. 8 h after the injection, the tumors were exposed to 808 nm laser (0.8 W.cm-2) for 10 min. During the irradiation, infrared thermal images were recorded by an infrared thermal imaging camera (TiX520, Fluke, USA). The body weight and tumor volume of the mice were measured every 2 d for a total of 14 d.
[0054] As shown in FIG. 3, after laser irradiation, the tumor growth of ICGO,NIPs-treated mice was partially arrested, and a tumor inhibition rate was 75%. This was mainly due to the photothermal effect. However, irradiated ARS@NPs had almost no tumor inhibitory effect, and the tumor growth rate was as high as that of the blank group (saline or laser only). However, after laser irradiation, the tumors in the ICG-ARS@NPs group gradually shrunk on a 10th day, and finally disappeared, and did not continue to grow until a 14th day. This demonstrated that ICG-ARS@NPs had a highly effective synergistic effect of the PTT and TDT.
100551 The above description of embodiments is merely provided to help understand the method of the present disclosure and a core idea thereof It should be noted that several improvements and modifications may be made by those of ordinary skill in the art without departing from the principle of the present disclosure, and these improvements and modifications should also fall within the protection scope of the present disclosure. Various amendments to these embodiments are apparent to those of professional skill in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present disclosure. Thus, the present disclosure is not limited to the examples shown herein but falls within the widest scope consistent with the principles and novel features disclosed herein.
Claims (8)
- WHAT IS CLAIMED IS: I. Use of artemisinin and a derivative thereof in preparation of a sensitizer for thermodynamic therapy (TDT) of a tumor, wherein the artemisinin or the derivative thereof is directly used as the sensitizer for the TDT of the tumor; alternatively, a liposome nanocomplex prepared by the artemisinin or the derivative thereof with indocyanine green (ICG) is used as the sensitizer for the TDT or a photothennal agent for photothennal therapy (PTT) in the TDT and/or the PTT of the tumor; the artemisinin derivative is any one selected from the group consisting of artemether, dihydroartemisinin, and artesunate; and a thermal effect is implemented by raising a temperature to not less than 48°C by a direct or indirect heating technique, and the heating technique comprises heating, laser, ultrasonic, and microwave.
- 2. The use of artemisinin and a derivative thereof in preparation of a sensitizer for TDT of a tumor according to claim 1, wherein a preparation method of the liposome nanocompl ex with the artesunate and the ICG as raw materials comprises the following steps: 1) adding dipalmitoylphosphatidylcholine (DPPC), 1,2-di stearoyl-sn-glycero-3-phosphoethanol am i ne-N-[m ethoxy(polyethyl en e glycol)-2000] (DSPE-PEG 2000), cholesteryl hemisuccinate (CHEMS), the artesunate, and the ICG in a proportion to a mixed solvent of chloroform and methanol, completely dissolving, and then conducting an ultrasonic treatment for 1 min to 5 min; 2) subjecting an obtained solution to rotary evaporation to dryness, and conducting hydration with redistilled water to form a liposome suspension; and 3) crushing the liposome suspension with an ultrasonic cell disruptor at 0°C to 20°C for 5 min to 10 mm, and then conducting dialysis with redistilled water at 4°C to 25°C for 12 h to 48 h to remove free ICG and artesunate to obtain the liposome nanocompl ex.
- 3. The use of artemisinin and a derivative thereof in preparation of a sensitizer for TDT of a tumor according to claim 1, wherein in step 1), the DPPC, the DSPE-PEG 2000, the CHEMS, the artesunate, and the ICG are at a molar ratio of 12:1.5:9:3:13; and in the mixed solvent of chloroform and methanol, the chloroform and the methanol are at a volume ratio of 11,
- 4. The use of artemisinin and a derivative thereof in preparation of a sensitizer for TDT of a tumor according to claim 1, wherein in step 3), the dialysis is conducted using a filter membrane with a molecular weight cut-off (MWCO) of 10,000.
- 5. A liposome nanocompl ex prepared by artesunic amber and ICG.
- 6. A preparation method of the liposome nanocomplex according to claim 5, comprising the following steps: 1) adding DPPC, DSPE-PEG 2000, CHEMS, artesunate, and ICG in a proportion to a mixed solvent of chloroform and methanol, completely dissolving, and then conducting an ultrasonic treatment for 1 min to 5 min; 2) subjecting an obtained solution to rotary evaporation to dryness, and conducting hydration with redistilled water to form a liposome suspension; and 3) crushing the liposome suspension with an ultrasonic cell disruptor at 0°C to 20°C for 5 min to 10 mm, and then conducting dialysis with redistilled water at 4°C to 25°C for 12 h to 48 h to remove free ICG and artesunate to obtain the liposome nanocomplex.
- 7. The preparation method according to claim 6, wherein in step 1), the DPPC, the DSPE-PEG 2000, the CHEMS, the artesunate, and the ICG are at a molar ratio of 12:1.5:9:3:13; and in the mixed solvent of chloroform and methanol, the chloroform and the methanol are at a volume ratio of 1:1.
- 8. The preparation method according to claim 6, wherein in step 3), the dialysis is conducted using a filter membrane with an MWCO of 10,000.
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