CN115197229B - Terpenoid assembled organic single-molecule photo-thermal reagent with triple response of chemotherapy, photo-thermal and photodynamic, preparation and application thereof - Google Patents
Terpenoid assembled organic single-molecule photo-thermal reagent with triple response of chemotherapy, photo-thermal and photodynamic, preparation and application thereof Download PDFInfo
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- CN115197229B CN115197229B CN202210877217.5A CN202210877217A CN115197229B CN 115197229 B CN115197229 B CN 115197229B CN 202210877217 A CN202210877217 A CN 202210877217A CN 115197229 B CN115197229 B CN 115197229B
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- photo
- thermal
- reagent
- terpenoid
- chemotherapy
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- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 40
- 238000002512 chemotherapy Methods 0.000 title claims abstract description 33
- 150000003505 terpenes Chemical class 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 230000004044 response Effects 0.000 title claims abstract description 18
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 10
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 9
- 239000000463 material Substances 0.000 claims abstract description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 24
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 20
- 239000005457 ice water Substances 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 14
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 238000001338 self-assembly Methods 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 9
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 claims description 8
- YCLSOMLVSHPPFV-UHFFFAOYSA-N 3-(2-carboxyethyldisulfanyl)propanoic acid Chemical compound OC(=O)CCSSCCC(O)=O YCLSOMLVSHPPFV-UHFFFAOYSA-N 0.000 claims description 8
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 claims description 8
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 claims description 6
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 claims description 6
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 claims description 6
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 claims description 6
- 150000003648 triterpenes Chemical class 0.000 claims description 6
- 239000012154 double-distilled water Substances 0.000 claims description 5
- 238000009210 therapy by ultrasound Methods 0.000 claims description 5
- 239000012452 mother liquor Substances 0.000 claims description 4
- 239000012221 photothermal agent Substances 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 2
- 229940034982 antineoplastic agent Drugs 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 21
- 239000007822 coupling agent Substances 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 7
- 239000003504 photosensitizing agent Substances 0.000 abstract description 7
- OYINILBBZAQBEV-UWJYYQICSA-N (17s,18s)-18-(2-carboxyethyl)-20-(carboxymethyl)-12-ethenyl-7-ethyl-3,8,13,17-tetramethyl-17,18,22,23-tetrahydroporphyrin-2-carboxylic acid Chemical compound N1C2=C(C)C(C=C)=C1C=C(N1)C(C)=C(CC)C1=CC(C(C)=C1C(O)=O)=NC1=C(CC(O)=O)C([C@@H](CCC(O)=O)[C@@H]1C)=NC1=C2 OYINILBBZAQBEV-UWJYYQICSA-N 0.000 abstract description 5
- 150000003384 small molecules Chemical class 0.000 abstract description 5
- 235000007586 terpenes Nutrition 0.000 abstract description 5
- 230000008878 coupling Effects 0.000 abstract description 4
- 238000010168 coupling process Methods 0.000 abstract description 4
- 238000005859 coupling reaction Methods 0.000 abstract description 4
- 239000002243 precursor Substances 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- 206010028980 Neoplasm Diseases 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000002428 photodynamic therapy Methods 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000003480 eluent Substances 0.000 description 8
- KYNFOMQIXZUKRK-UHFFFAOYSA-N 2,2'-dithiodiethanol Chemical compound OCCSSCCO KYNFOMQIXZUKRK-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000006185 dispersion Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- DYNISIGUMYFVJW-UHFFFAOYSA-N 12α-12-hydroxy-7,13-abietadien-18-oic acid Chemical compound C12CC(O)C(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O DYNISIGUMYFVJW-UHFFFAOYSA-N 0.000 description 4
- BTXXTMOWISPQSJ-UHFFFAOYSA-N 4,4,4-trifluorobutan-2-one Chemical compound CC(=O)CC(F)(F)F BTXXTMOWISPQSJ-UHFFFAOYSA-N 0.000 description 4
- BQACOLQNOUYJCE-FYZZASKESA-N Abietic acid Natural products CC(C)C1=CC2=CC[C@]3(C)[C@](C)(CCC[C@@]3(C)C(=O)O)[C@H]2CC1 BQACOLQNOUYJCE-FYZZASKESA-N 0.000 description 4
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229940076810 beta sitosterol Drugs 0.000 description 2
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 229930004069 diterpene Natural products 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 2
- 229950005143 sitosterol Drugs 0.000 description 2
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 2
- 229940032091 stigmasterol Drugs 0.000 description 2
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 2
- 235000016831 stigmasterol Nutrition 0.000 description 2
- 238000007669 thermal treatment Methods 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- ILQLITDRYFHAGM-NSISKUIASA-N (1r,4as,10ar)-7-(2-hydroxypropan-2-yl)-1,4a-dimethyl-2,3,4,9,10,10a-hexahydrophenanthrene-1-carboxylic acid Chemical compound OC(=O)[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)(O)C)C=C3CC[C@H]21 ILQLITDRYFHAGM-NSISKUIASA-N 0.000 description 1
- MPDGHEJMBKOTSU-WFJWTYAKSA-N (2s,4as,6as,6br,10s,12as)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid Chemical compound C12C(=O)C=C3C4C[C@@](C)(C(O)=O)CC[C@]4(C)CC[C@@]3(C)[C@]1(C)CCC1[C@]2(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-WFJWTYAKSA-N 0.000 description 1
- ILQLITDRYFHAGM-UHFFFAOYSA-N 15-hydroxydehydroabietic acid Natural products OC(=O)C1(C)CCCC2(C)C3=CC=C(C(C)(O)C)C=C3CCC21 ILQLITDRYFHAGM-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-UHFFFAOYSA-N 0.000 description 1
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-UHFFFAOYSA-N 0.000 description 1
- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- QGJZLNKBHJESQX-FZFNOLFKSA-N betulinic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000004141 diterpene derivatives Chemical class 0.000 description 1
- 125000000567 diterpene group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002114 nanocomposite Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000002165 photosensitisation Effects 0.000 description 1
- 238000007626 photothermal therapy Methods 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000001878 scanning electron micrograph Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A terpenoid assembled organic single-molecule photothermal reagent with triple response of chemotherapy, photo-thermal and photodynamic, and its preparation and application are provided. The invention belongs to the field of biological medicine materials and preparation thereof. The invention aims to solve the technical problems that the existing photosensitizer cannot synchronously realize triple effects of chemotherapy, photo-thermal and photodynamic and cannot achieve both high PTT activity and PDT activity. The photothermal reagent is formed by covalent coupling of terpenoid Natural Small Molecules (NSMs) and chlorin e6 (Ce 6) through a coupling agent containing disulfide bonds. Through covalent coupling of disulfide bonds with NSMs and Ce6 molecules, different connecting arms are selected according to the terpene micromolecule active sites, so that a single-molecule photothermal reagent precursor NSMs-SS-Ce6 is constructed, and finally, the nano system of the photothermal reagent precursor has high-efficiency PTT activity, chemotherapy and PDT activity. The terpenoid assembled organic single-molecule photo-thermal reagent is used for preparing anti-tumor drugs.
Description
Technical Field
The invention belongs to the field of biomedical materials and preparation thereof, and particularly relates to a terpenoid assembled organic single-molecule photo-thermal reagent with triple response of chemotherapy, photo-thermal and photodynamic, and preparation and application thereof.
Background
Based on challenges and demands faced by clinical transformation of nano-drugs, currently, synchronous realization of multiple therapeutic effects by a single-molecule multifunctional nano-system is gradually becoming a research hotspot and trend in the anticancer field. Among them, photo-thermal treatment (PTT) and photodynamic treatment (PDT) show good application prospects in clinical cancer treatment due to their low toxicity, high efficiency, non-invasiveness and other characteristics. Organic photothermal molecules present potential advantages in the field of photothermal therapy due to their unique biodegradability compared to numerous photothermal agents. In particular, it has been found that organic small molecule self-assembled materials developed based on porphyrins or porphins can achieve photo-thermal (PTT) properties. However, such photoactive compounds are commonly used in photodynamic therapy (PDT). It has been found that when photosensitizers self-assemble, fluorescence and active oxygen quenching of the photosensitizing drug occurs due to their specific self-aggregation induced quenching (ACQ) effect, which in turn promotes the occurrence of PTT effects. Porphyrin-like molecules are thus the best wall materials to construct while achieving PDT/PTT. How to induce the photosensitizer to generate ordered self-assembly to realize PTT, and keep the original PDT activity, and the selection of proper functional self-assemblies is very critical.
Disclosure of Invention
The invention aims to solve the technical problems that the existing photosensitizer cannot synchronously realize the triple effect of chemotherapy, photo-heat and photodynamic and cannot achieve both high PTT activity and PDT activity, and provides a terpenoid assembled organic single-molecule photo-thermal reagent with triple response of chemotherapy, photo-heat and photodynamic, and preparation and application thereof.
The invention relates to a terpenoid assembled organic single-molecule photo-thermal reagent with triple response of chemotherapy/photo-thermal/photodynamic, which is formed by covalent coupling of terpenoid Natural Small Molecules (NSMs) and chlorin e6 (Ce 6) through a coupling agent containing disulfide bonds.
Further defined, the NSMs are Tricyclic Diterpenes (TDs), tetracyclic Triterpenes (TTs), or Pentacyclic Triterpenes (PTs).
Further defined, the TD has the formulaWherein R is one of a straight chain or branched alkyl group of not less than one carbon.
Further defined, the structural formula of TD is specifically
Further defined, TT has the structural formula ofWherein R is one of a straight chain or branched alkyl group having 5 or more carbon atoms.
Further defined, the structural formula of TT is specifically
Further defined, PT is of the formulaWherein R is one of a straight chain or branched hydrocarbon group of not less than 0 carbon atoms.
Further defined, the PT is of the formula
Further defined, the disulfide bond-containing coupling agent is 3,3 '-dithiodipropionic acid or 2,2' -dithiodiethanol.
Further defined, the molar ratio of NSMs to disulfide-containing coupling agent is 1: (1.2-2).
Further defined, the molar ratio of NSMs to Ce6 is (1-1.4): 1.
the preparation method of the terpenoid assembled organic single-molecule photo-thermal reagent with triple response of chemotherapy, photo-thermal and photodynamic comprises the following steps:
step 1: dissolving TD and disulfide bond-containing coupling agent in anhydrous CH 2 Cl 2 Adding DCC/DMAP condensing agent, reacting at room temperature, extracting, concentrating, purifying to obtain TD-SS;
step 2: mixing TD-SS with chlorin e6 (Ce 6) in anhydrous CH 2 Cl 2 Stirring and mixing the materials in ice water bath, adding EDCI and DIPEA, reacting at room temperature, extracting, concentrating and purifying to obtain the terpenoid assembled organic single-molecule photo-thermal reagent.
Further defined, the molar amount of TD in step 1 is calculated from the dry CH 2 Cl 2 Is 1mmol: (20-80) mL.
Further defined, the molar ratio DCC/DMAP to TD in step 1 is 1: (1.2-1.5).
Further defined, the reaction time in step 1 is 8-36 hours.
Further defined, the purification in step 1 is performed using a chromatography column eluting with ethyl acetate/petroleum ether (v/v=3/1).
Further defined, the molar ratio of TD-SS to Ce6 in step 2 is (1-1.5): 1.
further defined, the molar amount of TD-SS in step 2 is calculated with anhydrous CH 2 Cl 2 Is 1mmol: (20-80) mL.
Further defined, the molar ratio of EDCI to Ce6 in step 2 is 1.2: the molar ratio of edci to DIPEA is 1: (0.2-1).
And (3) further limiting, namely stirring the mixture in the step (2) under the ice water bath for 20-40min, wherein the reaction time is 8-36h.
Further defined, the purification in step 2 is performed using a chromatography column eluting with methylene chloride/acetone (v/v=1/1).
The preparation method of the terpenoid assembled organic single-molecule photo-thermal reagent with triple response of chemotherapy, photo-thermal and photodynamic comprises the following steps:
step 1: dissolving NSMs and disulfide bond-containing coupling agent in anhydrous CH 2 Cl 2 Adding DCC/DMAP condensing agent, reacting at room temperature, extracting, concentrating and purifying to obtain NSMs-SS; NSMs are TT or PT;
step 2: dissolving NSMs-SS and N-Boc ethylenediamine in anhydrous CH 2 Cl 2 Then EDC/NHS condensing agent is added for reaction at room temperature, then CF is added 3 COOH is reacted in ice water bath to obtainTo NSMs-SS-NH 2 ；
Step 3: NSMs-SS-NH 2 Miscible with chlorin e6 (Ce 6) in anhydrous CH 2 Cl 2 Stirring and mixing the materials in ice water bath, adding EDCI and DIPEA, reacting at room temperature, extracting, concentrating and purifying to obtain the terpenoid assembled organic single-molecule photo-thermal reagent.
Further defined, the molar amount of NSMs in step 1 is relative to anhydrous CH 2 Cl 2 Is 1mmol: (20-80) mL.
Further defined, the molar ratio of DCC/DMAP to NSMs in step 1 is 1: (1.2-1.5).
Further defined, the reaction time in step 1 is 8-36 hours.
Further defined, the purification in step 1 is performed using a chromatography column eluting with ethyl acetate/petroleum ether (v/v=3/1).
Further defined, the molar amount of NSMs-SS in step 2 is relative to anhydrous CH 2 Cl 2 Is 1mmol: (20-80) mL.
Further limited, the molar ratio of the step 2N-Boc ethylenediamine to NSMs-SS is more than or equal to 1.2/1.
Further defined, the molar ratio of EDC/NHS to NSMs-SS in step 2 is 1: (1.2-1.5).
Further defined, NSMs-SS and CF in step 2 3 The molar ratio of COOH is 1: (2-5).
Further limiting, in the step 2, the reaction is carried out for 8-36h at room temperature, and the reaction is carried out for 2-4h in an ice water bath.
Further defined, NSMs-SS-NH in step 3 2 Molar ratio to Ce6 (1-1.5): 1.
further defined, NSMs-SS-NH in step 3 2 Molar mass of (C) and anhydrous CH 2 Cl 2 Is 1mmol: (20-80) mL.
Further defined, the molar ratio of EDCI to Ce6 in step 3 is 1.2: the molar ratio of edci to DIPEA is 1: (0.2-1).
Further limited, stirring is carried out for 20-40min under the ice water bath in the step 3, and the reaction time is 8-36h.
Further defined, the purification in step 3 is performed using a chromatography column eluting with methylene chloride/acetone (v/v=1/1).
The terpenoid assembled organic single-molecule photo-thermal reagent with triple response of chemotherapy, photo-thermal and photodynamic is used for preparing anti-tumor drugs.
Further defined, the preparation process of the antitumor drug comprises the following steps: adding DMSO mother liquor of a photothermal reagent into double distilled water solution of NaOH, and centrifuging after ultrasonic treatment to obtain NSMs-SS-Ce6NPs self-assembly body, namely the antitumor drug.
Compared with the prior art, the invention has the remarkable effects that:
according to the invention, NSMs and Ce6 molecules are covalently coupled through disulfide bonds (SS), different connecting arms are selected according to terpene micromolecule active sites (such as carboxyl and hydroxyl), and a single-molecule photo-thermal reagent NSMs-SS-Ce6 is constructed through dehydration condensation reaction, and can synchronously realize triple anti-tumor effects of chemotherapy/photo-thermal/photodynamic. The preparation method is mainly based on a series of self-assembled terpene natural small molecules, adopts a chemical bridging mode to construct a GSH-responsive chlorin e6 (Ce 6) single-molecule drug, then utilizes the ACQ effect of a photosensitizer Ce6 to promote the self-assembly of synthetic single molecules to generate a PTT effect, and further solves the assembly and play of PDT and chemotherapy functions based on the GSH with tumor microenvironment reducibility, thereby realizing the triple functions of chemotherapy/PDT/PTT.
Drawings
FIG. 1 shows the ET-SS-Ce6 (inD 6-DMSO) prepared in example 1 1 H-NMR；
FIG. 2 is HRMS (ESI) of ET-SS-Ce6 (inD 6-DMSO) prepared in example 1;
FIG. 3 is an SEM image of ET-SS-Ce6NPs prepared in application example 1;
FIG. 4 is a photo-thermal schematic diagram of an aqueous dispersion of ET-SS-Ce6NPs of application example 1 after illumination;
FIG. 5 is a photo-thermal heating curve of an aqueous dispersion of ET-SS-Ce6NPs of application example 1 after illumination;
FIG. 6 is a graph of tumor growth curves for different treatment groups;
fig. 7 is a bar graph of tumor inhibition obtained from isolated tumors for different treatment groups.
Detailed Description
The first embodiment is as follows: the terpenoid assembled organic single-molecule photo-thermal reagent with chemotherapy/photo-thermal/photodynamic triple response is formed by covalent coupling of NSMs and Ce6 through a coupling agent containing disulfide bonds.
The second embodiment is as follows: the first difference between this embodiment and the specific embodiment is that: NSMs are TD, TT or PT, the coupling agent containing disulfide bonds is 3,3 '-dithiodipropionic acid or 2,2' -dithiodiethanol, and the molar ratio of NSMs to the coupling agent containing disulfide bonds is 1: (1.2-2), the molar ratio of NSMs to Ce6 is (1-1.4): 1. other steps and parameters are the same as in the first embodiment.
And a third specific embodiment: the second difference between this embodiment and the second embodiment is that: TD has the structural formula ofWherein R is one of a straight chain or branched alkyl group having not less than one carbon, and TT has the structural formulaWherein R is one of straight chain or branched alkyl having 5 or more carbon atoms, and PT is of the formulaWherein R is one of a straight chain or branched hydrocarbon group of not less than 0 carbon atoms. Other steps and parameters are the same as in the second embodiment.
The specific embodiment IV is as follows: the third difference between this embodiment and the third embodiment is that: TD has a structural formula of Dehydroabietic acid15-hydroxydehydroabietic acid (15-hydroxydehydroabietic acid)>Abietic acid (abietic acid)>Or 12-Hydroxyabietic acid (12-hydroxy abietic acid)/(F)>TT is specifically ergosterol (ergsterol)Stigmasterol (Stigmasterol)>Or beta-Sitosterol (beta-Sitosterol)>PT has a structural formula of Glycyrrhetinic acidUrsolic acid->Or Betulinical acid (betulinic acid)Other steps and parameters are the same as in the third embodiment.
Fifth embodiment: the preparation method of the terpenoid assembled organic single-molecule photo-thermal reagent with chemotherapy/photo-thermal/photodynamic triple response in the embodiment comprises the following steps:
step 1: dissolving TD and disulfide bond-containing coupling agent in anhydrous CH 2 Cl 2 Adding DCC/DMAP condensing agent, reacting at room temperature, extracting, concentrating, purifying to obtain TD-SS;
step 2: mixing TD-SS and Ce6 in anhydrous CH 2 Cl 2 Stirring and mixing the materials in ice water bath, adding EDCI and DIPEA, reacting at room temperature, extracting, concentrating and purifying to obtain the terpenoid assembled organic single-molecule photo-thermal reagent.
The reaction process of this embodiment is as follows:
specific embodiment six: the fifth difference between this embodiment and the third embodiment is that: molar amount of TD in step 1 with anhydrous CH 2 Cl 2 Is 1mmol: (20-80) mL, the molar ratio of DCC/DMAP to TD in step 1 is 1: (1.2-1.5), the reaction time in the step 1 is 8-36h, and the purification in the step 1 is performed by using a chromatographic column using ethyl acetate/petroleum ether (v/v=3/1) as eluent. Other steps and parameters are the same as in the fifth embodiment.
Seventh embodiment: the fifth difference between this embodiment and the third embodiment is that: the mole ratio of TD-SS to Ce6 in step 2 is (1-1.5): 1, molar weight of TD-SS and Anhydrous CH in step 2 2 Cl 2 Is 1mmol: (20-80) mL, the molar ratio of EDCI to Ce6 in step 2 is 1.2: the molar ratio of edci to DIPEA is 1: (0.2-1), stirring for 20-40min under ice-water bath in the step 2, wherein the reaction time is 8-36h, and purifying in the step 2 by using a chromatographic column with dichloromethane/acetone (v/v=1/1) as eluent. Other steps and parameters are the same as in the fifth embodiment.
Eighth embodiment: the preparation method of the terpenoid assembled organic single-molecule photo-thermal reagent with chemotherapy/photo-thermal/photodynamic triple response in the embodiment comprises the following steps:
step 1: dissolving NSMs and disulfide bond-containing coupling agent in anhydrous CH 2 Cl 2 Adding DCC/DMAP condensing agent, reacting at room temperature, extracting, concentrating and purifying to obtain NSMs-SS; NSMs are TT or PT;
step 2: dissolving NSMs-SS and N-Boc ethylenediamine in anhydrous CH 2 Cl 2 Then EDC/NHS condensing agent is added for reaction at room temperature, then CF is added 3 COOH reacts in ice water bath to obtain NSMs-SS-NH 2 ；
Step 3: NSMs-SS-NH 2 Miscibility with Ce6 in anhydrous CH 2 Cl 2 In the process, stirring and mixing are carried out under an ice water bath, and then are addedEDCI and DIPEA react at room temperature, and the organic single-molecule photo-thermal reagent assembled by terpenes is obtained after extraction, concentration and purification.
The reaction process of this embodiment is as follows:
detailed description nine: this embodiment differs from the eighth embodiment in that: molar amount of NSMs in step 1 and anhydrous CH 2 Cl 2 Is 1mmol: (20-80) mL, the molar ratio of DCC/DMAP to NSMs in step 1 is 1: (1.2-1.5), the reaction time in the step 1 is 8-36h, and the purification in the step 1 is performed by using a chromatographic column using ethyl acetate/petroleum ether (v/v=3/1) as eluent. Other steps and parameters are the same as in embodiment eight.
Detailed description ten: this embodiment differs from the eighth embodiment in that: molar amount of NSMs-SS in step 2 and anhydrous CH 2 Cl 2 Is 1mmol: (20-80) mL, the molar ratio of N-Boc ethylenediamine to NSMs-SS in step 2 is not less than 1.2/1, and the molar ratio of EDC/NHS to NSMs-SS in step 2 is 1: (1.2-1.5), NSMs-SS and CF in step 2 3 The molar ratio of COOH is 1: (2-5), in the step 2, the reaction is carried out for 8-36h at room temperature, and the reaction is carried out for 2-4h in an ice water bath. Other steps and parameters are the same as in embodiment eight.
Eleventh embodiment: this embodiment differs from the eighth embodiment in that: NSMs-SS-NH in step 3 2 Molar ratio to Ce6 (1-1.5): 1, NSMs-SS-NH in step 3 2 Molar mass of (C) and anhydrous CH 2 Cl 2 Is 1mmol: (20-80) mL, the molar ratio of EDCI to Ce6 in step 3 is 1.2: the molar ratio of edci to DIPEA is 1: (0.2-1), stirring for 20-40min under ice water bath in the step 3, wherein the reaction time is 8-36h, and purifying in the step 3 by using a chromatographic column with dichloromethane/acetone (v/v=1/1) as eluent. Other steps and parameters are the same as in embodiment eight.
Twelve specific embodiments: the terpenoid assembled organic single-molecule photo-thermal reagent with triple response of chemotherapy, photo-thermal and photodynamic in the first embodiment is used for preparing antitumor drugs.
Thirteen specific embodiments: the present embodiment is different from the twelfth embodiment in that: the preparation process of the antitumor drug comprises the following steps: adding DMSO mother liquor of a photothermal reagent into double distilled water solution of NaOH, and centrifuging after ultrasonic treatment to obtain NSMs-SS-Ce6NPs self-assembly body, namely the antitumor drug. Other steps and parameters are the same as those of the embodiment twelve.
Fourteen specific embodiments: the present embodiment is different from the thirteenth embodiment in that: the concentration of the DMSO stock of the photothermal reagent is 20-50mM. Other steps and parameters are the same as those of the thirteenth embodiment.
Fifteen embodiments: the present embodiment is different from the thirteenth embodiment in that: the concentration of the double distilled aqueous solution of NaOH was 30mM. Other steps and parameters are the same as those of the thirteenth embodiment.
Sixteen specific embodiments: the present embodiment is different from the thirteenth embodiment in that: the volume ratio of DMSO mother liquor of photo-thermal reagent to double distilled water solution of NaOH is (0.005-0.06): 1. other steps and parameters are the same as those of the thirteenth embodiment.
Seventeenth embodiment: the present embodiment is different from the thirteenth embodiment in that: ultrasonic treatment for 5-25min. Other steps and parameters are the same as those of the thirteenth embodiment.
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials, reagents, methods and apparatus used, without any particular description, are those conventional in the art and are commercially available to those skilled in the art.
The terms "comprising," "including," "having," "containing," or any other variation thereof, as used in the following embodiments, are intended to cover a non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, step, method, article, or apparatus.
When an equivalent, concentration, or other value or parameter is expressed as a range, preferred range, or a range bounded by a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. For example, when ranges of "1 to 5" are disclosed, the described ranges should be construed to include ranges of "1 to 4", "1 to 3", "1 to 2 and 4 to 5", "1 to 3 and 5", and the like. When a numerical range is described herein, unless otherwise indicated, the range is intended to include its endpoints and all integers and fractions within the range. In the present specification and claims, the range limitations may be combined and/or interchanged, such ranges including all the sub-ranges contained therein if not expressly stated.
The indefinite articles "a" and "an" preceding an element or component of the invention are not limited to the requirement (i.e. the number of occurrences) of the element or component. Thus, the use of "a" or "an" is to be interpreted as including one or at least one, and the singular reference of an element or component includes the plural reference unless the plural reference is obvious that there is a singular reference
Example 1: the preparation method of the terpenoid assembled organic single-molecule photo-thermal reagent with chemotherapy/photo-thermal/photodynamic triple response in the embodiment comprises the following steps:
step 1: preparation of ET-SS-COOH:
0.2mmol of the tetracyclic triterpene Ergosterol (ET) and 0.4mmol of 3,3' -dithiodipropionic acid (SS-COOH) were dissolved in 8mL of anhydrous CH 2 Cl 2 Then 0.3mmol of DCC/DMAP condensing agent (DCC/DMAP=1:0.5) is added, the reaction is carried out for 24 hours at room temperature, extraction, concentration and reduced pressure distillation are carried out, and the obtained crude product is adopted by ethyl acetate/petroleum etherSeparating and purifying the chromatographic column with the eluent (v/v=3/1) to obtain ET-SS-COOH;
step 2: ET-SS-NH 2 Is prepared from the following steps:
0.2mmol of ET-SS-COOH and 0.3mmol of N-Boc ethylenediamine are dissolved in 10mL of anhydrous CH 2 Cl 2 Then 0.3mmol of EDC/NHS condensing agent (EDC/NHS=1:0.5) was added, reacted at room temperature for 24h, then 1mmol of CF was added 3 COOH is reacted for 3 hours in ice water bath to obtain NSMs-SS-NH 2 ；
Step 3: preparation of ET-SS-Ce 6:
0.2mmol of ET-SS-NH 2 Miscibility with 0.15mmol Ce6 in 4mL anhydrous CH 2 Cl 2 In the process, stirring and mixing for 30min under ice water bath, then adding 0.18mmol of EDCI and 0.09mmol of DIPEA, reacting for 24h at room temperature, extracting, concentrating, and purifying by using a chromatographic column with methylene dichloride/acetone (v/v=1/1) as eluent to obtain ET-SS-Ce6, namely the organic single-molecule photothermal reagent assembled by terpenes.
The molecular structure of ET-SS-Ce6 is as follows:
application example 1: the method for preparing the anti-tumor NSMs-SS-Ce6NPs self-assembly body by using the ET-SS-Ce6 of the example 1 is as follows:
preparing a DMSO mother solution of the ET-SS-Ce6 with the concentration of 30mM by adopting a reverse precipitation method, adding the DMSO mother solution of the 20 mu LET-SS-Ce6 into 1mL of a double-distilled aqueous solution of NaOH with the concentration of 30mM, carrying out ultrasonic treatment for 10min, and centrifuging at 13500rpm to obtain an antitumor drug NSMs-SS-Ce6NPs self-assembly.
Example 2: the preparation method of the terpenoid assembled organic single-molecule photo-thermal reagent with chemotherapy/photo-thermal/photodynamic triple response in the embodiment comprises the following steps:
step 1: preparation of AA-SS-OH:
0.2mmol of tricyclic diterpene Abietic Acid (AA) and 0.25mmol of 2,2' -dithiodiethanol (SS-OH) are dissolved in 8mL of anhydrous CH 2 Cl 2 Adding 0.3mmol of DCC/DMAP condensing agent (DCC/DMAP=1:0.5), reacting for 24 hours at room temperature, extracting, concentrating, decompressing and distilling, and separating and purifying the obtained crude product by adopting a chromatographic column with ethyl acetate/petroleum ether (v/v=4/1) as eluent to obtain AA-SS-OH;
step 2: preparation of AA-SS-Ce 6:
0.2mmol of AA-SS-OH and 0.15mmol of Ce6 were mixed in 4mL of anhydrous CH 2 Cl 2 In the process, stirring and mixing for 30min under ice water bath, then adding 0.18mmol of EDCI and 0.09mmol of DIPEA, reacting for 24h at room temperature, extracting, concentrating, and purifying by using a chromatographic column with methylene dichloride/acetone (v/v=1/1) as eluent to obtain AA-SS-Ce6, namely the terpenoid assembled organic single-molecule photo-thermal reagent.
The molecular structure of AA-SS-Ce6 is as follows:
detection test
Nuclear magnetic hydrogen spectrum and mass spectrum detection:
FIG. 1 is a nuclear magnetic resonance spectrum of the photo-thermal reagent ET-SS-Ce6 prepared in example 1, and the data of the nuclear magnetic resonance spectrum are as follows: 1 H-NMR(400MHz,D6-DMSO)δ:9.77(1H,s,H-10,Ce6),9.65(1H,s,H-5,Ce6),9.11(1H,s,H-20,Ce6),8.36(1H,dd,H-3 1 ,Ce6),8.06(1H,br,N-H,CONH),7.95(2H,s,COOH,Ce6),6.46(1H,d,H-3 2a ,Ce6),6.16(1H,d,H-3 2b ,Ce6),5.25(5H,m,1HforH-15ofCe6,4Hfor CH＝CHofETS),3.55(3H,s,CH 3 -12,Ce6),3.50(3H,s,CH 3 -2,Ce6),3.34(3H,s,CH 3 -7,Ce6),0.95(3H,m,CH 3 ,ETS),0.93(6H,m,CH 3 -19/28,ETS),0.91(6H,m,CH 3 -26/27, ets), -2.00 (1H, s, n-H, ce 6), 2.61 (1H, s, n-H, ce 6). FIG. 2 is a high resolution mass spectrum (ESI electron source) of the photo-thermal reagent ET-SS-Ce6 prepared in example 1, theoretical calculation of C 70 H 93 N 6 O 8 S 2 + (M+H) + m/z was 1209.64908 and was actually detected as 1209.64929.
(II) morphology characterization: FIG. 3 is an SEM photograph of NSMs-SS-Ce6NPs obtained in application example 1 (scale: 2 μm). From the figure, the ET-SS-Ce6NPs are uniform spherical nano particles with the average particle diameter of about 60nm, and the photosensitive drug ET-SS-Ce6 mediated by the surface self-assembled small molecule ET also has self-assembly property and has the potential of inducing the ACQ effect of Ce 6.
(III) photo-thermal heating performance:
preparation of aqueous ET-SS-Ce6NPs (30. Mu.g/mL) dispersion of application example 1 was placed in a 3mL quartz cuvette, the thermocouple tip was inserted below the level of the dispersion, and then a near infrared laser of 665nm (1.0W/cm 2 ) The dispersion sample was irradiated for 10min, and the temperature change of the dispersion was automatically monitored every 60s using an artificial temperature intelligent recorder. The results of the double distilled water alone as a blank are shown in fig. 4-5.
Fig. 4 is a schematic photo-thermal diagram directly after 10min of illumination, and fig. 5 is a photo-thermal heating curve. The graph shows that the temperature of the ET-SS-Ce6NPs (30 mug/mL) is increased to 40.1 degrees from 23.4 degrees before illumination for 10min, and the temperature is increased by 16.7 degrees, which is obviously higher than that of 5.2 degrees increased by blank group water, so that the ET-SS-Ce6NPs has the photo-thermal conversion performance and can be used as a potential organic photo-thermal micromolecule for tumor photo-thermal treatment.
(IV) in vitro PTT/PDT-chemotherapy multiple synergic anticancer efficacy:
tumor volume of 4T1 tumor-bearing mice is 75-100mm 3 Tumor-bearing mice were divided into 6 groups altogether.
1) Blank group: 0.5% glucose;
2) Laser group: 0.5% glucose+laser (665nm1.0W/cm) 2 )；
3) Chemotherapy group: 200 mu L and concentration of 0.8mgmL -1 The use of the 0.5% dextrose solution of ET-SS-Ce6NPs of example 1 was not subjected to any light treatment;
4) PTT + chemotherapy group: equivalent to group 3) the ET-SS-Ce6NPs of application example 1 were irradiated for 5min at the 2h time point after administration (665nm1.0W/cm 2 ) Simultaneously, vitamin C is injected in situ in the tumor to eliminate the influence of ROS so as to fully prove the PTT effectiveness;
5) Pdt+chemotherapy group: equivalent of the ET-SS-Ce6NPs of application example 1 to group 3) was irradiated for 10min (6615 nm0.1w/cm after 6h of administration 2 )；
6) PTT-pdt+chemotherapy group: the same amount of ET-SS-Ce6NPs of application example 1 as group 3) was subjected to the same PTT treatment 2h after administration and the same PDT treatment immediately after 4h. Since the PTT curative effect is exerted by laser with high power, the laser is at 0.1W/cm 2 The photo-thermal effect is basically weak; while PDT at low power 0.1W/cm 2 The effect is generally remarkable, so that the nano system is distinguished to have PTT and PDT curative effects at the same time, and different dosages of light are used for distinguishing PTT and PDT.
All drugs were injected via tail vein, and observed for 14 days after one treatment, the body weight of mice and the length and width of tumor were recorded every two days. Tumor volume was used: calculated as length x width/2. And evaluating the multiple anti-tumor effects of the medicine according to the size of the tumor volume. The results are shown in FIGS. 6-7.
Fig. 6 shows the tumor growth curves of the different treatment groups, and fig. 7 shows the tumor inhibition obtained from the isolated tumors of the corresponding treatment groups. The results clearly show that the ET-SS-Ce6NPs triple PTT-PDT-Chemo alone exhibited the best tumor inhibition efficiency, nearly approaching 100%, much higher than 92.6% for PTT-Chemo, 58% for PDT-Chemo, and 29% for Chemo alone. The result fully shows that the self-assembled ET-SS-Ce6NPs have excellent photothermal anti-tumor performance, and simultaneously realize triple chemotherapy-photodynamic-photothermal anti-tumor curative effects. The method fully shows that the terpenoid micromolecules with anticancer activity and self-assembly function have the purpose of mediating the generation of the photosensitizer to realize the PTT curative effect, and have great prospect in the construction of a single-molecule multifunctional nano composite system.
In the foregoing, the present invention is merely preferred embodiments, which are based on different implementations of the overall concept of the invention, and the protection scope of the invention is not limited thereto, and any changes or substitutions easily come within the technical scope of the present invention as those skilled in the art should not fall within the protection scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope of the claims.
Claims (5)
1. A terpenoid assembled organic single-molecule photo-thermal reagent with chemotherapy/photo-thermal/photodynamic triple response is characterized in that the photo-thermal reagent is。
2. The method for preparing the terpenoid assembled organic single-molecule photo-thermal reagent with chemotherapy/photo-thermal/photodynamic triple response as claimed in claim 1, which is characterized by comprising the following steps:
step 1: dissolving tetracyclic triterpene ergosterol and 3,3' -dithiodipropionic acid in anhydrous CH 2 Cl 2 Adding DCC/DMAP condensing agent, reacting at room temperature, extracting, concentrating, purifying to obtain ET-SS-COOH; the structural formula of the ET-SS-COOH is
；
Step 2: dissolving ET-SS-COOH and N-Boc ethylenediamine in anhydrous CH 2 Cl 2 Then EDC/NHS condensing agent is added for reaction at room temperature, then CF is added 3 COOH reacts in ice water bath to obtain ET-SS-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the The ET-SS-NH 2 Is of the structure of
；
Step 3: ET-SS-NH 2 Miscibility with Ce6 in anhydrous CH 2 Cl 2 Stirring and mixing the materials in ice water bath, adding EDCI and DIPEA, reacting at room temperature, extracting, concentrating and purifying to obtain the terpenoid assembled organic single-molecule photo-thermal reagent.
3. The method according to claim 2, wherein the molar ratio DCC/DMAP to tetracyclic triterpene ergosterol in step 1 is 1:1.2-1.5, the reaction time is 8-36 h; in the step 2, the mol ratio of N-Boc ethylenediamine to ET-SS-COOH is more than or equal to 1.2:1, EDC/NHThe molar ratio of S to ET-SS-COOH was 1:1.2-1.5, ET-SS-COOH and CF 3 The molar ratio of COOH is 1:2-5, reacting at room temperature by 8-36 and h, and reacting at ice water bath by 2-4 and h; ET-SS-NH in step 3 2 Molar ratio to Ce6 1-1.5:1, the molar ratio of EDCI to Ce6 is 1.2:1, the molar ratio of EDCI to DIPEA is 1:0.2-1, stirring for 20-40min under ice water bath, and reacting for 8-36h.
4. The use of a terpenoid-assembled organic single-molecule photothermal reagent with a chemotherapy/photothermal/photodynamic triple response according to claim 1 in the preparation of an antitumor drug.
5. The use according to claim 4, wherein the antineoplastic agent is a self-assembly of photothermal agents prepared by: and adding the DMSO mother liquor of the photo-thermal reagent into a double-distilled water solution of NaOH, and centrifuging after ultrasonic treatment to obtain the photo-thermal reagent self-assembly.
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| CN109846857A (en) * | 2019-04-15 | 2019-06-07 | 哈尔滨工业大学 | A kind of preparation method and applications of the natural supermolecule photosensitizer of activity |
| CN111558043A (en) * | 2020-06-03 | 2020-08-21 | 哈尔滨工业大学 | Preparation method of terpene micromolecule assembled redox response photosensitive drug |
| CN111643664A (en) * | 2020-05-15 | 2020-09-11 | 哈尔滨工业大学 | Preparation method and application of active natural small molecule mediated co-assembled photosensitive drug |
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| CN111643664A (en) * | 2020-05-15 | 2020-09-11 | 哈尔滨工业大学 | Preparation method and application of active natural small molecule mediated co-assembled photosensitive drug |
| CN111558043A (en) * | 2020-06-03 | 2020-08-21 | 哈尔滨工业大学 | Preparation method of terpene micromolecule assembled redox response photosensitive drug |
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