CN116327967A - 一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和在抗肿瘤药物中的应用 - Google Patents
一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和在抗肿瘤药物中的应用 Download PDFInfo
- Publication number
- CN116327967A CN116327967A CN202310215985.9A CN202310215985A CN116327967A CN 116327967 A CN116327967 A CN 116327967A CN 202310215985 A CN202310215985 A CN 202310215985A CN 116327967 A CN116327967 A CN 116327967A
- Authority
- CN
- China
- Prior art keywords
- graphene quantum
- quantum dots
- platinum
- composite nanomaterial
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 133
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 67
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 41
- 239000002131 composite material Substances 0.000 title claims abstract description 38
- 239000002086 nanomaterial Substances 0.000 title claims abstract description 32
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 title abstract description 29
- 229910021389 graphene Inorganic materials 0.000 title abstract description 29
- 239000002096 quantum dot Substances 0.000 title abstract description 28
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims abstract description 49
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 18
- 230000009467 reduction Effects 0.000 claims abstract description 12
- 229910000449 hafnium oxide Inorganic materials 0.000 claims abstract description 3
- WIHZLLGSGQNAGK-UHFFFAOYSA-N hafnium(4+);oxygen(2-) Chemical compound [O-2].[O-2].[Hf+4] WIHZLLGSGQNAGK-UHFFFAOYSA-N 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- 150000003384 small molecules Chemical class 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 6
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 claims description 6
- 229960000304 folic acid Drugs 0.000 claims description 6
- 235000019152 folic acid Nutrition 0.000 claims description 6
- 239000011724 folic acid Substances 0.000 claims description 6
- 238000004108 freeze drying Methods 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- 230000008685 targeting Effects 0.000 claims description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000012528 membrane Substances 0.000 claims description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000002135 nanosheet Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 claims description 3
- KLOIYEQEVSIOOO-UHFFFAOYSA-N carbocromen Chemical compound CC1=C(CCN(CC)CC)C(=O)OC2=CC(OCC(=O)OCC)=CC=C21 KLOIYEQEVSIOOO-UHFFFAOYSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 150000004985 diamines Chemical class 0.000 claims description 3
- YXVFQADLFFNVDS-UHFFFAOYSA-N diammonium citrate Chemical compound [NH4+].[NH4+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O YXVFQADLFFNVDS-UHFFFAOYSA-N 0.000 claims description 3
- 229920002674 hyaluronan Polymers 0.000 claims description 3
- 229960003160 hyaluronic acid Drugs 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000002159 nanocrystal Substances 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- FBEIPJNQGITEBL-UHFFFAOYSA-J tetrachloroplatinum Chemical compound Cl[Pt](Cl)(Cl)Cl FBEIPJNQGITEBL-UHFFFAOYSA-J 0.000 claims description 3
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 claims description 3
- 229960002685 biotin Drugs 0.000 claims description 2
- 235000020958 biotin Nutrition 0.000 claims description 2
- 239000011616 biotin Substances 0.000 claims description 2
- 239000011148 porous material Substances 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 25
- 238000002512 chemotherapy Methods 0.000 abstract description 14
- 231100000331 toxic Toxicity 0.000 abstract description 8
- 230000002588 toxic effect Effects 0.000 abstract description 8
- 230000000973 chemotherapeutic effect Effects 0.000 abstract description 6
- 239000003381 stabilizer Substances 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 6
- 238000001308 synthesis method Methods 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 4
- 238000010493 gram-scale synthesis Methods 0.000 abstract 1
- 229940126585 therapeutic drug Drugs 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 description 48
- 201000011510 cancer Diseases 0.000 description 26
- 239000003814 drug Substances 0.000 description 21
- 229940044683 chemotherapy drug Drugs 0.000 description 19
- 229940079593 drug Drugs 0.000 description 18
- 238000012360 testing method Methods 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 10
- 238000006722 reduction reaction Methods 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000002243 precursor Substances 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- 150000003058 platinum compounds Chemical class 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 230000005540 biological transmission Effects 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- -1 platinum ions Chemical class 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- 238000009777 vacuum freeze-drying Methods 0.000 description 3
- 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
- 206010009944 Colon cancer Diseases 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000035508 accumulation Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 229940045985 antineoplastic platinum compound Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000009702 cancer cell proliferation Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000001027 hydrothermal synthesis Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000002539 nanocarrier Substances 0.000 description 2
- 239000002114 nanocomposite Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 244000248349 Citrus limon Species 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 238000011789 NOD SCID mouse Methods 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000002498 deadly effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 229940127022 high-dose drug Drugs 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000002428 photodynamic therapy Methods 0.000 description 1
- 238000007626 photothermal therapy Methods 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229940043267 rhodamine b Drugs 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000004729 solvothermal method Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 230000036326 tumor accumulation Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B32/00—Carbon; Compounds thereof
- C01B32/15—Nano-sized carbon materials
- C01B32/182—Graphene
- C01B32/184—Preparation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B22—CASTING; POWDER METALLURGY
- B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
- B22F1/00—Metallic powder; Treatment of metallic powder, e.g. to facilitate working or to improve properties
- B22F1/05—Metallic powder characterised by the size or surface area of the particles
- B22F1/054—Nanosized particles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B22—CASTING; POWDER METALLURGY
- B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
- B22F1/00—Metallic powder; Treatment of metallic powder, e.g. to facilitate working or to improve properties
- B22F1/12—Metallic powder containing non-metallic particles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B22—CASTING; POWDER METALLURGY
- B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
- B22F9/00—Making metallic powder or suspensions thereof
- B22F9/16—Making metallic powder or suspensions thereof using chemical processes
- B22F9/18—Making metallic powder or suspensions thereof using chemical processes with reduction of metal compounds
- B22F9/24—Making metallic powder or suspensions thereof using chemical processes with reduction of metal compounds starting from liquid metal compounds, e.g. solutions
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y20/00—Nanooptics, e.g. quantum optics or photonic crystals
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B32/00—Carbon; Compounds thereof
- C01B32/15—Nano-sized carbon materials
- C01B32/182—Graphene
- C01B32/194—After-treatment
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/08—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
- C09K11/65—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing carbon
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Nanotechnology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Inorganic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Materials Engineering (AREA)
- Physics & Mathematics (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- General Physics & Mathematics (AREA)
- General Chemical & Material Sciences (AREA)
- Composite Materials (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Optics & Photonics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Manufacturing & Machinery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本申请公开了一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和在抗肿瘤药物中的应用,属于生物医药材料制备领域。所述复合纳米材料包括铂纳米粒子和石墨烯量子点;所述铂纳米粒子以聚集体形式分散于所述石墨烯量子点中;所述石墨烯量子点与所述纳米氧化铪络合。该材料溶解性高、物化性能稳定且化疗效果显著。该制备方法为简便的热还原合成方法,克级别合成高溶解性的铂纳米粒子/石墨烯量子点化疗药物。在制备过程中,不需要额外加入有毒还原剂,石墨烯量子点同时作为具有化疗作用的超细铂纳米粒子的多功能辅助基质和稳定剂。
Description
技术领域
本申请涉及一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和在抗肿瘤药物中的应用,属于生物医药材料制备领域。
背景技术
癌症是危害人类生命健康的全球性疾病,预计将取代心血管疾病成为全球第一大致死疾病。随着患癌率越来越高,人们对各类癌症早已不陌生。世界卫生组织国际癌症研究机构(IARC)发布了全球癌症负担数据,2021年全球新发癌症病例超过2000万例,癌症死亡病例达到1002万例,其中,中国新发癌症和死亡病例均位居全球第一。国家癌症中心最新数据显示:2022年中国癌症新发病例约482万例,癌症死亡病例约321万例。癌症治疗方法包括手术、放疗、化疗、光动力治疗、光热治疗、磁热治疗、基因治疗和免疫治疗等。每种方法的适用范围不一样,各有优点和局限性,但是,由于癌细胞的易转移特性,通常的治疗方案中都会采用化疗药物。化疗是利用化学药物阻止癌细胞的增殖、浸润和转移,直至最终杀灭癌细胞的一种全身性治疗方式。
近年来,铂纳米粒子(Platinum nanoparticles,PtNPs)的化疗作用受到广泛关注。在肿瘤特殊微环境下(如酸性偏高、过氧化氢浓度偏高等),具有表面效应的高活性PtNPs被氧化分解,释放出癌细胞毒性的离子铂或相关二价铂配合物,产生化疗作用,另一方面,在正常中性或弱碱性体液中,PtNPs难以被氧化分解,而且通过肿瘤的增强渗透滞留效应(Enhanced permeability and retention effect,EPR)蓄集于肿瘤组织,从而呈现出相比于铂类分子药物更小的毒副作用。此外,PtNPs是一种多功能抗肿瘤药物,还具有人工酶、高能射线增敏、高效光热转换等特殊性能。所以,相对于临床常用的顺铂、奥沙利铂等铂类分子药物,具有化疗作用的PtNPs表现出更低的毒副作用,对铂类分子药物耐药的一些肿瘤也表现出明显的抑制作用,PtNPs化疗药物有望成为下一代铂类抗癌药物。
PtNPs化疗药物的临床应用仍然面临着巨大挑战,原因主要有:1)在稳定剂和还原剂(如硼氢化钠、水合肼、抗坏血酸等)存在下,通过直接湿法还原得到超细PtNPs是广泛使用的一种合成方法,在合成过程中,稳定剂、还原剂、高价铂化合物、有机溶剂、反应副产物、以及毒素或细菌污染都可能是体内毒副作用的来源,导致纳米药物的纯化过程比较繁杂;2)静脉注射的纳米药物需经过体内血液循环、肿瘤蓄积、肿瘤内渗透、被癌细胞内吞和在胞内释放五步级联过程才能在肿瘤细胞内发挥药效,在肿瘤组织中渗透能力的缺失是大多数纳米药物的“短板”,它们在肿瘤的递送效率少于0.7%,主要原因是分散性和溶解性差;3)药物的物理化学稳定性、药理学、药代动力学、毒理学需要综合评估,以验证药物的有效性和安全性。
发明内容
针对现有技术中具有化疗作用的铂纳米粒子难以批量合成、稳定性差、溶解性低等癌症临床治疗上的用药问题,为解决现有技术的不足,本发明提供一种铂纳米粒子/石墨烯量子点化疗药物,提供上述纳米材料的高剂量绿色制备方法。所合成的上述纳米药物的化疗效果稳定且显著,具有很好应用前景。利用高生物相容的GQDs保护具有化疗作用的PtNPs,可有效提高药物的分散性和溶解性,并通过EPR效应加大PtNPs@GQDs化疗药物在肿瘤组织中的蓄积,使之被动靶向于癌细胞。此外,作为纳米载体的GDQs可以负载靶向分子(生物素、叶酸、RGD肽、透明质酸、TAT穿膜肽等),提高复合药物对肿瘤和癌细胞的主动靶向能力,增强抗肿瘤效果。
根据本申请的第一个方面,提供了一种复合纳米材料。该材料由石墨烯量子点络合保护超细铂纳米粒子得到的产物。具体的,利用石墨烯量子点中的羧基、羟基、氨基等基团增加纳米复合物的分散性和溶解性,石墨烯量子点作为超细铂纳米粒子的多功能辅助基质和稳定剂,有力保护高活性超细铂纳米粒子,使之在肿瘤特殊微环境下析出抗癌活性组分并有效杀灭癌细胞。超细铂纳米粒子(粒径为1.5-3nm)以聚集体形式分散于无定形石墨烯量子点基质中,此复合物高效溶解于去离子水中,全部溶质能通过220nm孔径的微孔滤膜,水溶解度大于80mg/mL,放置2个月后无沉集现象。
一种复合纳米材料,所述复合纳米材料包括铂纳米粒子和石墨烯量子点;
所述铂纳米粒子以聚集体形式分散于所述石墨烯量子点中;
所述石墨烯量子点与所述纳米氧化铪络合。
可选地,所述石墨烯量子点中含有氮、硫、氧。
可选地,所述石墨烯量子点中相互堆叠形成纳米片。
可选地,所述铂纳米晶的粒径为1.5-3nm。
可选地,在所述复合纳米材料中,铂的含量为10%-20%。
可选地,在所述复合纳米材料中,铂的含量独立地选自10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%中的任意值或任意两者之间的范围值。
可选地,所述复合纳米材料的水溶液中,全部溶质能通过220nm孔径的微孔滤膜。
可选地,所述复合纳米材料的水溶解度大于80mg/mL。
可选地,所述复合纳米材料的水溶解度独立地选自80mg/mL、85mg/mL、90mg/mL、95mg/mL、100mg/mL、110mg/mL、120mg/mL、130mg/mL、140mg/mL、150mg/mL、160mg/mL、170mg/mL、180mg/mL、190mg/mL、200mg/mL中的任意值或任意两者之间的范围值。
可选地,所述石墨烯量子点含有羧基、羟基、氨基。
所述石墨烯量子点作为所述铂纳米粒子的辅助基质和稳定剂。
根据本申请的第二个方面,提供了一种复合纳米材料的制备方法。该方法为简便的热还原法,克级别合成高溶解性的PtNPs@GQDs化疗药物。在制备过程中,不需要额外加入有毒还原剂,所加入的还原剂(甲醇或乙醇)可以通过旋蒸、冻干等工艺去除。由于PtNPs与GQDs的协同作用,所合成的复合药物具有高分散性和高水溶性。
一种复合纳米材料的制备方法,包括以下步骤:
S1、获得石墨烯量子点;
S2、将含有所述石墨烯量子点、铂源、还原剂的混合物,热还原得到所述复合纳米材料;
所述还原剂选自甲醇、乙醇中的至少一种。
可选地,所述铂源选自氯亚铂酸钠、氯亚铂酸钾、氯亚铂酸铵、四氯化铂、氯铂酸、氯铂酸钠中的至少一种。
可选地,所述石墨烯量子点的质量与所述铂源的摩尔比为7g/mmol-8g/mmol。
可选地,所述石墨烯量子点的质量与所述铂源的摩尔比独立地选自7g/mmol、7.1g/mmol、7.2g/mmol、7.3g/mmol、7.4g/mmol、7.5g/mmol、7.6g/mmol、7.7g/mmol、7.8g/mmol、7.9g/mmol、8g/mmol中的任意值或任意两者之间的范围值。
可选地,所述石墨烯量子点的质量与所述还原剂的体积比为0.04g/ml-0.08g/ml。
可选地,所述石墨烯量子点的质量与所述还原剂的体积比独立地选自0.040、0.045、0.050、0.055、0.060、0.065、0.070、0.075、0.080中的任意值或任意两者之间的范围值。
可选地,热还原的条件如下:
第一阶段的温度为45-55℃;
时间为0.3-0.7h;
可选地,第一阶段的温度独立地选自45℃、46℃、47℃、48℃、49℃、50℃、51℃、52℃、53℃、54℃、55℃中的任意值或任意两者之间的范围值。
可选地,时间独立地选自0.3h、0.35h、0.40h、0.45h、0.50h、0.55h、0.60h、0.65h、0.70h中的任意值或任意两者之间的范围值。
第二阶段的温度为55-65℃;
时间为0.8-1.2h。
可选地,第二阶段的温度独立地选自55℃、56℃、57℃、58℃、59℃、60℃、61℃、62℃、63℃、64℃、65℃中的任意值或任意两者之间的范围值。
可选地,时间独立地选自0.8h、0.85h、0.90h、0.95h、1.00h、1.05h、1.10h、1.15h、1.20h中的任意值或任意两者之间的范围值。
可选地,热还原后还包括纯化、冷冻干燥。
可选地,步骤S2中,将含有铂源的溶液加入到含有所述石墨烯量子点的溶液中,再加入还原剂。
可选地,步骤S1中,石墨烯量子点的制备如下:
将含有单一小分子的混合物置于密闭容器中,反应得到所述石墨烯量子点;
所述单一小分子选自柠檬酸铵、柠檬酸氢二铵、柠檬酸、叶酸、尿素、硫脲、二氰二胺中的至少一种。
可选地,所述单一小分子的浓度为0.2mmol/ml-0.4mmol/ml。
可选地,所述单一小分子的浓度独立地选自0.2mmol/ml、0.25mmol/ml、0.30mmol/ml、0.35mmol/ml、0.40mmol/ml中的任意值或任意两者之间的范围值。
可选地,反应的条件如下:
温度为180-250℃;
时间为8-12h。
可选地,温度独立地选自180℃、185℃、190℃、195℃、200℃、205℃、210℃、215℃、220℃、225℃、230℃、235℃、240℃、245℃、250℃中的任意值或任意两者之间的范围值。
可选地,时间独立地选自8h、8.5h、9.0h、9.5h、10.0h、10.5h、11.0h、11.5h、12.0h中的任意值或任意两者之间的范围值。
可选地,所述单一小分子为0.2mmol/ml-0.4mmol/ml的柠檬酸氢二胺。
可选地,所述单一小分子为0.2mmol/ml-0.3mmol/ml的柠檬酸和0.3mmol/ml-0.35mmol/ml的二氰二胺。
可选地,所述单一小分子为0.2mmol/ml-0.3mmol/ml的柠檬酸和0.45mmol/ml-0.55mmol/ml的尿素。
根据本申请的一个实施方式,上述铂纳米粒子/石墨烯量子点化疗药物的制备方法,基本步骤包括:1)石墨烯量子点前体的合成和纯化;2)利用石墨烯量子点配位锚定高价铂化合物,并在石墨烯量子点基质上原位热还原高价铂化合物,形成超细铂纳米粒子/石墨烯量子点复合物;3)铂纳米粒子/石墨烯量子点复合物的纯化和冷冻干燥。
石墨烯量子点前体的合成包括由上而下法和由下而上法,优选的,采用由下而上法合成高水溶性、高生物相容性的石墨烯量子点。具体的,由柠檬酸铵、柠檬酸氢二铵、柠檬酸、叶酸、尿素、硫脲、二氰二胺等单一小分子或混合物作为起始原料,采用溶剂热法缩合成石墨烯量子点。优选的,合成含氮、硫、氧等的石墨烯量子点,以便有利于配位锚定高价铂化合物并进行原位还原。近一步优选的,采用高温水热合成石墨烯量子点,有利于形成石墨烯纳米片,使之对超细铂纳米粒子具有适中的保护能力,有利于超细铂纳米粒子在肿瘤微环境下发挥化疗作用。
铂纳米粒子/石墨烯量子点化疗药物的高剂量合成方法,原位热还原锚定在含氮、硫、氧等石墨烯量子点的铂离子,精确控制温度,使铂离子缓慢还原形成超细铂纳米粒子/石墨烯量子点复合物。热还原合成所用溶剂为高纯度去离子水,还原剂选用挥发性的有机溶剂乙醇或甲醇(优选乙醇)。加入的高价铂化合物为溶于水的氯亚铂酸钠、氯亚铂酸钾、氯亚铂酸铵、四氯化铂、氯铂酸、氯铂酸钠等中一种,优选同时溶于水和乙醇的氯亚铂酸钠、氯铂酸、氯铂酸钠等中一种。
随着还原反应的进行,溶液颜色逐渐加深,由黄色-棕色-棕黑色变化,说明铂纳米粒子缓慢形成。在制备过程中,不需要额外加入有毒还原剂,所加入的还原剂(甲醇或乙醇)可以通过旋蒸、冻干等工艺去除。未反应的氯亚铂酸钠、氯铂酸、氯铂酸钠等铂化合物可以通过乙醇洗涤去除。此绿色合成方法适合于铂纳米粒子化疗药物的可控高剂量合成。
根据本申请的第三个方面,提供了一种复合纳米材料在抗肿瘤药物中的应用。该复合材料可以高效杀灭各种人癌细胞,在人癌小鼠移植瘤模型试验中表现出良好的抗肿瘤效果。各种体外人癌细胞增殖抑制试验表明,所述铂纳米粒子/石墨烯量子点复合物的半数抑制浓度IC50小于0.6μgPt/mL(以铂含量计算),而且放置1-2月后样品的化疗效果并未改变。作为对比,合成的石墨烯量子点前体具有良好生物相容性,无细胞毒性。以上说明所述铂纳米粒子/石墨烯量子点化疗药物具有优越的溶解性、物化稳定性及药效稳定性。
本申请能产生的有益效果包括:
1)本申请所提供的一种复合纳米材料,其溶解性高、物化性能稳定且化疗效果显著。利用高生物相容的石墨烯量子点保护具有化疗作用的铂纳米粒子,可有效提高药物的分散性和溶解性,并通过增强的渗透滞留效应加大铂纳米粒子/石墨烯量子点复合药物在肿瘤组织中的蓄积,被动靶向于癌细胞。此外,作为纳米载体的石墨烯量子点可以负载生物活性剂和靶向剂(抗体、叶酸、RGD肽、透明质酸、TAT穿膜肽等),提高复合药物的主动靶向能力,增强肿瘤治疗效果并减少毒副作用。
2)本申请所提供的一种复合纳米材料的制备方法,通过简便的热还原合成方法,克级别合成高溶解性的铂纳米粒子/石墨烯量子点化疗药物。在制备过程中,不需要额外加入有毒还原剂,石墨烯量子点同时作为具有化疗作用的超细铂纳米粒子的多功能辅助基质和稳定剂。所述超细铂纳米粒子/石墨烯量子点化疗药物具有优越的溶解性和物理化学稳定性,并且高效杀灭各种人癌细胞,在人癌小鼠移植瘤模型试验中表现出良好的抗肿瘤效果。此外,由于铂纳米粒子与石墨烯量子点的协同作用,其纳米复合材料在催化领域也具有潜在应用价值。铂纳米粒子/石墨烯量子点纳米材料将成为抗肿瘤治疗和催化有应用前景的平台,同时也将在其它领域得到广泛的应用。
附图说明
图1为本申请实施例1中的GQDs的粉末衍射。
图2为本申请实施例1中的GQDs的透射电镜图,其中,a的标尺为100nm,b的标尺为5nm。
图3为本申请实施例1中的PtNPs@GQDs的高分辨透射电镜,标尺为5nm。
图4为本申请实施例1中的PtNPs@GQDs化疗药物对人结肠癌HT-29小鼠移植瘤的治疗作用。
具体实施方式
下面结合实施例详述本申请,但本申请并不局限于这些实施例。
如无特别说明,本申请的实施例中的原料均通过商业途径购买。
如无特别说明,采用常规的测试方法或者仪器推荐的测试方法。
实施例1
GQDs前体制备:称取柠18mmol柠檬酸三胺(4.37g)于反应釜聚四氟乙烯材质内衬中(容积为100毫升),加入60毫升去离子水,超声溶解10分钟,然后210℃水热反应10小时。反应液自然冷却至室温后,高速离心(12000r/min)5分钟,除去溶液中的橙黄色大颗粒残渣。之后,60℃真空旋蒸离心液至近干,除去溶液中的挥发性小分子。旋蒸得到的橙黄色粘稠物通过冷冻干燥除去溶剂水,之后用无水乙醇多次洗涤离心,得到不溶于乙醇的淡黄色石墨烯量子点,真空冷冻干燥得到1.2克GQDs产物。通过测试证实了石墨烯量子点的特征:粉末衍射在2θ=26°出现石墨烯量子点的特征峰(图1);透射电镜测试看到15-30nm的石墨烯量子点相互堆叠形成纳米片(图2)。
PtNPs@GQDs化疗药物制备:称取1.2克上述GQDs前体于圆底烧瓶中,加入20毫升去离子水溶解。配制600毫克Na2PtCl4(铂含量>48%)的20毫升去离子水溶液,缓慢滴加于GQDs水溶液中,搅拌反应,再加入20毫升无水乙醇。此时的溶液颜色为黄色,并伴有少量沉淀。缓慢升温反应溶液至50℃,恒温反应0.5小时,溶液颜色由黄色变为棕色,沉淀也完全溶解,表明铂纳米粒子缓慢形成。再次缓慢升温反应溶液至60℃,恒温反应1小时,溶液颜色逐渐变深,最终呈现出棕黑色的澄清液。停止反应后,真空旋蒸(50℃)除去乙醇至水溶液体积约20毫升,用NaOH调节溶液pH值至7-7.5。高速离心溶液(12000r/min)4分钟,除去溶液中的极少量黑色大颗粒。棕黑色澄清液真空冷冻干燥得到黑色固体,用乙醇洗涤离心,再次真空冷冻干燥除去乙醇和水,得到黑色PtNPs@GQDs固体产物1.5克。通过透射电镜测试看到超细铂纳米晶(粒径为1.5-3nm)以聚集体形式分散于无定形石墨烯量子点基质中(图3),ICP测试得到固体样品中铂和钠的含量分别为16.05%和8.54%。
PtNPs@GQDs化疗药物的体外癌细胞增殖抑制试验:将不同浓度PtNPs@GQDs受试物对人肿瘤细胞(细胞数为3K)作用3天后,采用磺酰罗丹明B(SRB)法测定吸光度值,计算半数抑制浓度IC50。表1为所述PtNPs@GQDs化疗药物对不同人肿瘤细胞的IC50值(以铂含量计算,小于0.6μg Pt/mL),所述PtNPs@GQDs化疗药物具有高效化疗作用。
PtNPs@GQDs化疗药物的人癌小鼠移植瘤模型试验:人肿瘤细胞系传3代后接种于Balb/c裸鼠或NOD-SCID小鼠皮下,建立人癌异体移植瘤模型,评估PtNPs@GQDs的体内抗肿瘤活性。待移植瘤生长至少达100mm3后,将小鼠随机分组(每组10只)尾静脉给药,包括高、中、低3个剂量的给药组、阳性对照组和阴性对照组。图4给出了所述PtNPs@GQDs化疗药物对人结肠癌HT-29小鼠移植瘤的治疗作用。在此试验中,以医用顺铂(DDP,包含聚乙二醇400和氯化钠)为阳性对照药物。PtNPs@GQDs受试物剂量的选择体现出量效关系,高剂量药物的最终肿瘤抑制率为90.19%,高于医用顺铂的最终肿瘤抑制率(66.97%)。而且,在治疗过程中,注射入PtNPs@GQDs化疗药物的三组小鼠未见死亡,但是,注射入医用顺铂的一组小鼠中,中途有两只小鼠死亡。人癌小鼠移植瘤模型试验表明,所述PtNPs@GQDs是有应用前景的化疗药物。
表1
实施例2
石墨烯量子点的组成结构及合成条件直接影响PtNPs@GQDs药物的化疗作用。不改变实施例1中制备合成中所有方案及配比,唯一改变的是石墨烯量子点前体合成中的小分子,我们得到了一系列具有高效化疗作用的PtNPs@GQDs药物,其化疗效果不再赘述,在此公开石墨烯量子点前体制备中加入的初始小分子,由18mmol柠檬酸三胺分别改为:1)18mmol柠檬酸氢二胺;2)15mmol柠檬酸和20mmol二氰二胺;3)15mmol柠檬酸和30mmol尿素。
以上所述,仅是本申请的几个实施例,并非对本申请做任何形式的限制,虽然本申请以较佳实施例揭示如上,然而并非用以限制本申请,任何熟悉本专业的技术人员,在不脱离本申请技术方案的范围内,利用上述揭示的技术内容做出些许的变动或修饰均等同于等效实施案例,均属于技术方案范围内。
Claims (10)
1.一种复合纳米材料,其特征在于,所述复合纳米材料包括铂纳米粒子和石墨烯量子点;
所述铂纳米粒子以聚集体形式分散于所述石墨烯量子点中;
所述石墨烯量子点与所述纳米氧化铪络合。
2.根据权利要求1所述的复合纳米材料,其特征在于,所述石墨烯量子点中含有氮、硫、氧;
优选地,所述石墨烯量子点相互堆叠形成纳米片;
优选地,所述铂纳米晶的粒径为1.5-3nm;
优选地,在所述复合纳米材料中,铂的含量为10%-20%。
3.根据权利要求1所述的复合纳米材料,其特征在于,所述复合纳米材料的水溶液中,全部溶质能通过220nm孔径的微孔滤膜;
优选地,所述复合纳米材料的水溶解度大于80mg/mL;
优选地,所述石墨烯量子点含有羧基、羟基、氨基。
4.一种复合纳米材料的制备方法,其特征在于,包括以下步骤:
S1、获得石墨烯量子点;
S2、将含有所述石墨烯量子点、铂源、还原剂的混合物,热还原得到所述复合纳米材料;
所述还原剂选自甲醇、乙醇中的至少一种。
5.根据权利要求4所述的制备方法,其特征在于,所述铂源选自氯亚铂酸钠、氯亚铂酸钾、氯亚铂酸铵、四氯化铂、氯铂酸、氯铂酸钠中的至少一种;
优选地,所述石墨烯量子点的质量与所述铂源的摩尔比为7g/mmol-8g/mmol;
优选地,所述石墨烯量子点的质量与所述还原剂的体积比为0.04g/ml-0.08g/ml;
优选地,热还原的条件如下:
第一阶段的温度为45-55℃;
时间为0.3-0.7h;
第二阶段的温度为55-65℃;
时间为0.8-1.2h;
优选地,热还原后还包括纯化、冷冻干燥。
6.根据权利要求4所述的制备方法,其特征在于,步骤S2中,将含有铂源的溶液加入到含有所述石墨烯量子点的溶液中,再加入还原剂。
7.根据权利要求4所述的制备方法,其特征在于,步骤S1中,石墨烯量子点的制备如下:
将含有单一小分子的混合物置于密闭容器中,反应得到所述石墨烯量子点;
所述单一小分子选自柠檬酸铵、柠檬酸氢二铵、柠檬酸、叶酸、尿素、硫脲、二氰二胺中的至少一种。
8.根据权利要求7所述的制备方法,其特征在于,所述单一小分子的浓度为0.2mmol/ml-0.4mmol/ml;
优选地,反应的条件如下:
温度为180-250℃;
时间为8-12h;
优选地,所述单一小分子为0.2mmol/ml-0.4mmol/ml的柠檬酸氢二胺;
优选地,所述单一小分子为0.2mmol/ml-0.3mmol/ml的柠檬酸和0.3mmol/ml-0.35mmol/ml的二氰二胺;
优选地,所述单一小分子为0.2mmol/ml-0.3mmol/ml的柠檬酸和0.45mmol/ml-0.55mmol/ml的尿素。
9.权利要求1-3中任一项所述的复合纳米材料和/或权利要求4-8中任一项所述的制备方法得到的复合纳米材料在抗肿瘤药物中的应用。
10.根据权利要求9所述的的应用,其特征在于,所述复合纳米材料中的石墨烯量子点作为载体,负载有靶向分子;
优选地,所述靶向分子选自生物素、叶酸、RGD肽、透明质酸、TAT穿膜肽中的至少一种。
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310215985.9A CN116327967A (zh) | 2023-03-08 | 2023-03-08 | 一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和在抗肿瘤药物中的应用 |
CN202410169232.3A CN118416097A (zh) | 2023-03-08 | 2024-02-06 | 一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310215985.9A CN116327967A (zh) | 2023-03-08 | 2023-03-08 | 一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和在抗肿瘤药物中的应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116327967A true CN116327967A (zh) | 2023-06-27 |
Family
ID=86892277
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310215985.9A Pending CN116327967A (zh) | 2023-03-08 | 2023-03-08 | 一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和在抗肿瘤药物中的应用 |
CN202410169232.3A Pending CN118416097A (zh) | 2023-03-08 | 2024-02-06 | 一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和应用 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202410169232.3A Pending CN118416097A (zh) | 2023-03-08 | 2024-02-06 | 一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (2) | CN116327967A (zh) |
-
2023
- 2023-03-08 CN CN202310215985.9A patent/CN116327967A/zh active Pending
-
2024
- 2024-02-06 CN CN202410169232.3A patent/CN118416097A/zh active Pending
Also Published As
Publication number | Publication date |
---|---|
CN118416097A (zh) | 2024-08-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102025743B1 (ko) | 금속성 및 산화하프늄 소재를 포함하는 나노입자, 이의 제조 및 용도 | |
Liu et al. | Controllable growth of drug-encapsulated metal-organic framework (MOF) on porphyrinic MOF for PDT/chemo-combined therapy | |
WO2007033578A1 (fr) | Metallo-fullerenols et leur application dans la preparation de medicaments visant a inhiber la croissance tumorale | |
CN113751079B (zh) | 一种生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂及其构建方法和应用 | |
CN112107556A (zh) | 一种含砷纳米药物及其制备方法 | |
CN111317812B (zh) | 一种自组装肌肽荧光纳米颗粒、制备方法和应用 | |
CN110981918B (zh) | 一种修饰的铂类化合物及其制备方法与应用 | |
Chen et al. | Platinum (IV) Complex-Loaded nanoparticles with photosensitive activity for cancer therapy | |
Zhang et al. | Oxygen-deficient tungsten oxide perovskite nanosheets-based photonic nanomedicine for cancer theranostics | |
CN108904817B (zh) | 一种PEG/g-C3N4量子点复合荧光纳米微球及其应用 | |
Ding et al. | Applications of ROS-InducedZr-MOFs platform in multimodal synergistic therapy | |
CN112618514A (zh) | 氨硼烷/中空介孔聚多巴胺/聚乙二醇纳米复合粒子及其制备与应用 | |
CN113750252A (zh) | 一种钴掺杂的金属有机框架的纳米颗粒的制备方法及其应用 | |
CN116327967A (zh) | 一种铂纳米粒子/石墨烯量子点复合纳米材料及其制备方法和在抗肿瘤药物中的应用 | |
CN115590838A (zh) | 一种喜树碱纳米晶肿瘤靶向递送系统的制备方法及其应用 | |
Zhu et al. | Polyoxometalates immobilized on MIL-100 (Fe) as an emerging platform for eliminating breast cancer tumor cells | |
CN114432269A (zh) | 一种刺激响应性纳米递药系统的制备方法及其应用 | |
CN109276720B (zh) | 一种金属-有机物配合物纳米材料及其制备方法和应用 | |
Wang et al. | Metal‐Coordinated Polydopamine Structures for Tumor Imaging and Therapy | |
CN114949247B (zh) | 一种可稳定装载dna的杂化纳米粒及其制备方法与应用 | |
Thalkari et al. | Nanotechnology: The Future | |
CN113368235B (zh) | 一种Gd-NGQDs/BTS@PLGA-PEG纳米材料及其制备方法和应用 | |
Tuli | Nanotherapeutics in Cancer: Materials, Diagnostics, and Clinical Applications | |
CN116236459B (zh) | 一种羟乙基淀粉稳定的CuET纳米颗粒、纳米颗粒分散液及其制备方法和应用 | |
CN115252776B (zh) | 上转换-金属酚醛网络复合纳米材料的制备及其在肿瘤治疗方面的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20230627 |
|
WD01 | Invention patent application deemed withdrawn after publication |