JP2016531840A - 抗癌化学療法剤用のケージ化された白金ナノクラスタ - Google Patents
抗癌化学療法剤用のケージ化された白金ナノクラスタ Download PDFInfo
- Publication number
- JP2016531840A JP2016531840A JP2016510669A JP2016510669A JP2016531840A JP 2016531840 A JP2016531840 A JP 2016531840A JP 2016510669 A JP2016510669 A JP 2016510669A JP 2016510669 A JP2016510669 A JP 2016510669A JP 2016531840 A JP2016531840 A JP 2016531840A
- Authority
- JP
- Japan
- Prior art keywords
- dendrimer
- complex
- caged
- platinum
- ptcl
- 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.)
- Granted
Links
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 188
- 229910052697 platinum Inorganic materials 0.000 title claims abstract description 76
- 230000001093 anti-cancer Effects 0.000 title description 10
- 239000002246 antineoplastic agent Substances 0.000 title description 9
- 229940127089 cytotoxic agent Drugs 0.000 title description 7
- 239000000412 dendrimer Substances 0.000 claims abstract description 117
- 229920000736 dendritic polymer Polymers 0.000 claims abstract description 117
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 48
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 28
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 24
- 239000002131 composite material Substances 0.000 claims abstract description 23
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910003446 platinum oxide Inorganic materials 0.000 claims abstract description 12
- 201000011510 cancer Diseases 0.000 claims abstract description 9
- 210000004027 cell Anatomy 0.000 claims description 61
- 150000001450 anions Chemical class 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 19
- 230000002194 synthesizing effect Effects 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 10
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 9
- 150000002500 ions Chemical class 0.000 claims description 7
- 239000002262 Schiff base Substances 0.000 claims description 5
- 150000004753 Schiff bases Chemical class 0.000 claims description 5
- 231100000135 cytotoxicity Toxicity 0.000 claims description 5
- 230000003013 cytotoxicity Effects 0.000 claims description 5
- 229920000962 poly(amidoamine) Polymers 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000000149 penetrating effect Effects 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 230000004565 tumor cell growth Effects 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims 2
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 231100000433 cytotoxic Toxicity 0.000 abstract 1
- 230000001472 cytotoxic effect Effects 0.000 abstract 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 25
- 229960004316 cisplatin Drugs 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 238000002347 injection Methods 0.000 description 19
- 239000007924 injection Substances 0.000 description 19
- 239000000243 solution Substances 0.000 description 17
- 238000011282 treatment Methods 0.000 description 17
- 230000002601 intratumoral effect Effects 0.000 description 16
- 150000001412 amines Chemical class 0.000 description 13
- XDHNQDDQEHDUTM-JQWOJBOSSA-N bafilomycin A1 Chemical compound CO[C@H]1\C=C\C=C(C)\C[C@H](C)[C@H](O)[C@H](C)\C=C(/C)\C=C(OC)\C(=O)O[C@@H]1[C@@H](C)[C@@H](O)[C@H](C)[C@]1(O)O[C@H](C(C)C)[C@@H](C)[C@H](O)C1 XDHNQDDQEHDUTM-JQWOJBOSSA-N 0.000 description 13
- XDHNQDDQEHDUTM-ZGOPVUMHSA-N bafilomycin A1 Natural products CO[C@H]1C=CC=C(C)C[C@H](C)[C@H](O)[C@H](C)C=C(C)C=C(OC)C(=O)O[C@@H]1[C@@H](C)[C@@H](O)[C@H](C)[C@]1(O)O[C@H](C(C)C)[C@@H](C)[C@H](O)C1 XDHNQDDQEHDUTM-ZGOPVUMHSA-N 0.000 description 13
- XDHNQDDQEHDUTM-UHFFFAOYSA-N bafliomycin A1 Natural products COC1C=CC=C(C)CC(C)C(O)C(C)C=C(C)C=C(OC)C(=O)OC1C(C)C(O)C(C)C1(O)OC(C(C)C)C(C)C(O)C1 XDHNQDDQEHDUTM-UHFFFAOYSA-N 0.000 description 13
- YHTTWXCDIRTOQX-FQJIPJFPSA-N (6S,9S,15S,18R,23R,26S,29S)-18-amino-6-(4-aminobutyl)-9,26-bis(carboxymethyl)-15-[3-(diaminomethylideneamino)propyl]-2,5,8,11,14,17,25,28-octaoxo-20,21-dithia-1,4,7,10,13,16,24,27-octazabicyclo[27.3.0]dotriacontane-23-carboxylic acid Chemical compound NCCCC[C@@H]1NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]2CCCN2C(=O)CNC1=O)C(O)=O YHTTWXCDIRTOQX-FQJIPJFPSA-N 0.000 description 10
- 229960005540 iRGD Drugs 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- 239000002609 medium Substances 0.000 description 10
- 230000037361 pathway Effects 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000030833 cell death Effects 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
- 230000006907 apoptotic process Effects 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 206010006187 Breast cancer Diseases 0.000 description 7
- 208000026310 Breast neoplasm Diseases 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 150000001299 aldehydes Chemical class 0.000 description 7
- 230000009089 cytolysis Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- 230000002132 lysosomal effect Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 108010040476 FITC-annexin A5 Proteins 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000002105 nanoparticle Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 230000004614 tumor growth Effects 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QZPSXPBJTPJTSZ-UHFFFAOYSA-N aqua regia Chemical compound Cl.O[N+]([O-])=O QZPSXPBJTPJTSZ-UHFFFAOYSA-N 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 210000001163 endosome Anatomy 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 210000003463 organelle Anatomy 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 230000005760 tumorsuppression Effects 0.000 description 4
- 102000003952 Caspase 3 Human genes 0.000 description 3
- 108090000397 Caspase 3 Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 238000012288 TUNEL assay Methods 0.000 description 3
- 238000004833 X-ray photoelectron spectroscopy Methods 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 239000003929 acidic solution Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 3
- 229960004562 carboplatin Drugs 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000012202 endocytosis Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 235000012631 food intake Nutrition 0.000 description 3
- 150000002466 imines Chemical group 0.000 description 3
- 238000001095 inductively coupled plasma mass spectrometry Methods 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 210000003712 lysosome Anatomy 0.000 description 3
- 230000001868 lysosomic effect Effects 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- GOUHYARYYWKXHS-UHFFFAOYSA-N 4-formylbenzoic acid Chemical compound OC(=O)C1=CC=C(C=O)C=C1 GOUHYARYYWKXHS-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 229920005654 Sephadex Polymers 0.000 description 2
- 239000012507 Sephadex™ Substances 0.000 description 2
- 238000003917 TEM image Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 2
- 229960002576 amiloride Drugs 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000005571 anion exchange chromatography Methods 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 230000004700 cellular uptake Effects 0.000 description 2
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 2
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 2
- 229960001076 chlorpromazine Drugs 0.000 description 2
- 230000006395 clathrin-mediated endocytosis Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000002149 energy-dispersive X-ray emission spectroscopy Methods 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 231100000682 maximum tolerated dose Toxicity 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000004898 mitochondrial function Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229960000988 nystatin Drugs 0.000 description 2
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100000057 systemic toxicity Toxicity 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- VQVUBYASAICPFU-UHFFFAOYSA-N (6'-acetyloxy-2',7'-dichloro-3-oxospiro[2-benzofuran-1,9'-xanthene]-3'-yl) acetate Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(Cl)=C(OC(C)=O)C=C1OC1=C2C=C(Cl)C(OC(=O)C)=C1 VQVUBYASAICPFU-UHFFFAOYSA-N 0.000 description 1
- HSTOKWSFWGCZMH-UHFFFAOYSA-N 3,3'-diaminobenzidine Chemical compound C1=C(N)C(N)=CC=C1C1=CC=C(N)C(N)=C1 HSTOKWSFWGCZMH-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 230000007018 DNA scission Effects 0.000 description 1
- AHCYMLUZIRLXAA-SHYZEUOFSA-N Deoxyuridine 5'-triphosphate Chemical compound O1[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C=C1 AHCYMLUZIRLXAA-SHYZEUOFSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 238000001237 Raman spectrum Methods 0.000 description 1
- 231100000991 Reactive Oxygen Species (ROS) Photosafety Assay Toxicity 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 238000000026 X-ray photoelectron spectrum Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 230000006721 cell death pathway Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000006059 cover glass Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 238000000724 energy-dispersive X-ray spectrum Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000001046 green dye Substances 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 238000000024 high-resolution transmission electron micrograph Methods 0.000 description 1
- 238000002173 high-resolution transmission electron microscopy Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007309 lysosomal acidification Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- SMBBZHGTZJNSRQ-UHFFFAOYSA-N n'-(6,6-dichlorohexyl)methanediimine Chemical compound ClC(Cl)CCCCCN=C=N SMBBZHGTZJNSRQ-UHFFFAOYSA-N 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000021962 pH elevation Effects 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000010069 protein adhesion Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000021419 recognition of apoptotic cell Effects 0.000 description 1
- 239000001044 red dye Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- -1 silver ions Chemical class 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- JUJBNYBVVQSIOU-UHFFFAOYSA-M sodium;4-[2-(4-iodophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=N1 JUJBNYBVVQSIOU-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000010301 surface-oxidation reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000013298 xenograft nude mouse model Methods 0.000 description 1
Classifications
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K47/59—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/595—Polyamides, e.g. nylon
-
- 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
- A61K47/59—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- 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
- 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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Biomedical Technology (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
(a)八面体のヘキサクロロ白金酸アニオンを含む第1の溶液を、アミン終端デンドリマー又はヒドロキシル終端デンドリマーを含む第2の溶液と混和して、PtCl6 2−アニオン/デンドリマー複合体を含む混合物を形成する工程と、
(b)PtCl6 2−アニオン/デンドリマー複合体を含む混合物を所定時間インキュベートする工程と、
(c)PtCl6 2−アニオン/デンドリマー複合体中のPtCl6 2−アニオンを還元して、デンドリマーでケージ化された白金ナノクラスタ複合体を含む混合物を形成する工程と、
(d)デンドリマーでケージ化された白金ナノクラスタ複合体を含む混合物をフィルタに通過させて、デンドリマーでケージ化された白金ナノクラスタ複合体を含む濾液を取得する工程と、
(e)濾液を凍結乾燥して、デンドリマーでケージ化された白金ナノクラスタ複合体を取得する工程とを含むケージ化された白金ナノクラスタ複合体を合成する方法に関する。
(i)溶媒に、
(a)アミン終端デンドリマー又はヒドロキシル終端デンドリマーと、
(b)酸化白金を含み、アミン終端デンドリマー又はヒドロキシル終端デンドリマーの内部に閉じ込められる白金ナノクラスタと、
を含む上述のデンドリマーでケージ化された白金ナノクラスタ複合体を溶解させて溶液を形成し、
(ii)デンドリマーがアミンで終端された条件でPEGアルデヒドを溶液中に添加、又は、デンドリマーがヒドロキシル終端された条件でPEG−NH2を溶液中に添加し、
(iii)PEGアルデヒドをアミン終端デンドリマーの第一級アミンと反応させる、又は、PEG−NH2をヒドロキシル終端デンドリマーと反応させて、二重ケージ化された白金ナノクラスタ複合体を取得する、二重ケージ化された白金ナノクラスタ複合体を合成する方法に関する。
(a)治療に有効な量の上述の複合体と、
(b)医薬上許容される担体と、
を含む、医薬組成物に関する。
本明細書中に使用される用語は概して、本発明の文脈において、また各々の用語が使用される特定の文脈において、当該技術分野におけるそれらの通常の意味を有するものである。本発明を記載するために使用される特定の用語は、以下、又は本明細書中の他の部分で論じられ、本発明の記載に関わる実務者に付加的な手引きを提供するものである。便宜上、幾つかの用語を強調することもあり、例えば、イタリック及び/又は引用符を使用することもある。強調を使用しても用語の範囲及び意味に影響を与えることはなく、それが強調されるにせよされないにせよ、同様の文脈において用語の範囲及び意味は同じである。同じ事項を、2つ以上の方法で述べることがあることを理解されたい。したがって、ここで論じられる用語のいずれか1つ又は複数に、代替的な用語及び同義語を使用してもよく、また、用語がここで補足説明されるか又は述べられるかにせよされないにせよ、それに特殊な意義が課されることもない。幾つかの用語に対して同義語を提示している。1つ又は複数の同義語の詳説は、他の同義語の使用を排除するものではない。ここに述べられるあらゆる用語の用例を含む本明細書全体での用例の使用は、例示を目的とするにすぎず、本発明又は例を挙げた全ての用語の範囲及び意味を限定するものではない。同様に、本発明は本明細書中に与えられる様々な実施形態に限定されるものでもない。
HED=動物の投与量(mg/kg)×(動物の体重(kg)/ヒトの体重(kg))0.33
による計算によって得ることができることを開示している。HEDは、投与の経路等の他の因子に応じて様々な値をとることができる。例えばDCPNのi.v.投与では、マウス(20グラムBW)の投与量が16.6μmol/kgであれば、その際、HEDは16.6μmol/kg×(0.02/患者の体重)0.33と算出することができる。CPNのIT注射では、マウスの投与量が7.5mg/kgであれば、その際、HEDは7.5mg/kg×(0.02/患者の体重)0.33となる。
(a)アミン終端デンドリマーと、
(b)酸化白金を含み、アミン終端デンドリマーの内部(内側)に閉じ込められる白金ナノクラスタと、
から本質的になるか又はそれらからなる。
(a)治療に有効な量の上述の複合体と、
(b)医薬上許容される担体と、
を含む、医薬組成物に関する。
(a)八面体のヘキサクロロ白金酸アニオンを含む第1の溶液を、アミン終端デンドリマー又はヒドロキシル終端デンドリマーを含む第2の溶液と混和して、PtCl6 2−アニオン/デンドリマー複合体を含む混合物を形成する工程と、
(b)PtCl6 2−アニオン/デンドリマー複合体を含む混合物を所定時間インキュベートする工程と、
(c)PtCl6 2−アニオン/デンドリマー複合体中のPtCl6 2−アニオンを還元して、デンドリマーでケージ化された白金ナノクラスタ複合体を含む混合物を形成する工程と、
(d)デンドリマーでケージ化された白金ナノクラスタ複合体を含む混合物をフィルタに通過させて、デンドリマーでケージ化された白金ナノクラスタ複合体を含む濾液を取得する工程と、
(e)濾液を凍結乾燥して、デンドリマーでケージ化された白金ナノクラスタ複合体を取得する工程と、
を含む、上述のケージ化された白金ナノクラスタ複合体を合成する方法に関する。
(i)溶媒に、
(a)アミン終端デンドリマー又はヒドロキシル終端デンドリマーと、
(b)アミン終端デンドリマー又はヒドロキシル終端デンドリマーの内部に閉じ込められた酸化白金を含む白金ナノクラスタと、
を含む上述のデンドリマーでケージ化された白金ナノクラスタ複合体を溶解して溶液を形成する工程と、
(ii)複合体がアミン終端デンドリマーを含む条件でPEGアルデヒドを溶液中に添加する、又は、複合体がヒドロキシル終端デンドリマーを含む条件でPEG−NH2を溶液中に添加する工程と、
(iii)PEGアルデヒドを、アミン終端デンドリマーの第一級アミンと反応させる、又は、PEG−NH2をヒドロキシル終端デンドリマーと反応させて、二重ケージ化された白金ナノクラスタ複合体を取得する工程と、
を含む、二重ケージ化された白金ナノクラスタ複合体を合成する方法に関する。
CPNの合成及び特性解析。H2PtCl6(Acros、200μL、30μmol、150mM)及びK2PtCl4(UniRegion Bio-Tech、200μL、30μmol、150mM)をそれぞれ、G2NH2又はG2OH又はG2COOH(Aldrich、94.7μL、5μmol、20wt%メタノール溶液)を含有する20mLの脱イオン水に添加した。マイクロ波によって照射(CEM、Discover LabMate System、300W/120℃及び30分間)する前に、G2NH2又はG2OH又はG2COOHと、H2PtCl6又はK2PtCl4との混合物を室温で一晩インキュベートした。還元後、0.22μmメンブレンフィルタ(Millipore、PES膜、白金ナノクラスタ用)に通して沈殿した大きい白金ナノ粒子を濾過した。溶液を凍結乾燥させた後、約1mLの水に溶解させて、更に精製する必要がある。過剰なアニオン(PtCl6 2−及びPtCl4 2−)を更に除去するために、アニオン交換クロマトグラフィ(Merck、Fractogel EMD TMAE Hicap)を使用し、精製されたCPNとPNの凝集物(aggregations)が得られた。高分解能透過型電子顕微鏡(HRTEM、JEOL−2010)を用いて、CPNとPNの集合体のサイズを特定した。
本発明者らは、低世代のアミン終端デンドリマー(G2NH2)をケージとして使用し、特異的な幾何学的形状を有するアニオンを捕捉することにより、ケージ化されたPN(CPN、図1A、経路ii)を形成した。CPNは、追加される開裂性のPEGコロナ及びiRGD(CRGDKGPDC;配列番号1)等の標的可能な分子で更に改変されることで、腫瘍を標的化するとともに、外側のPEGコロナを取って抗癌化学療法剤にかかる腫瘍内活性化を作用させて悪性細胞に対して毒素を放出することができた(図1B)。
Claims (20)
- (a)デンドリマーと、
(b)酸化白金を含み、前記デンドリマーの内部に閉じ込められる白金ナノクラスタと、
(c)前記デンドリマーの表面を被覆するポリエチレングリコール(PEG)と、
を含む二重ケージ化された白金ナノクラスタ複合体。 - 前記酸化白金が、PtO、PtOH、PtO2、PtxOy、及びそれらの任意の組合せ(式中、x、yはそれぞれ0より大きい整数である)からなる群から選択される請求項1に記載の複合体。
- 前記デンドリマーがアミン終端デンドリマーである請求項1に記載の複合体。
- 前記PEGがシッフ塩基を通じて前記アミン終端デンドリマーの第一級アミンと結合する、請求項3に記載の複合体。
- 表面にpH応答性結合を含む請求項1に記載の複合体。
- 前記デンドリマーの表面上に吸収される腫瘍浸透ペプチドを更に含む請求項1に記載の複合体。
- pH5.0未満の条件下で、Pt2+イオン、PtCl4 2−イオン及び/又はPtCl6 2−イオンを放出する請求項1に記載の複合体。
- 前記白金ナノクラスタが、pH5.0未満の条件下で溶解性を示す請求項3に記載の複合体。
- 前記ナノクラスタが1.3nm未満の平均サイズを有する請求項1に記載の複合体。
- 前記デンドリマーが、世代−0(G−0)、世代−1(G−1)、世代−2(G−2)及び世代−3(G−3)デンドリマーからなる群から選択される請求項1に記載の複合体。
- 腫瘍細胞の成長を抑制する医薬品の製造における、請求項1〜10のいずれか一項に記載の二重ケージ化された白金ナノクラスタ複合体の使用。
- 請求項1〜10のいずれか一項に記載の二重ケージ化された白金ナノクラスタ複合体を合成する方法であって、
(a)八面体のヘキサクロロ白金酸アニオンを含む第1の溶液を、アミン終端デンドリマー又はヒドロキシル終端デンドリマーを含む第2の溶液と混和して、PtCl6 2−アニオン/デンドリマー複合体を含む混合物を形成し、
(b)前記PtCl6 2−アニオン/デンドリマー複合体を含む前記混合物を所定時間インキュベートし、
(c)前記PtCl6 2−アニオン/デンドリマー複合体中のPtCl6 2−アニオンを還元して、デンドリマーでケージ化された白金ナノクラスタ複合体を含む混合物を形成し、
(d)前記デンドリマーでケージ化された白金ナノクラスタ複合体を含む前記混合物をフィルタに通過させて、前記デンドリマーでケージ化された白金ナノクラスタ複合体を含む濾液を取得し、
(e)前記濾液を凍結乾燥して前記デンドリマーでケージ化された白金ナノクラスタ複合体を取得し、
(f)前記デンドリマーでケージ化された白金ナノクラスタ複合体を溶媒に溶解して溶液を形成し、
(g)前記デンドリマーがアミン終端された条件でPEGアルデヒドを前記溶液中に添加、又は、前記デンドリマーがヒドロキシル終端された条件でPEG−NH2を前記溶液中に添加し、
(h)前記PEGアルデヒドを前記アミン終端デンドリマーの第一級アミンと反応させる、又は、前記PEG−NH2を前記ヒドロキシル終端デンドリマーと反応させて、二重ケージ化された白金ナノクラスタ複合体を取得する、二重ケージ化された白金ナノクラスタ複合体を合成する方法。 - (a)アミン終端デンドリマーと、
(b)酸化白金を含むと共に0.22nmの標準偏差を伴う0.93nmの平均直径を有し、前記アミン終端デンドリマーの内部に閉じ込められる白金ナノクラスタと、
を含むケージ化された白金ナノクラスタ複合体。 - 請求項13に記載の複合体を合成する方法であって、
(a)八面体のヘキサクロロ白金酸アニオンを含む第1の溶液を、アミン終端デンドリマーを含む第2の溶液と混和して、PtCl6 2−アニオン/デンドリマー複合体を含む混合物を形成し、
(b)前記PtCl6 2−アニオン/デンドリマー複合体を含む前記混合物を所定時間インキュベートし、
(c)前記PtCl6 2−アニオン/デンドリマー複合体中のPtCl6 2−アニオンを還元して、デンドリマーでケージ化された白金ナノクラスタ複合体を含む混合物を形成し、
(d)前記デンドリマーでケージ化された白金ナノクラスタ複合体を含む前記混合物をフィルタに通過させて、前記デンドリマーでケージ化された白金ナノクラスタ複合体を含む濾液を取得し、
(e)前記濾液を凍結乾燥して、前記デンドリマーでケージ化された白金ナノクラスタ複合体を取得する、複合体を合成する方法。 - 前記還元する工程は、マイクロ波を照射して行う請求項12又は14に記載の方法。
- 前記インキュベートする工程は、室温で一晩行う請求項12又は14に記載の方法。
- 工程(e)は、余分なPtCl6 2−を除去することによって、前記デンドリマーでケージ化された白金ナノクラスタ複合体を精製することを更に含む請求項12又は14に記載の方法。
- 前記デンドリマーは、ポリアミドアミン(PAMAM)デンドリマーである請求項1〜10及び13のいずれか一項に記載の複合体。
- ヘキサクロロ白金酸アニオン及び/又はテトラクロロ白金酸アニオンを含まない請求項1〜10及び13のいずれか一項に記載の複合体。
- 癌細胞に対する細胞毒性を示す請求項1〜10及び13のいずれか一項に記載の複合体。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361766281P | 2013-02-19 | 2013-02-19 | |
US61/766,281 | 2013-02-19 | ||
PCT/US2014/016826 WO2014130429A2 (en) | 2013-02-19 | 2014-02-18 | Caged platinum nanoclusters for anticancer chemotherapeutics |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018206566A Division JP2019038836A (ja) | 2013-02-19 | 2018-11-01 | 抗癌化学療法剤用のケージ化された白金ナノクラスタ |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2016531840A true JP2016531840A (ja) | 2016-10-13 |
JP6693868B2 JP6693868B2 (ja) | 2020-05-13 |
Family
ID=51351349
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016510669A Active JP6693868B2 (ja) | 2013-02-19 | 2014-02-18 | 抗癌化学療法剤用のケージ化された白金ナノクラスタ |
JP2018206566A Pending JP2019038836A (ja) | 2013-02-19 | 2018-11-01 | 抗癌化学療法剤用のケージ化された白金ナノクラスタ |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018206566A Pending JP2019038836A (ja) | 2013-02-19 | 2018-11-01 | 抗癌化学療法剤用のケージ化された白金ナノクラスタ |
Country Status (12)
Country | Link |
---|---|
US (1) | US9095616B2 (ja) |
EP (1) | EP2958553B1 (ja) |
JP (2) | JP6693868B2 (ja) |
KR (1) | KR101999421B1 (ja) |
CN (1) | CN105451721B (ja) |
AU (1) | AU2014219129B2 (ja) |
BR (1) | BR112015019949A2 (ja) |
CA (1) | CA2901050C (ja) |
IL (1) | IL240652A0 (ja) |
RU (1) | RU2015135133A (ja) |
TW (1) | TWI508732B (ja) |
WO (1) | WO2014130429A2 (ja) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI594794B (zh) * | 2015-01-26 | 2017-08-11 | 國立臺灣科技大學 | 催化性的中孔徑多孔奈米複合材料、其製備方法及應用 |
TWI601534B (zh) * | 2016-03-03 | 2017-10-11 | 財團法人國家衛生研究院 | 內毒素奈米微粒:親水性奈米金控制內毒素聚集結構形成奈米微粒進而調節免疫反應 |
AU2017306328B2 (en) * | 2016-08-05 | 2021-05-06 | Shenzhen Profound-View Pharma Tech Co., Ltd. | Substance containing gold cluster and preparation method and use thereof |
US20210015944A1 (en) * | 2017-01-09 | 2021-01-21 | The Curators Of The University Of Missouri | Targeted Doxorubicin-Gold Nanocojugates for Tumor Therapy |
EP4141110A1 (en) | 2020-04-24 | 2023-03-01 | Obshchestvo S Ogranichennoy Otvetstvennost'yu "Ingenik" | Method for producing particles of bacteriophages of the genus levivirus |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009269998A (ja) * | 2008-05-07 | 2009-11-19 | Osaka Prefecture Univ | ヘッド−テイル型共重合体の中空ナノ微粒子 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2130553A1 (en) * | 2008-06-05 | 2009-12-09 | Nanobiotix | Inorganic nanoparticles of high density to destroy cells in-vivo |
CN109293927A (zh) * | 2009-02-04 | 2019-02-01 | 布里格姆及妇女医院股份有限公司 | 纳米级铂化合物及其使用方法 |
-
2014
- 2014-02-18 BR BR112015019949A patent/BR112015019949A2/pt not_active IP Right Cessation
- 2014-02-18 US US14/182,532 patent/US9095616B2/en active Active
- 2014-02-18 AU AU2014219129A patent/AU2014219129B2/en active Active
- 2014-02-18 CN CN201480012173.3A patent/CN105451721B/zh active Active
- 2014-02-18 JP JP2016510669A patent/JP6693868B2/ja active Active
- 2014-02-18 RU RU2015135133A patent/RU2015135133A/ru not_active Application Discontinuation
- 2014-02-18 CA CA2901050A patent/CA2901050C/en active Active
- 2014-02-18 EP EP14754414.2A patent/EP2958553B1/en active Active
- 2014-02-18 KR KR1020157025760A patent/KR101999421B1/ko active IP Right Grant
- 2014-02-18 WO PCT/US2014/016826 patent/WO2014130429A2/en active Application Filing
- 2014-02-19 TW TW103105579A patent/TWI508732B/zh active
-
2015
- 2015-08-18 IL IL240652A patent/IL240652A0/en unknown
-
2018
- 2018-11-01 JP JP2018206566A patent/JP2019038836A/ja active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009269998A (ja) * | 2008-05-07 | 2009-11-19 | Osaka Prefecture Univ | ヘッド−テイル型共重合体の中空ナノ微粒子 |
Non-Patent Citations (3)
Title |
---|
ADVANCED MATERIALS, 1999, 11, NO.3, P.217-220, JPN6017045455 * |
ADVANCED MTERIALS, AUGUST 2013, VOL.25, P.5067-5073, JPN6017045458 * |
BIOCONJUGATE CHEM., 2000, VOL.11, P.910-917, JPN6017045457 * |
Also Published As
Publication number | Publication date |
---|---|
BR112015019949A2 (pt) | 2017-08-29 |
CN105451721B (zh) | 2019-01-04 |
TWI508732B (zh) | 2015-11-21 |
EP2958553B1 (en) | 2018-02-14 |
WO2014130429A3 (en) | 2014-10-23 |
IL240652A0 (en) | 2015-10-29 |
CA2901050A1 (en) | 2014-08-28 |
AU2014219129B2 (en) | 2016-07-28 |
EP2958553A2 (en) | 2015-12-30 |
JP6693868B2 (ja) | 2020-05-13 |
RU2015135133A (ru) | 2017-03-24 |
AU2014219129A1 (en) | 2015-08-20 |
KR20150119417A (ko) | 2015-10-23 |
JP2019038836A (ja) | 2019-03-14 |
KR101999421B1 (ko) | 2019-07-11 |
WO2014130429A2 (en) | 2014-08-28 |
US9095616B2 (en) | 2015-08-04 |
CN105451721A (zh) | 2016-03-30 |
EP2958553A4 (en) | 2016-10-12 |
TW201444565A (zh) | 2014-12-01 |
US20140234413A1 (en) | 2014-08-21 |
CA2901050C (en) | 2017-06-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2019038836A (ja) | 抗癌化学療法剤用のケージ化された白金ナノクラスタ | |
Kundu et al. | Tumor targeted delivery of umbelliferone via a smart mesoporous silica nanoparticles controlled-release drug delivery system for increased anticancer efficiency | |
Cui et al. | Renal clearable Ag nanodots for in vivo computer tomography imaging and photothermal therapy | |
Zhang et al. | Dual-stimuli-responsive, polymer-microsphere-encapsulated CuS nanoparticles for magnetic resonance imaging guided synergistic chemo-photothermal therapy | |
Zhai et al. | Self-activated arsenic manganite nanohybrids for visible and synergistic thermo/immuno-arsenotherapy | |
Jing et al. | A multifunctional micellar nanoplatform with pH‐triggered cell penetration and nuclear targeting for effective cancer therapy and inhibition to lung metastasis | |
JP7537779B2 (ja) | ビリルビン誘導体及び金属を含む粒子 | |
Wei et al. | OFF–ON nanodiamond drug platform for targeted cancer imaging and therapy | |
Zhang et al. | In vivo tailor-made protein corona of a prodrug-based nanoassembly fabricated by redox dual-sensitive paclitaxel prodrug for the superselective treatment of breast cancer | |
Zhao et al. | Programmable co-assembly of various drugs with temperature sensitive nanogels for optimizing combination chemotherapy | |
Zuo et al. | Macrophage-mimic hollow mesoporous fe-based nanocatalysts for self-amplified chemodynamic therapy and metastasis inhibition via tumor microenvironment remodeling | |
Quarta et al. | Novel synthesis of platinum complexes and their intracellular delivery to tumor cells by means of magnetic nanoparticles | |
Du et al. | A tumor-targeted, intracellular activatable and theranostic nanodiamond drug platform for strongly enhanced in vivo antitumor therapy | |
Muj et al. | Synergistic action of lactoferrin in enhancing the safety and effectiveness of docetaxel treatment against prostate cancer | |
Kaur et al. | Glycol chitosan stabilized nanomedicine of lapatinib and doxorubicin for the management of metastatic breast tumor | |
Zhang et al. | Construction of a pH/TGase “dual key”-responsive gold nano-radiosensitizer with liver tumor-targeting ability | |
Wang et al. | Reactive Oxygen Species Amplifier for Apoptosis-Ferroptosis Mediated High-Efficiency Radiosensitization of Tumors | |
Kaur et al. | Gold-capsuled polymeric nanomedicine for synergistic breast cancer photo-chemotherapy | |
Yeroslavsky et al. | Polydopamine Nanoparticles Containing a Cisplatin Analog for Anticancer Treatment and Diagnostics | |
Shi et al. | Fluorescent realgar nanoclusters for nuclear targeting-triggered tumor theranostics | |
Liu et al. | Treatment of microvascular invasion in hepatocellular carcinoma with drug‐loaded nanocomposite platform under synergistic effect of magnetic field/near‐infrared light | |
Cheng et al. | Biotin-Conjugated Upconversion KMnF3/Yb/Er Nanoparticles for Metabolic Magnetic Resonance Imaging of the Invasive Margin of Glioblastoma | |
Maiti et al. | Terbium-Rose Bengal Coordination Nanocrystals-Induced ROS Production under Low-Dose X-rays in Cultured Cancer Cells for Photodynamic Therapy | |
Bai et al. | Enhancing Ovarian Cancer Treatment with Maleimide-Modified Pt (IV) Prodrug Nanoparticles | |
Zhao et al. | Facile Synthesis of Basic Copper Carbonate Nanosheets for Photoacoustic Imaging-Guided Tumor Apoptosis and Ferroptosis and the Extension Exploration of the Synthesis Method |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20170213 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20171129 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20171205 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20180301 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20180501 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20180703 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20181102 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200416 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6693868 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |