WO1992006378A1 - Agents de diagnostic fluorescents auto-rassemblants - Google Patents
Agents de diagnostic fluorescents auto-rassemblants Download PDFInfo
- Publication number
- WO1992006378A1 WO1992006378A1 PCT/US1991/007380 US9107380W WO9206378A1 WO 1992006378 A1 WO1992006378 A1 WO 1992006378A1 US 9107380 W US9107380 W US 9107380W WO 9206378 A1 WO9206378 A1 WO 9206378A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- components
- aldehyde
- hydrazine
- target
- cells
- Prior art date
Links
- 229940039227 diagnostic agent Drugs 0.000 title description 2
- 239000000032 diagnostic agent Substances 0.000 title description 2
- 210000004027 cell Anatomy 0.000 claims description 33
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 10
- 239000003446 ligand Substances 0.000 claims description 8
- 230000008685 targeting Effects 0.000 claims description 6
- 238000000338 in vitro Methods 0.000 claims description 4
- 239000012634 fragment Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 210000004881 tumor cell Anatomy 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 7
- 125000003118 aryl group Chemical group 0.000 claims 2
- -1 phosphonium aldehyde Chemical class 0.000 claims 2
- 150000001299 aldehydes Chemical class 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 150000007857 hydrazones Chemical class 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 238000001000 micrograph Methods 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 201000008275 breast carcinoma Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 238000002073 fluorescence micrograph Methods 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000001338 self-assembly Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000011149 active material Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 238000012921 fluorescence analysis Methods 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 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
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0058—Antibodies
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
- G01N33/533—Production of labelled immunochemicals with fluorescent label
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
Definitions
- U.S. Patent 4,812,449 issued to the applicant herein and incorporated herein by reference discloses the general approach of providing active materials in the form of component precursors so as to permit self assembly in a target microenviron ent.
- a target refers to an organism, tissue, cell, or other biologically responsive material which it is desired to modify.
- the target will occur in a general environment which may be an j_n vitro or an n vivo environment, and supplies its own “microenvironment”.
- the patent discloses a large number of reaction types which may be employed to form a conjugate jLn situ, including hydrazone formation.
- the invention herein represents a particularly advantageous specific embodiment of this general approach—namely, use of a self-assembling conjugate to generate fluorescence for detection of target conditions either jj vivo or ij vitro.
- a self-assembling conjugate to generate fluorescence for detection of target conditions either jj vivo or ij vitro.
- it is possible to enhance the selectivity for target by conjugating one or both of the components of the self-assembling conjugate to a target-specific ligand.
- Figure 2 shows the ability of the conjugate M preformed or formed jln situ to label MCF-7 cells .in vitro.
- Figure 4 shows the effect of compounds K, M, and L on fluorescence emitted by MIA PaCa cells in . vitro.
- Figure 5 shows an isobologram for inhibition of MIA PaCa cells by various combinations of components K and L.
- the invention method relies in part on the ability of the components of the conjugates to migrate preferentially to the target organism, cell or tissue.
- suitable targets include those moieties whose detection is of medical interest, such as tumor cells, infectious organisms, diseased tissue, and the like.
- the homing specificity of the components can be enhanced by coupling the component to a targeting ligand using general coupling methods known in the art, including direct coupling, but preferentially utilizing linker molecules which permit more controlled coupling reactions.
- Commercially available linkers such as those from Pierce Chemical Company, Rockford, IL, may be used, for example.
- Figure 2A and B show the phase contrast photograph and fluorescent micrograph of MCF-7 cells treated with a saline control. No fluorescence is seen.
- C, E and G show the phase contrast photographs and D, F and H show fluorescence micrographs of MCF-7 cells which have been treated with reagents L, K or M, respectively, for 24 hours.
- panels D and F neither 11.2 ⁇ g/ml L or 16.8 ⁇ g/ml of K provided any fluorescence labeling for these cells.
- only 5 2.6 ⁇ g/ml of M provided a high contrast micrograph.
- panels A 1 and B 1 are the . corresponding results for MCF-7 cells incubated simultaneously for 24 hours with 5.6 ⁇ g/ml L and 8.5 ⁇ g/ml K.
- Panel B shows that a fluorescent signal is
- panels C and D' show that if L is administered before , even in higher amount, no fluorescence is obtained. Administration of 11.2 ⁇ g/ml L for 24 hours followed by washing and treatment with 16.8 ⁇ g/ml K for 24 hours did not result
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Urology & Nephrology (AREA)
- Cell Biology (AREA)
- Physics & Mathematics (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3517584A JPH06504365A (ja) | 1990-10-04 | 1991-10-03 | 自己組み立て蛍光診断薬 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US59247790A | 1990-10-04 | 1990-10-04 | |
US592,477 | 1990-10-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992006378A1 true WO1992006378A1 (fr) | 1992-04-16 |
Family
ID=24370806
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1991/007380 WO1992006378A1 (fr) | 1990-10-04 | 1991-10-03 | Agents de diagnostic fluorescents auto-rassemblants |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0554331A1 (fr) |
JP (1) | JPH06504365A (fr) |
WO (1) | WO1992006378A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0534380A1 (fr) * | 1991-09-24 | 1993-03-31 | Kyoto Daiichi Kagaku Co., Ltd. | Agent et procédé pour augmenter la chemiluminescence |
US20100216132A1 (en) * | 2008-09-05 | 2010-08-26 | Schwartz David A | Methods and compositions for direct detection of dna damage |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4671958A (en) * | 1982-03-09 | 1987-06-09 | Cytogen Corporation | Antibody conjugates for the delivery of compounds to target sites |
US4812449A (en) * | 1986-07-03 | 1989-03-14 | Scripps Clinic And Research Foundation | In situ active compound assembly |
US4868103A (en) * | 1986-02-19 | 1989-09-19 | Enzo Biochem, Inc. | Analyte detection by means of energy transfer |
US4937183A (en) * | 1988-02-03 | 1990-06-26 | Cytogen Corporation | Method for the preparation of antibody-fragment conjugates |
US5047227A (en) * | 1988-02-08 | 1991-09-10 | Cytogen Corporation | Novel and improved antibodies for site specific attachment of compounds |
-
1991
- 1991-10-03 WO PCT/US1991/007380 patent/WO1992006378A1/fr not_active Application Discontinuation
- 1991-10-03 EP EP19910919114 patent/EP0554331A1/fr not_active Withdrawn
- 1991-10-03 JP JP3517584A patent/JPH06504365A/ja active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4671958A (en) * | 1982-03-09 | 1987-06-09 | Cytogen Corporation | Antibody conjugates for the delivery of compounds to target sites |
US4868103A (en) * | 1986-02-19 | 1989-09-19 | Enzo Biochem, Inc. | Analyte detection by means of energy transfer |
US4812449A (en) * | 1986-07-03 | 1989-03-14 | Scripps Clinic And Research Foundation | In situ active compound assembly |
US4937183A (en) * | 1988-02-03 | 1990-06-26 | Cytogen Corporation | Method for the preparation of antibody-fragment conjugates |
US5047227A (en) * | 1988-02-08 | 1991-09-10 | Cytogen Corporation | Novel and improved antibodies for site specific attachment of compounds |
Non-Patent Citations (2)
Title |
---|
Analyst (London), Volume 115, No. 11, issued 1990, UZU et al., "Fluorogenic reagents: 4-amino sulfonyl-7-hydrazion-2,1.3-benzoxadiazol. 4-(N.N-dimethy)-aminosulfonyl)-7-hydrazino-2.1.3.-benzoxadiazole and 4-hydrazion-7-hydrazino-2.1.3-benzoxadiazole and 4-hydrazino-7-nitro-2.1.3-benzoxadiazole hydrazing for aldehydes and ketones", pages 1477-82. see CHEM. Abstract No.114:55043u. * |
Chemical & Pharmaceudical Bulletin, Volume 17, No. 11, issued 1969, MIZUTAN et al., "Fluorescence Assay of aOxo Acids with 4-Hydrazino-2-stibazole", pages 2340-2348, see entire document. * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0534380A1 (fr) * | 1991-09-24 | 1993-03-31 | Kyoto Daiichi Kagaku Co., Ltd. | Agent et procédé pour augmenter la chemiluminescence |
US20100216132A1 (en) * | 2008-09-05 | 2010-08-26 | Schwartz David A | Methods and compositions for direct detection of dna damage |
EP2604702A1 (fr) * | 2008-09-05 | 2013-06-19 | The University of Chicago | Procédés et compositions pour la détection directe de lésions de l'ADN |
US8580516B2 (en) * | 2008-09-05 | 2013-11-12 | University Of Chicago | Methods and compositions for direct detection of DNA damage |
Also Published As
Publication number | Publication date |
---|---|
JPH06504365A (ja) | 1994-05-19 |
EP0554331A1 (fr) | 1993-08-11 |
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