WO1992014493A1 - Elements conjugues non proteiques de liaison de recepteur intracellulaire - Google Patents

Elements conjugues non proteiques de liaison de recepteur intracellulaire Download PDF

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Publication number
WO1992014493A1
WO1992014493A1 PCT/US1992/001072 US9201072W WO9214493A1 WO 1992014493 A1 WO1992014493 A1 WO 1992014493A1 US 9201072 W US9201072 W US 9201072W WO 9214493 A1 WO9214493 A1 WO 9214493A1
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Prior art keywords
therapeutic
agent
agents
intracellular
diagnostic agent
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PCT/US1992/001072
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English (en)
Inventor
Christopher Capelli
Herbert Paaren
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Christopher Capelli
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Publication of WO1992014493A1 publication Critical patent/WO1992014493A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • 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
    • A61K49/0052—Small organic molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

Definitions

  • This invention relates to non-protein intracellular receptor binding molecules (hereinafter referred to as "receptor binding molecules”) conjugated to therapeutic, or to diagnostic agents via a linker molecule and a method for the in vivo intracellular delivery of such agents.
  • receptor binding molecules non-protein intracellular receptor binding molecules conjugated to therapeutic, or to diagnostic agents via a linker molecule and a method for the in vivo intracellular delivery of such agents.
  • a number of targeting agents have been utilized with varying degrees of success in the in vivo delivery of diagnostic and/or therapeutic agents to target sites.
  • Antibodies, certain hormones, such as insulin, and other proteins are exemplary of such targeting agents.
  • linker moieties have been reported for use with antibodies.
  • therapeutic agents conjugated to antibodies via certain peptide linking molecules which are susceptible to cleavage by enzymes are disclosed by Goers et al. in U.S. patent No. 4,876,973.
  • Goers also discloses linker moieties comprised of non-cleavable molecules such as amino acids, peptides and other organic compounds.
  • metal-ions conjugated to antibodies via chelating compounds are reported in U.S. patent No. 4,741,900.
  • Pozansky in U.S. patent No. 4,749,570, discloses the use of an insulin conjugate.
  • Pozansky discloses a complex comprising insulin, a protein, conjugated to an enzyme, the therapeutic agent, via albumin, the linker molecule. This complex is used to deliver the enzyme to the surface of the targeted cell.
  • Wilbur et al. utilized a modified cellular substrate as a linking group to attach a ligand, such as a drug or radionuclide, to a targeting antibody or antibody fragment.
  • the targeting antibody brings the modified cellular substrate linker into close contact with the targeted cell membrane. The linker is then transported across the cell membrane. Once inside the cell, the modified linker cannot be readily metabolized. Thus, the time the substrate is retained in the cell is greatly extended and the amount of time the cell is exposed to the therapeutic or diagnostic agent bound to the linker is concomitantly increased.
  • targeting agents are large molecular weight moieties that share the common characteristic of specifically binding epitopes located on the cell surface.
  • the most commonly employed targeting agents are antibodies and antibody fragments which are large molecular weight molecules which specifically bind epitopes located on the cell surface. The size of such targeting agents alone prevents their transport across the cell membrane.
  • targeting agents Because of these properties, the usefulness of these targeting agents in bringing the therapeutic or diagnostic agent into close proximity with the targeted cell is limited. As a result, the effect of the therapeutic or diagnostic agent on the intracellular region of the targeted cell is minimized.
  • a targeting agent that binds intracellular receptors is transported across the cell membrane. Therapeutic or diagnostic agents conjugated to such a receptor binding molecule may also be transported into the intracellular region of the targeted cell where they are likely to be more effective.
  • 123 I-17-/S-estradiol as a labeled targeting agent in certain imaging and therapeutic methods. These methods are specifically used for the treatment or imaging of tissue which contain steroid receptors. Although j8-estradiol is a relatively small molecule with an approximate molecular weight of 350, it can be labeled with 123 I because 123 I readily substitutes for a hydrogen atom on the estradiol molecule. Due to the small size of such non-protein intracellular receptor binding molecules, direct conjugation of therapeutic or diagnostic agents other than a radionuclide such as 123 I is not feasible. Therefore, a need continues to exists for a means of conjugating therapeutic and diagnostic agents to intracellular receptor binding molecules so that these receptor binding molecules can be more effectively exploited as targeting agents for the in vivo intracellular delivery of therapeutic and diagnostic agents.
  • a targeting agent for the intracellular delivery of a therapeutic or diagnostic agent comprising a conjugate comprised of (i) a non- protein molecule which binds an intracellular receptor, (ii) a therapeutic or diagnostic agent and (iii) a linker moiety joining said agent to said non-protein molecule.ffi a preferred embodiment, the linker molecule is any functional organic compound or reagent with a functionality greater than 1 that is capable of covalently attaching to both the non-protein molecule which binds to an intracellular receptor and the therapeutic or diagnostic agent.
  • the therapeutic agent is selected from the group consisting of pharmaceutical agents, enzymes, antibiotics, antimetabolites, antiproliferative agents, neurotransmitters, DNA radio-opaque dyes, radioactive isotopes, fluorogenic compounds, marker compounds, lectins, cell membrane altering comgenic compounds, photochemicals and boron-containing agents.
  • the diagnostic agent is selected from the group consisting of chelated radiopharmaceuticals, paramagnetic metals, and photodynamic agents.
  • a pharmaceutical composition is provided that is suitable for in vivo administration, comprising an effective amount of a conjugate comprised of (i) a non-protein molecule which binds an intracellular receptor, (ii) a therapeutic or diagnostic agent and (iii) a linker moiety joining said agent to said non-protein molecule and a pharmaceutically acceptable carrier.
  • a use is provided of a conjugate comprised of aforementioned components (i) , (ii) and (iii) in the preparation of an agent for use in a method for intracellular delivery in vivo of a therapeutic or diagnostic agent.
  • conjugated non-protein intracellular receptor binding molecules can be effectively employed as targeting agents for the in vivo delivery of a number of therapeutic and diagnostic agents. It is the specificity of such a receptor binding molecule that renders it ideally suitable for the delivery of these agents to specific cells, tissues, organs or any other site with the particular receptor.
  • Intracellular receptor binding molecules are relatively small molecules that possess distinct structural characteristics which are critical to their ability to bind to a receptor. Conjugation of a therapeutic or diagnostic agent to such a molecule causes substantial interference with the structural features which determine the molecule's ability to bind a receptor. Thus, these molecules were not previously considered to be useful as targeting agents for the in vivo delivery of therapeutic and diagnostic agents. In accordance with the present invention, it has been determined that structural binding incompatibilities of this nature can be avoided by conjugating therapeutic or diagnostic agents to a receptor binding molecule via a suitable linker molecule.
  • intracellular receptor binding molecule that can be conjugated to a therapeutic or diagnostic agent via a linker compound which retains its ability to bind to the receptor is suitable for use within the present invention.
  • suitable intracellular receptor binding molecules are adrenocorticosteroids, progestins, anti-progestins, estrogens, anti-estrogens (steroidal or non-steroidal) , androgens and anti-androgens, as well as thyroid hormone compounds, vitamin D compounds and their respective analogs.
  • the intracellular receptor binding molecule is comprised of an analog of estradiol.
  • a linker molecule within the present invention binds to the receptor binding molecule without compromising the critical structural characteristics which permit the conjugated molecule to be bound by the receptor. Moreover, a suitable linker molecule can bind to a number of therapeutic and diagnostic agents without interfering with the activity of the agent.
  • Linker molecules suitable for use within the present invention are comprised of at least two functional groups which bind with "the non-protein targeting agent and the diagnostic or therapeutic agent. Linker molecules comprised of more than one functional group are described herein as possessing a "functionality greater than 1.”
  • a linker molecule may include any compatible organic or inorganic compound which does not adversely affect the binding capacity of the receptor binding molecule.
  • Suitable linker molecules include but are not limited to organic and inorganic compounds with a functionality greater than 1 such as ethylene diamine and diisocyanates, synthetic polymers such as polyethers, polyethyleneamines and polyamides; biologic molecules and biologic molecule analogs such as peptides, monosaccharides and fatty acids; and biopolymers, for example polypeptides such as poly-L- lysine, poly-L-lysyl-DL-alanine, and polysaccharides and polysaccharide analogs, for example carbocyclic analogs of sugar such as ribose.
  • the linker molecule is comprised of ethylene diamine conjugated to an acetylenic organic acid spacer of 7 atoms in length.
  • intracellular receptor binding molecules can be conjugated to any therapeutic or diagnostic agent which retains its essential properties after attachment to the receptor binding molecule via the linker molecule.
  • therapeutic agent includes therapeutic agents which have been chemically modified or any other derivative forms of such agents which substantially retain their biological activity.
  • exemplary of such therapeutic agents are pharmaceuticals, toxins, fragments of toxins, alkylating agents, enzymes, antimicrobials, antimetabolites, antiproliferative agents, neurotransmitters, DNA, radio-opaque dyes, radionuclides, fluorogenic compounds, marker compounds, lectins, comgenic compounds which alter cell membrane permeability, photochemical compounds and boron- containing compounds for use in boron neutron capture therapy.
  • Antimicrobials suitable for use within the present invention include, are not limited to, streptomycin, neomycin, kanamycin, gentamicin, amikacin, tobramycin, streptomycinB, spectinomycin, ampicillin, sulfanilamide, polymyxin, chloramphenicol, acyclovir, vira A, symmetrel, nystatin and tylosine.
  • antineoplastics within the present invention include, but are not limited to, adriamycin, cerubidine, bleomycin, alkeran, velban, oncovin, fluorouracil, methotrexate, thiotepa, bisantrene, novatrone, thioguanin, pro ⁇ arabizine and cytarabine.
  • Pharmaceutical compositions comprising such agents conjugated to a receptor binding molecule via a linker molecule in a suitable carrier, including serum or physiological saline, with or without another protein such as human serum albumin. Dosage may be readily determined by a skilled artisan and may differ depending on the nature of the cellular disorder and the agents employed.
  • Photodynamic agents suitable for use with the present invention include, but are not limited to, porphyrins and modified porphy ins such as hematoporphyrin, he atoporphyrin dihydrazide, deuteroporphyrin dihydrazide and protoporphyrin dihydrazide, rose bengal, acridines, thiazines, xanthenes, anthraquinones, azines, flavin and nonmetal- containing porphyrins, porphyrin-like compounds, methylene blue, eosin, psoralin and the like.
  • Photosensitizers such as tetracyclines, sulfonamides, griseofulvin, phinothiazines, thiazides and sulfonylurea may be conjugated to receptor binding molecules pursuant to the present invention.
  • Such photochemicals may be modified or synthetically prepared to absorb light at specific wavelengths.
  • photothermolytic agents such as Azure A, that can be activated at the targeted site by a light source, are suitable for use with the present invention.
  • Photodynamic agents conjugated to receptor binding molecules may involve the use of pharmaceutical compositions comprising the conjugate and any suitable carrier, including serum or physiological saline, with or without another protein such as human serum albumin.
  • suitable carrier including serum or physiological saline, with or without another protein such as human serum albumin.
  • Dosage of pharmaceutical compositions according to the present invention may be readily determined by one of ordinary skill and will differ depending upon the nature of the cellular disorder and the agents used.
  • the route of administration may be parenteral, with intravenous injection generally preferred.
  • Photosensitive agents may be activated by a light source which causes the reduction of singlet oxygen resulting in a toxic cellular effect. The specificity of the reaction can be maintained by selection of proper wavelength and photosensitive agent.
  • the photosensitive agent can be activated at the targeted site with a laser or other light source via optical fibers or any other appropriate method.
  • metal ions chosen for their cell killing properties can be conjugated to receptor binding molecules according to the present invention.
  • suitable beta- emitting ions for therapeutic uses include, but are not limited to, " "Sc, 47 Sc, 48 Sc, 78 Ga and
  • an alpha-emitting metal ion comprised of 212 Bi is conjugated via a suitable linker molecule to a non-protein intracellular receptor molecule.
  • Pharmaceutical compositions comprising a metal ion conjugated via a linker molecule to a receptor binding molecule and a suitable carrier can be administered parenterally. The preferred route of administration is intravenous and the proper dosage can be determined without undue experimentation be one skilled in the art.
  • Radionuclides suitable for therapeutic and diagnostic imaging according to the present invention include, but are not limited to, ⁇ Y, 67 Cu, 67 Ga, 68 Ga, 89 Zr, ""Tc, In, 123 I, 125 I, 131 I, 75 Br, 76 Br, ⁇ Br, 198 Au, 199 Au, 18 F, 105 Rh, 186 Re, 188 Re, 211 At, 203 Pb and 212 Pb.
  • Examples of non-radioactive paramagnetic metals such as 157 Gd , ⁇ Fe, 56 Fe, 57 Fe, 58 Fe and 55 Mn which can be detected by nuclear magnetic resonance spectroscopy are suitable for tissue imaging according to the present invention.
  • radionuclides and metal ions may be conjugated to receptor binding molecules via a linker molecule and a chelating compound.
  • Compatible chelators capable of coordinated bonding with a metal ion are utilized to attach the metal ions or radionuclides to the linker molecule.
  • compatible chelator means any compound that is able to donate electrons and combine to coordinate bonding with a metal ion to form structures called chelates or chelation complexes and is suitable for attachment to a receptor binding molecule via a linker molecule without loss of ability to chelate metal ions or radionuclides or loss of binding activity or specificity of the receptor binding molecule.
  • Suitable chelators are diethylene-triamine- pentaacetic acid (DPTA) , ethylene-diamine-tetraacetic acid (EDTA) , desferr ⁇ xamine, dimercaptosuccinic acid, 2,3-dimercaptopropane- sulfonic acid, metallothioein and cryptates, such as those described by Gansow et al. in J. Heterocyclic Chem. 18: 297 (1981).
  • DPTA diethylene-triamine- pentaacetic acid
  • EDTA ethylene-diamine-tetraacetic acid
  • desferr ⁇ xamine dimercaptosuccinic acid
  • 2,3-dimercaptopropane- sulfonic acid 2,3-dimercaptopropane- sulfonic acid
  • metallothioein and cryptates such as those described by Gansow et al. in J. Heterocyclic Chem. 18: 297 (1981).
  • Example 1 Preparation of a Conjugated Targeting Agent for NMR Imaging.
  • An estradiol/DPTA conjugate capable of chelating the paramagnetic ion gadolinium (Gd) for use in NMR imaging, was synthesized.
  • the structure of the estradiol/DPTA conjugate is presented below:
  • Example 2 Conjugation of Diagnostic Imaging Agent to Estradiol/Linker Molecule
  • the estradiol/DTPA conjugate was prepared according to Example 1. A 10 mM solution of the conjugate dissolved in water was prepared and the pH of the solution was adjusted to 7.0 using 0.1 N sodium hydroxide. To this solution, an equimolar amount of gadolinium (Gd) chloride was added. The mixture was stirred for 1 hour at room temperature.
  • Gd gadolinium
  • mice Animal studies were performed to evaluate the effectiveness of an estradiol/gadolinium conjugate prepared according to Example 2 in targeting tissues rich in estrogen receptors.
  • a test group consisting of 6 healthy female mice, each weighing 20-25 grams, were injected with an estradiol/gadolinium conjugate prepared according to Example 2. Prior to administration of the conjugate, the mice were anesthetized using ketamine chloride at a dosage of 150 mg per kilogram body weight. The conjugate was injected intravenously in the tail twice daily for three days at a dosage of 1 ⁇ M per kilogram body weight. Three hours after the last infusion of conjugate, the test mice were euthanized and NMR studies were performed.
  • An MR scan was performed utilizing a 9.4/8.9 cm (400MHz) Bruker AM-400 wide-bore multinuclear spectrometer. One to eight 1 mm cross- sectional MR images of the pelvic region were taken of each animal. The relative contrast of the uterine tissue was determined by comparing the signal intensity of the surrounding tissue to the signal intensity of the uterine tissue. MR scans were performed on a control group of 8 healthy female mice of the same age and weight as the test group. The scan data obtained from the control group provided the baseline of the relative contrast between normal uterine tissue and surrounding tissue. The results are presented in Table 1.
  • the signal intensity of the uterine tissue was greater than that of the surrounding tissue.
  • the signal intensity of the uterine tissue was approximately equal to that of the surrounding tissue.

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  • Radiology & Medical Imaging (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
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Abstract

On décrit une molécule non protéique de liaison de récepteur intracellulaire, conjuguée à des agents thérapeutiques et diagnostiques par l'intermédiaire d'une molécule de liaison. On décrit aussi un procédé d'administration intracellulaire in vivo d'agents thérapeutiques ou diagnostiques.
PCT/US1992/001072 1991-02-20 1992-02-20 Elements conjugues non proteiques de liaison de recepteur intracellulaire WO1992014493A1 (fr)

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US56777291A 1991-02-20 1991-02-20
US567,772 1991-02-20

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0565449A1 (fr) * 1992-04-10 1993-10-13 La Region Wallonne Marquage des hormones par le Rhenium et le technetium
WO1994029327A1 (fr) * 1993-06-07 1994-12-22 British Technology Group Limited Composes anti-cancer
EP0773719A1 (fr) * 1994-07-29 1997-05-21 Emory University Compositions de ciblage de materiaux sur des cellules contenant des recepteurs androgenes
WO1997034637A2 (fr) * 1996-03-22 1997-09-25 Trustees Of Boston University Therapie photodynamique dans laquelle des recepteurs d'hormones nucleaires sont utilises pour cibler des photosensibilisateurs
EP1017397A1 (fr) * 1997-03-06 2000-07-12 The General Hospital Corporation Conjugues de photosensibilisant destines au ciblage de pathogenes
EP1384488A3 (fr) * 1992-04-07 2004-06-23 Immunomedics, Inc. Méthode et Kit pour l'imagerie des organes et des tissus, utilisant des anticorps.
US6929797B2 (en) * 1997-02-13 2005-08-16 Bone Care International, Inc. Targeted therapeutic delivery of vitamin D compounds
US9173950B2 (en) 2012-05-17 2015-11-03 Extend Biosciences, Inc. Vitamin D-ghrelin conjugates
US9585934B2 (en) 2014-10-22 2017-03-07 Extend Biosciences, Inc. Therapeutic vitamin D conjugates
US9616109B2 (en) 2014-10-22 2017-04-11 Extend Biosciences, Inc. Insulin vitamin D conjugates
US9789197B2 (en) 2014-10-22 2017-10-17 Extend Biosciences, Inc. RNAi vitamin D conjugates

Citations (5)

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Publication number Priority date Publication date Assignee Title
US4215045A (en) * 1978-06-29 1980-07-29 The United States Of America As Represented By The United States Department Of Energy 123m Te-Labeled biochemicals and method of preparation
US4541957A (en) * 1983-09-07 1985-09-17 The George Washington University Process for preparing iodovinyl-estradiol
US4933157A (en) * 1988-06-27 1990-06-12 The University Of Michigan Radioiodinated arylaliphatic ether analogues of cholesterol
US4938897A (en) * 1985-06-21 1990-07-03 Kureha Kagaku Kogyo Kabushiki Kaisha Chlorambucil derivatives and cell-discriminating agent containing the same
US4983646A (en) * 1982-09-23 1991-01-08 Centre National De La Recherche Scientifique Organometallic complexes of estrogens and their application to the determination of hormone receptors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4215045A (en) * 1978-06-29 1980-07-29 The United States Of America As Represented By The United States Department Of Energy 123m Te-Labeled biochemicals and method of preparation
US4983646A (en) * 1982-09-23 1991-01-08 Centre National De La Recherche Scientifique Organometallic complexes of estrogens and their application to the determination of hormone receptors
US4541957A (en) * 1983-09-07 1985-09-17 The George Washington University Process for preparing iodovinyl-estradiol
US4938897A (en) * 1985-06-21 1990-07-03 Kureha Kagaku Kogyo Kabushiki Kaisha Chlorambucil derivatives and cell-discriminating agent containing the same
US4933157A (en) * 1988-06-27 1990-06-12 The University Of Michigan Radioiodinated arylaliphatic ether analogues of cholesterol

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1384488A3 (fr) * 1992-04-07 2004-06-23 Immunomedics, Inc. Méthode et Kit pour l'imagerie des organes et des tissus, utilisant des anticorps.
US7811570B2 (en) 1992-04-07 2010-10-12 Immunomedics, Inc. Method of affecting a function of or ablating a non-malignant cell
EP0565449A1 (fr) * 1992-04-10 1993-10-13 La Region Wallonne Marquage des hormones par le Rhenium et le technetium
WO1994029327A1 (fr) * 1993-06-07 1994-12-22 British Technology Group Limited Composes anti-cancer
EP0773719A1 (fr) * 1994-07-29 1997-05-21 Emory University Compositions de ciblage de materiaux sur des cellules contenant des recepteurs androgenes
EP0773719A4 (fr) * 1994-07-29 1998-09-02 Univ Emory Compositions de ciblage de materiaux sur des cellules contenant des recepteurs androgenes
US6468981B1 (en) 1994-07-29 2002-10-22 Emory University Compositions and methods for targeting pharmaceutically active materials to cells containing androgen receptors
WO1997034637A2 (fr) * 1996-03-22 1997-09-25 Trustees Of Boston University Therapie photodynamique dans laquelle des recepteurs d'hormones nucleaires sont utilises pour cibler des photosensibilisateurs
WO1997034637A3 (fr) * 1996-03-22 1998-01-29 Therapie photodynamique dans laquelle des recepteurs d'hormones nucleaires sont utilises pour cibler des photosensibilisateurs
US6929797B2 (en) * 1997-02-13 2005-08-16 Bone Care International, Inc. Targeted therapeutic delivery of vitamin D compounds
EP1017397A4 (fr) * 1997-03-06 2004-06-16 Gen Hospital Corp Conjugues de photosensibilisant destines au ciblage de pathogenes
US7268155B2 (en) 1997-03-06 2007-09-11 The General Hospital Corporation Photosensitizer conjugates for pathogen targeting
EP1017397A1 (fr) * 1997-03-06 2000-07-12 The General Hospital Corporation Conjugues de photosensibilisant destines au ciblage de pathogenes
US9173950B2 (en) 2012-05-17 2015-11-03 Extend Biosciences, Inc. Vitamin D-ghrelin conjugates
US9289507B2 (en) 2012-05-17 2016-03-22 Extend Biosciences, Inc. Carriers for improved drug delivery
US9884124B2 (en) 2012-05-17 2018-02-06 Extend Biosciences, Inc. Carriers for improved drug delivery
US9616109B2 (en) 2014-10-22 2017-04-11 Extend Biosciences, Inc. Insulin vitamin D conjugates
US9789197B2 (en) 2014-10-22 2017-10-17 Extend Biosciences, Inc. RNAi vitamin D conjugates
US9585934B2 (en) 2014-10-22 2017-03-07 Extend Biosciences, Inc. Therapeutic vitamin D conjugates
US10406202B2 (en) 2014-10-22 2019-09-10 Extend Biosciences, Inc. Therapeutic vitamin D conjugates
US10420819B2 (en) 2014-10-22 2019-09-24 Extend Biosciences, Inc. Insulin vitamin D conjugates
US10702574B2 (en) 2014-10-22 2020-07-07 Extend Biosciences, Inc. Therapeutic vitamin D conjugates
US11116816B2 (en) 2014-10-22 2021-09-14 Extend Biosciences, Inc. Therapeutic vitamin d conjugates

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