WO1992019264A1 - Biomodulateurs utilises comme agents de contraste universels - Google Patents

Biomodulateurs utilises comme agents de contraste universels

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Publication number
WO1992019264A1
WO1992019264A1 PCT/US1992/003675 US9203675W WO9219264A1 WO 1992019264 A1 WO1992019264 A1 WO 1992019264A1 US 9203675 W US9203675 W US 9203675W WO 9219264 A1 WO9219264 A1 WO 9219264A1
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WO
WIPO (PCT)
Prior art keywords
biomodulator
tissue
imaging
agent
compound
Prior art date
Application number
PCT/US1992/003675
Other languages
English (en)
Inventor
Jerry L. Born
Dennis Eshima
Paul L. Mann
Nicholas A. Matwiyoff
Frank O. Kroh
Original Assignee
University Of New Mexico
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US07/694,325 external-priority patent/US5401489A/en
Priority claimed from US07/694,157 external-priority patent/US5240693A/en
Application filed by University Of New Mexico filed Critical University Of New Mexico
Publication of WO1992019264A1 publication Critical patent/WO1992019264A1/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
    • A61K49/06—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
    • 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
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/6415—Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins
    • 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
    • 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
    • A61K49/14—Peptides, e.g. proteins
    • 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
    • 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
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • 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
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/081—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the protein being an albumin, e.g. human serum albumin [HSA], bovine serum albumin [BSA], ovalbumin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • BIOMODULATORS AS UNIVERSAL IMAGING AGENTS
  • the imaging agent may comprise materials which are themselves opaque to the detection signal and simply increase the contrast between organs or tissues
  • the agent can be one which has a local effect on the. endogenous moiety active to the modality, as in the effect of- NMR contrast agents on protons in vivo .
  • such agents may comprise materials which are selectively biodistributed due to pharmacokinetics or affinity for a certain compound, cell type, tissue, organ, etc. In the latter case, the agent will highlight those areas containing the matter for which the agent has affinity; in the former, it will highlight the areas where it is selectively transported.
  • Many such imaging agents are well known in the relevant arts, as are methods of use thereof.
  • NMR imaging is the most safe in terms of the radiation used. It does not involve ionizing radiation as does X-ray.
  • contrast agents are limited in that they rely on administration of materials, e.g., antibodies, whose in vivo specificity is essentially unalterable.
  • the known contrast agents such as, e.g., gadolinium-DTPA for MRI, are not universally specific for all abnormal vs. normal tissue.
  • contrast agents for each modality which are specific for a wider variety of aberrant tissue versus its normal tissue counterpart, to provide overall applicability as universally as possible, and which can correspondingly be used to locate and diagnose aberrant tissues in a large proportion of the body of a living organism.
  • the present invention provides methods of imaging comprising administering an imaging-effective amount of a biomodulator, e.g., of enhancing the contrast of an NMR image of abnormal tissue of a host, comprising administration to a host of an amount of a ibiomodulator effective to enhance said contrast, e.g., wherein abnormal tissue of the host has enhanced contrast.
  • this invention provides a method of imaging tissue, preferably abnormal tissue, comprising administering a biomodulator, optionally labelled with a moiety detectable by a selected imaging modality, or optionally administered in conjunction with an imaging-active agent whose biodistribution is changed by the administration of a biomodulator, in an amount effective to image the tissue.
  • biomodulators of this invention selectively biodistribute in certain tissue whereby they modify the distribution of water (protons detectable by MRI) in the local environment, thereby producing an image of the environment which is different from that of the environment without biomodulator mediation. This difference alone will provide diagnostically useful information in MRI.
  • this invention provides a method of delivering a drug to a particular site in a body of a host containing abnormal tissue comprising administering a biomodulator and said drug, the amounts of said
  • biomodulator and said drug being effective to selectively concentrate said drug at said site of abnormal tissue.
  • the present invention also provides a method of enhancing the image of tissue obtainable by a particular imaging modality comprising administering a biomodulator and an imaging agent for said modality, said biomodulator and said agent and the amounts thereof being effective for enhancement or other modification of the imaging of said tissue, and said agent comprising:
  • a second, mono- or oligosaccharide portion effective to interact with cellular oligosaccharide displays.
  • this invention provides a method of delivering a drug to a particular site in a body of a host containing abnormal tissue comprising administering a biomodulator and said drug, the amounts of said biomodulator and said drug being effective to selectively concentrate said drug at said site of abnormal tissue, and said drug comprising:
  • a second, mono- or oligosaccharide portion effective to interact with cellular oligosaccharide displays.
  • the invention also provides a pharmaceutical kit comprising a container comprising a biomodulator and a separate container comprising a therapeutically active agent or an imaging agent for an imaging modality
  • a second, mono- or oligosaccharide portion effective to interact with cellular oligosaccharide displays.
  • the first portion of the imaging agent is non-tissue-specific or tissue-specific, the tissue is abnormal, such as that of a tumor, and the second portion of the imaging agent is a mono- or
  • Biomodulators are natural products or synthetic compounds, e.g., analogs of a natural product which perturb the normal cellular differentiative and proliferative activity of eucaryotic, particularly mammalian, particularly human, cells. This biomodulatory activity is non-cell-lineage specific, affecting differentiation and proliferation in substantially all species and substantially all cell types. The activity of these compounds is considered to be at a primitive level of cellular control, common to all cells, and the compounds are therefore non- specific in their effect and production by cells.
  • biomodulators as defined herein are distinct from so-called “biological response modifiers,” such as, e.g., interleukins', interferons and other "kines,” which have highly specific activities, and which are specific natural products of specific stimuli produced by specific highly specialized cell types.
  • biomodulators is based upon a generic, cell-surface oligosaccharide dependent model for "primitive" phenotypic expressions of differentiation. This theory is discussed in P.L. Mann, Intl. Rev. Cytol. 12, 67-95 (1988), which is incorporated herein by
  • biomodulators include compounds selected from
  • R 1 is an optionally substituted aromatic
  • R 2 is -CH-OH, -CHO, -COOR 3 , -COSR 3 , -CONR 8 R 9 or the corresponding lactone
  • R 3 is H or C 1-10 -alkyl
  • R 4 and R 5 are each independently H or C 1-6 -alkyl
  • R 6 and R 7 are each independently OR, NHR or SR wherein R is H or C 1-4 -alkanoyl
  • R 8 and R 9 are each independently H or C 1-10 -alkyl
  • X is C 2-3 -alkylene, C 2-3 -alkenylene, C 2-3 - alkynylene, a cyclopropylene group, -OCH 2 - or -SCH 2 -;
  • a first category of compounds useful in the methods of the present invention comprises compounds of formula
  • 3S,5R, 3S,5S or 3R,5R configurations of colletruncoic acid By “substantially electronically similar” is meant that in the energy minimized form, the interhydroxyl distance between the relevant hydroxyl groups is between 4.2-4.4 A, preferably about 4.3 A.
  • the electronic similarity of the compounds can be determined, e.g., by performing routine energy minimization calculations, e.g., utilising conventional calculations, such as those performed by the Chemdraft Computational Package, program MM-2, (C-Graph Software. Inc., Austin, Texas 78763).
  • the radical R 1 has a variable effect.
  • the R 1 radical is substantially hydrophobic with well defined pockets of electronegativity.
  • Suitable R 1 ring groups have 1-4 or more fused and/or covalently bonded rings, optionally substituted by substituents which render this portion of the molecule electronegative
  • the compounds of formula I can possess R 1 ring groups having a hydrophobicity and/or electronegativity on the order of those of one or more of the following suitable R 1 rings, including C 6-25 mono-/ bi-, tri- or polynuclear-aryl, -aryloxy, -cycloalkyl, -cycloalkenyl, -cycloalkadienyl, etc., as well as heterocyclic rings containing or sharing one or more, e.g., 2 or 3, O, S or N atoms.
  • each ring generally contains 4-7 atoms, 1-3, preferably, 1-2, of which are O, N or S atoms, the remainder being C atoms, these generally having 1-4 hetero atoms in total.
  • heteroaryl and hydroheteroaryl groups are suitable.
  • R 1 groups examples include benzyl, benzyloxy, phenyl, phenyloxy, naphthyl, naphthyloxy, tetrahydronaphthyl, hexahydronaphthyl, octahydronaphthyl, imida zolyl, pyrimidyl, pyrazolyl, indenyl, quinolinyl, pyrrolyl, indolyl, indolizinyl, etc.
  • particularly preferred compounds of formula (I) are those in which n is 1, R 2 is COOR 3 or the corresponding lactone, R 4 and R 5 are each H, R 6 and R 7 are each OH, and X contains a cis or trans double bond.
  • Colletruncoic acid can be isolated according to the method outlined in Stoessl et al. Z. Naturforsh.
  • Another subtype of these compounds are synthetic compounds of formula I having the required electronic structure at the 3,5-carbon atoms, as described above.
  • the acetylide R 1 -C ⁇ C can be added to an appropriate aldehyde or ketone.
  • R 1 O- or R 1 S- will be condensed with an
  • R 1 moieties bearing substituted groups can be synthesized either before or after linkage to the remainder of the molecule.
  • a second general category of compounds having a related structure and having biomodulator activity is constituted by other small, naturally occurring compounds such as, e.g., swainsonine,
  • Swainsonine is commercially available, e.g., from Boerringer- Mannheim, or can be isolated according to the method outlined in Hino, M., et al., J. Antibiotics 38., 926-935 (1985).
  • Other members of this category are, e.g., other indolizidine alkaloid compounds retaining the electronic structure of the important "1,3-diol array" of swainsonine, such as swainsonine substituted in the ortho and meta positions on the 6-membered ring by hydroxy groups (castanospermine) and other natural products having an electronically similar 1,3 diol array.
  • Still other suitable alkaloids are related compounds having two
  • a third major type of biomodulator is a new compound provided by the present invention having properties similar to the compounds of Formula I.
  • This compound, cellular activator and differentiator or CAD is isolated from Penicillium restrictum, has a molecular weight of about 500, and is believed, without wishing to be bound by theory, to have a similar structure to colletruncoic acid. It can be isolated according to the method outlined in
  • a fourth category of compounds useful in the methods of the present invention are high molecular weight compounds having biomodulator (activity, such as pokeweed mitogen (PWM) , which is a well known mixture of five isomitogenic glycopeptides extracted from Phytolacca
  • Pokeweed mitogen can be isolated according to well-known methods, e.g., according to the method outlined in Riesfeld, R.A., et al., Proc. Natl. Acad. Sci. (U.S.) 58, 2020-2027 (1967). It is noted that the differentiative and proliferative activities of PWM can be separated, i.e., by separating the isotypes, e.g., according to the method of Waxdal, M.J., Biochem. 13, 3671 (1974). The differentiative substance is preferred.
  • Preferred compounds include 3S,5R-colletruncoic acid and the compound obtained by switching the heptanoate chain of 3S,5R-colletruncoic acid with the adjacent methyl group on the ring.
  • Cellular functions can be broadly divisible into two general categories: proliferation (reproduction) and differentiation (specialization of function).
  • the proliferative function is continuously present in the normal cell, and is dominated in the mature cell by the differentiative function, which thus acts as an integrative force to regulate both differentiative and proliferative functions in the mature cell.
  • a failure in the biochemical mechanisms upon which the cell is dependent for control of cell differentiative and proliferative functions thus has important implications, as disruption of normal differentiative and proliferative controls may result in both abnormal cellular function and abnormal cellular growth regulation.
  • improperly enhanced cellular proliferation particularly when coupled to impaired cellular differentiation may be a basis for neoplasia.
  • the well-known phenomenon of cellular senescence couples a failure of proliferation of terminally differentiated cells after a defined number of cellular generations.
  • biomodulators exert their effects at the most fundamental level by influencing cellular differentiation behavior, particularly abnormalities therein. They, for instance, can induce differentiation by modulating expression of the cellular differentiative phenotype; inter alia, the biomodulators induce expression of unexpressed genes to significantly diversity cellular function, or to significantly increase existing cellular function.
  • the biomodulators are believed to induce proliferation in senescent cells by biomodulating expression of the cellular proliferative phenotype by similar mechanisms. Overall, the biomodulators counteract aberrant proliferative or differentiative cellular function by stimulating intracellular biochemical controls to normalize cellular behavior.
  • biomodulators to normalize abnormal cellular function, both differentiative and proliferative (usually indirectly by normalizing aberrant differentiative activity underlying the aberrant proliferation, but also directly, e.g., in the case of senescent cells), across a wide spectrum of cell types, which primarily underlies their usefulness.
  • biomodulators effect their results in very low concentrations and are generally characterized by a relatively low (less than 1,000 daltons) molecular
  • the compounds are non-toxic in the amounts Employed in the methods of the present invention. It is theorized that these compounds simulate or involve
  • biomodulators have been demonstrated to possess is their ability to normalize cellular function in cells which have become aberrant, e.g., tumor cells or senescent cells.
  • administration of biomodulators affects the conformational arrangements of simple cell-surface oligosaccharide structures in aberrant cells (Mann, P.L., et al., Mech. Ageing Devel. 44, 17-33 (1988)).
  • This has been shown, for example, by determination of binding- class affinities and capacities for specific lectin/ oligosaccharide combinations, with and without biomodulator influence. Scatchard analysis and the calculation of Gibb's Free Energy ( ⁇ G) were used for comparison purposes, as disclosed therein. The ⁇ G values obtained were found to be predictors of phenotypic changes and the efficacy of the biomodulators.
  • NMR proton line width changes as well as the subsequent development of the senescent phenotype.
  • neoplastic cells have cell surface oligosaccharide displays which are "in-between" those of normal and senescent cells, both in terms of ⁇ G values and the proton line widths.
  • Treatment of these cells with biomodulators "up-regulates” the oligosaccharide conformations, increases line width values, increases the ability of these cells to be recognized by cytotoxic lymphocytes (the normal phenotype) and decreases their generation times in vitro.
  • This modification of such displays thus mediates an altered biodistribution of an agent contacting tissue undergoing such a biomodulator modification, such as a drug or an imaging agent, especially when the latter is structurally modified by the presence of a mono- or oligosaccharide moiety, preferably a amino sugar.
  • a biomodulator modification such as a drug or an imaging agent
  • Assays for determining whether a new candidate structure is a biomodulator and/or for determining the activity profile of a biomodulator are given in detail.
  • biomodulators will selectively activate the biomodulators.
  • the biomodulators will concentrate in and around such cells on which they are active, whereby they are particularly useful for imaging diseased or otherwise abnormal tissue, thus providing a method for facilitating the staging thereof.
  • a biomodulator concentrates in normal tissue, which particular tissue is the target of a particular biomodulator will be routinely determinable by preliminary experiments involving administration of the biomodulator followed by conventional body scans by an imaging modality sensitive to the presence of a biomodulator, e.g., MRI as discussed herein.
  • MRI magnetic resonance imaging modality sensitive to the presence of a biomodulator
  • the biomodulators will concentrate in and around such cells on which they are active, they per se will have effect on such environments and not others.
  • a biomodulator may concentrate in normal tissue.
  • the coadministration of another imaging agent as detailed herein is particularly useful.
  • imaging enhancement occurs inherently due to concomitant changes in the water distribution around the tissue in which the biomodulator concentrates due to the presence of the biomodulator.
  • the amount of water in the biomodulator-containing tissue will be increased. This is particularly true in the case of tumors whose images are dramatically intensified by this invention.
  • contrast will, of course, still be enhanced for the image of the abnormal or other biomodulator-containing tissue due to the resultant differential intensity produced in MRI.
  • the underlying physical phenomenon being measured can be any of the known parameters including T 1 , T 2 , proton density,
  • biomodulators Because of the ability of biomodulators to selectively concentrate in abnormal or other tissue, they can be used as "targeting molecules,” analogously to the use of other targeting moieties such as monoclonal antibodies or fragments thereof, lipids, etc., for conventional targeting purposes. For example, they can be coupled, conjugated or otherwise bonded to any molecule which it is desired to enhance the concentration of in such
  • imaging-detectible active agents include, e.g., for MRI, paramagnetic moieties, e.g., metal ions, e.g., of atomic numbers
  • positron emission tomography via attachment of positron emitting isotopes, such as 43 Sc, 5 2 Fe, 55 Co, Cu, etc.
  • radioactivity is the operative modality
  • any of the conventional techniques for radioactivity "tagging" chemical structures can be used, e.g., as described in Crockford et al., U.S. 4,424,200; Rhodes, U.S. 4, 305,922; Alvarez et al., U.S. 4,741,900;
  • Imaging agent as used herein in the context of imaging means an agent which is detectible by an imaging modality which is either bonded to a biomodulator or whose biodistributiori is changed by being administered before, simultaneously with or after a biomodulator, such that the biomodulator and active agent are simultaneously bioeffective to enhance imaging by said modality.
  • the imaging-active agent may be, inter alia, an imaging- detectible moiety per se (e.g., a radionuclide), or an imaging-detectible moiety bound by or to a carrier (e.g., a radionucllde-labeled carrier protein or paramagnetic moiety bound to a chelate).
  • the chemical structure of the active agent is entirely non-critical as long as it is detectible by the imaging modality and can include simple molecules, complex molecules, polymers such as oligopeptides, polypeptides, proteins, carbohydrates, etc.
  • the imaging-detectible moiety will be bound either to a biomodulator, or to another moiety, such that the biodistribution of the imaging- detectible moiety is modified from its biodistribution when administered without a biomodulator.
  • Active agent as used herein in the context of a therapeutic agent is a drug which is either bonded to a biomodulator or whose biodistribution is changed by being administered before, simultaneously with or after a biomodulator, such that the biomodulator and active agent are simultaneously bioeffective to treat aberrant tissue.
  • the therapeutic-active agent may be linked to the
  • biomodulator by either a cleavable or non-cleavable linkage.
  • the conjugation of the biomodulator to. the "active" moiety can be accomplished using any of the plethora of conventional techniques. Generally, where a metal is involved this can be accomplished by attaching the metal to a binding molecule, typically a chelating agent. The resultant chelate is bound to the biomodulator. The order of these binding reactions is not critical. For instance, a chelate structure can be bound to a biomodulator by means of a substituent, on the non-critical ring portion or other non-critical portion of a biomodulator as described below. Typical substituents include OH, COOH, NH 2 , CONH 2 , and many others.
  • Linking the biomodulator and the chelating agent, carrier protein or drug can be by means of any of a host of conventional linkers.
  • useful chelating agents, linking moieties, chemical methods for effecting the couplings, etc. see, e.g., U.S. Patent Nos.
  • Hoseman et al. J. Nuc. Med. 12, 455-460 (1986)); Meares et al. (Intl. J. Cancer [Suppl.] U.S. 2 , 99-102 (1988); A.R. Fritzberg et al., "Specific and Stable Labeling of Antibodies with Technetium-99m with a Diamide Dithiolate Chelating Agent," Proc. Natl. Acad. Sci. 85, 4025-4029 (1988); D.A. Scheinberg et al., "Tumor Imaging with
  • radioactive iodine can be exchanged conventionally with non-radioactive iodine on the biomodulator, e.g., bonded to the ring portion of the molecule, especially an aryl ring.
  • Other radioactive species e.g., 99 Tc, etc., can be bonded, e.g., via conventional "tagging" procedures well known in the art, e.g., according to Rhodes, U.S.
  • the biomodulators can be administered in accordance with this invention for the visualization of any portion (organ, tissue, etc.) of the body in which a given biomodulator is determined to concentrate, especially those suspected of being in an aberrant state in view of the general capability of biomodulators to concentrate therein, e.g., especially for the visualization of tumors, including cancerous and benign tumors such as soft tumors, such as leukemias and lymphomas, and solid tumors, such as melanomas, ovarian tumors, cervical tumors, breast tumors, lung tumors (small cell and nonsmall cell), colon and stomach tumors, hepatocellular tumors, pancreatic, midgut, bladder and prostate tumors, brain tumors, myelomas, and larynx tumors; senescent tissues and cells; injured tissue, especially containing endothelial cells for which biomodulators will enhance repair; defective immune cells; etc.
  • cancerous and benign tumors such as soft tumors, such as leukemias and lymphomas
  • solid tumors such as
  • PWM has also been shown to localize in areas of arthritis and. in tissues affected in autoimmune disease.
  • TNF- ⁇ was tagged using the ascorbic acid method developed by M.L. Thakur et al., "Tc-99m Labeled Monoclonal Antibodies: Evaluation of Reducing Agents,"
  • abnormal tissue herein is meant any tissue in a condition other than normal for a healthy host, e.g., mammals including humans, e.g., cancerous, diseased, injured, etc. Also included is senescent tissue whether due to the "normal" aging process or otherwise.
  • the mono- and oligosaccharide-modified imaging agents of this invention can be administered in a manner analogous with other imaging agents in the conventional imaging and therapeutic methods, e.g., as described in Enhanced Magnetic Resonance Imaging, V.M. Runge, ed., C.V. Mosby Co. (1989) for MRI; e.g., in EP 188,256; Kozak et al., TIBTEC October 1986, 262; Radiotracers for
  • the administration may be simultaneous with the imaging where desired, e.g., in pharmacokinetic studies.
  • the optimum time period required for localization at the target site and optimum image enhancement will also vary with biomodulator and/or conjugate and/or tissue and/or imaging modality and will also be routinely determinable.
  • imaging will occur prior to significant clearance of the biomodulator from the site, which time period can also be routinely determined by those of skill in the art.
  • biomodulators or conjugates will be administered 15 minutes to 4 hours prior to performing the imaging procedure since the biomodulators are, advantageously, localized rapidly at their target sites and then cleared rapidly therefrom, as discussed further below.
  • agents of this invention may be administered alone, or more typically they may be administered in combination with one of the usual physiologically
  • biomodulator may vary with the patient, the method of imaging employed, the location to be imaged, the timing of imaging, etc., and is routinely determinable by one of ordinary skill in the art.
  • the amount of biomodulator or conjugate dosed for all the uses discussed herein above and below will be in the same range of the amounts thereof effective for observance of the therapeutic and other physiological effects of the biomodulators per se, e.g., their effects of normalizing cellular differentiative abnormalities, e.g., typically, 100 ng/kg-100 ⁇ g/kg. Since the imaging modalities are highly sensitive, these amounts will generally also be useful where imaging active moieties are coupled to the biomodulators. However, where
  • these active moiety dosages can be effectively increased by coupling more than one such moiety to a given biomodulator using the same conventional chemistry referred to above.
  • the amounts of imaging agents will be essentially the same as those amounts usually employed with such agents or with analogous agents for the given imaging modality as
  • Suitable such drugs include antitumor agents such as Ara-C, Melphalan, Methotrexate, and other folate analogs, Daunomycin, Doxorubicin, Mitomycins, Bleomycins,
  • Mitoxantrone Dactinomycin, etc., as well as toxins such as ricin, abrin, diptheria toxin, Pseudomonas exotoxin A, ribosomal inactivating proteins, mycotoxins, etc., but not limited thereto.
  • therapeutic agents in all of the major therapeutic areas including, but not limited to, anti-infectives, such as antibiotics and antiviral agents, analgesics and analgesic combinations, anthemidines, antiarthritics, antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic agents, anti-diarrheals, antihistamines, anti-inflammatory agents, antimigraine preparations, antimotion sickness,
  • anti-infectives such as antibiotics and antiviral agents, analgesics and analgesic combinations, anthemidines, antiarthritics, antiasthmatic agents, anticonvulsants, antidepressants, antidiabetic agents, anti-diarrheals, antihistamines, anti-inflammatory agents, antimigraine preparations, antimotion sickness,
  • anti-infectives such as antibiotics and antiviral agents, analgesics and analgesic combinations, anthemidines, antiarthritics, antiasthmatic agents,
  • antinauseants include antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, anti-spasmodics, including gastrointestinal and urinary;
  • anticholinergics sympathomimetics
  • xanthine derivatives cardiovascular preparations including calcium channel blockers, beta-blockers, antiarrythmics, antihypertensives, diuretics, vasodilators including general, coronary, peripheral and cerebral, central nervous system stimulants, cough and cold preparations, decongestants, hormones, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, parasympathomimetics, psychostimulants, sedatives and tranquilizers.
  • a biomodulator in another aspect of this invention, can be administered to a host in order to alter the nature of the interaction with a drug (such as those discussed herein) of tissue in a host.
  • a drug such as those discussed herein
  • a therapeutic agent subsequently contacting biomodulator-modified tissue will have a biodistribution different from that which it displays when interacting with tissue not treated with a
  • the drug is not modified with an oligosaccharide.
  • the therapeutically-active agent per se provides insufficient effect on or at tissue modifiable by a biomodulator in accordance with this invention as described herein, instead of administering such an agent alone, per this invention, there will also be administered a biomodulator of this invention. All details discussed above will correspondingly be applicable here. Thus, the latter may be administered before, simultaneously with or after the administration of the agent, as long as the resultant tissue modification of this invention is in existence at some time during the contact thereof with the therapeutic agent.
  • the biomodulator will be administered from about 15 minutes to about 4 hours prior to administration of the drug, longer and shorter times being satisfactory, as long as the effect of the biomodulator on the target tissue is still active when the active agent becomes bioavailable to such tissue, as is true for all aspects of this invention.
  • biomodulator/tissue to be selected in conjunction with the modification of the biodistribution of, and thus the therapeutic effect produced by, a particular modified drug will be routinely determinable in accordance with the principles and guidance described herein, e.g., with a few routine orientation experiments.
  • any biomodulator will modify such tissue and concomitantly its interaction with a therapeutic agent.
  • the corresponding treatment of such tissue and its environment will be different from that obtainable (if at all) in the absence of the
  • the invention will be most advantageous where a biomodulator/tissue/therapeutic agent combination is employed which results in a more concentrated treatment (rather than merely an alternative treatment regimen) for the abnormal tissue than is available with the drug without biomodulator added, as will generally be the case.
  • another advantage of this invention is that it dramatically increases the usefulness of therapeutic agents per se which are commercially available, e.g., as discussed above, thus to circumvent specific problems associated with an agent in normal use (e.g., side
  • This aspect of the invention will also be particularly applicable to abnormal tissue as discussed above, e.g., cancerous (or even benign) tumors, senescent cells, injured tissue, etc.
  • the amounts of biomodulator to be employed will be the same as described herein for the other aspects of the use of biomodulators; the amounts of the drugs to be used will be those conventionally employable.
  • Formulations of the biomodulator and drug are fully conventional using the usual pharmaceutically acceptable adjuvants, e.g., as described above. Similarly, other features of the administration of the biomodulator and/or drug are as described above or otherwise fully
  • biomodulators as universal imaging agents see, e.g., Examples 1-3 herein.
  • a biomodulator in another aspect of this invention, can be administered to a host in order to alter the nature of the interaction with non-tissue-specific imaging-active agents of tissue in a host. This effect is believed to be derived from the same fundamental relationships between biomodulator and tissue as described above. Thus, a non-specific, imaging-active agent subsequently contacting biomodulator-modified tissue will have a biodistribution different from that which it displays when interacting with tissue not treated with a biomodulator.
  • a biomodulator in accordance with this invention as described herein, instead of administering such an imaging-active agent alone, per this invention, there will also be administered a biomodulator of this invention.
  • the latter may be administered before, simultaneously with or after the administration of the non-specific, imaging-active agent, as long as the resultant tissue modification of this invention is in existence at some time during the contact thereof with the imaging-active agent.
  • the biomodulator will be administered from about 15 minutes to about 4 hours prior to
  • biomodulator/tissue to be selected in conjunction with the modification of the biodistribution of, and thus the image contrast produced by, a particular imaging-active agent will be routinely determinable in accordance with the principles and guidance described herein, e.g., with a few routine orientation experiments.
  • any biomodulator will modify such tissue and concomitantly its interaction with a non-specific imaging agent.
  • the corresponding image of such tissue and its environment will be different from that obtainable (if at all) in the absence of the
  • This first (or second) "view” of the tissue and the environment will provide valuable primary (or supplemental) information on the staging, extent and assessment of the abnormal tissue state.
  • the invention will be most advantageous where a biomodulator/tissue/ imaging agent combination is employed which results in an image of higher contrast for the abnormal tissue than is available with the imaging agent without biomodulator added, as will generally be the case with non-specific imaging agents.
  • another advantage of this invention is that it dramatically increases the usefulness of nonspecific imaging agents, preferably those which are commercially available, such as radiopharmaceuticals and magnetopharmaceuticals, e.g., by optimizing target-to-background ratios to enhance image quality.
  • This aspect of the invention is applicable to any imaging agent of any imaging modality which depends to any degree for its effect on interaction of the agent with tissue, e.g., which depends on the agent's biodistribution.
  • imaging agents include, for example, agents useful for NMR, X-ray, radio- (e.g., gamma camera), ultrasonic, PET, etc., imaging.
  • radiotherapy analogously to the other aspects of this invention discussed above, e.g., biodistribution of a radiotherapeutic agent can be advantageously modified per this aspect.
  • non-tissue-specific and variants thereof refer to agents which have essentially the same degree inter ⁇ action with, especially of imaging enhancement effect on, essentially all body tissue with which they comes in contact.
  • Especially useful agents for use in this invention include those suitable for radiodiagnostics, MRI, ultrasound or X-ray contrast, particularly, for example, without limitation, for nuclear medicine, radiolabeled proteins, e.g., radiolabeled human serum albumin, bovine serum albumin, etc.
  • Such agents may be endogenously detectable by a particular imaging modality, or may be exogenously labeled with an imaging-detectable label, e.g.,
  • the labeled non-specific agents can be made from available starting materials using standard chemical reactions which are routine to one of ordinary skill in the art.
  • 99m Tc-HSA is produced by labeling commercially available HSA with commercially available " 99m Tc-labeling kits (e.g., Mediphysics, Paramus, NJ), according to package inserts.
  • Other labeled non-specific imaging agents can be made analogously.
  • the exact nature of the bond between the imaging agent and the label is not critical, so long as the molecule as a whole is not denatured, not rendered insoluble, not rendered immunogenic, etc., and still functions as described.
  • biomodulator to be employed will be the same as described herein for the other aspects of the use of biomodulators; the amounts of non-specific imaging agents will be essentially the same as those amounts usually employed with such agents or with analogous agents for the given imaging modality as conventionally performed, e.g., 0.1 mmol per kg for Gd-complexes or MRI; generally doses as are well known and described, for example, in the reference material cited above.
  • Formulations of the biomodulator and imaging agent are fully conventional using the usual pharmaceutically acceptable adjuvants, e.g., as described above.
  • imaging agent i.e., one which per se is selective for a given site intthe body, such as Gd-DTPA for tumors, TNF, etc.
  • Gd-DTPA for tumors, TNF, etc.
  • tumor-specific active agents which are specific for tumor tissue, e.g., tumor necrosis factor- ⁇ (TNF- ⁇ ), which binds surface receptors on a variety of cell types.
  • TNF- ⁇ tumor necrosis factor- ⁇
  • agents are preferably structurally modified to possess an oligosaccharide component by which the agent's ability to take advantage of the effect of the biomodulator is enhanced.
  • GdDTPA for example, is modified with one or more galactosamine residues, it interacts with biomodulator-treated tissue over time in a fashion (linear decay) significantly different from how it interacts with the same tissue not treated with a
  • biomodulator logarithmic decay
  • Suitable oligosaccharides which can be used to modify imaging agents are mono-, di-, tri-, and tetra oligosaccharides and higher (e.g., up to 20 units) and combinations thereof.
  • Suitable non-limiting examples include: trioses, tetroses, pentoses, hexoses, heptoses and octoses, including aldoses and ketoses of each; homoand heteropolymers of each, up to 20 units, derivatives thereof, e.g., sugar alcohols, O-acyl derivatives,
  • O-methyl derivatives sugar acids, phosphoric acid esters, deoxy sugars, amino sugars, and amido sugars, including muramic and neuraminic acid.
  • oligosaccharides which are found on cell surfaces, or oligosaccharides having related structures, are
  • Monosaccharides such as galactose, glucose, mannose, fructose, N-acetyl neuraminic acid, N-acetyl muramic acid, glucuronic acid, glucosamine and
  • Suitable imaging agents include all conventional imaging agents for the various imaging modalities.
  • imaging agents include chelates of paramagnetic ions, wherein the
  • ligands include, e.g., DTPA (diethylenetriamine
  • DOTA 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
  • MAG3 mercaptoacetylglycylglycylglycine
  • oligosaccharides can be terminal or central on the
  • any conventional imaging agent for any conventional imaging modality can be similarly glycosylated.
  • Modified imaging agents can be routinely prepared, e.g., by employing in the standard chemical synthesis of a given conventional agent, instead of the usual starting materials, one or more of the latter containing the desired oligosaccharide moiety. Bonding of the latter to the suitable conventional starting material can be performed in any of several conventional ways involving standard linking of oligosaccharide residues to chemical agents via ester, ether, amide, etc., bonds, as discussed, e.g., in Inouye et al., J.Am. Chem. Soc. 78 4722-4724 (1956). Also, Sherry et al., Inorg. Chem. 28 620-622 (1989). For example,
  • galactosamine-DTPA-Gd was prepared by Gd(gal 2 -DTPA), prepared by the addition of anhydride of DTPA to aqueous galactosamine, followed by the addition of GdCl 3 according to the following procedure.
  • the agents consist of three or four components: the metal cation, the amino sugar, the ligand, and optionally an alkyl chain connecting the amino sugar to the ligand. After selecting the three or four specific components, assembly is most practically in the same order. First, the amino sugar (with or without an aminoalkyl group on the nitrogen of the amino sugar) is attached to the ligand (one or two amino sugars per ligand), then the structure and purity of the sugar-substituted ligand is determined by C NMR spectroscopy, and finally the metal ion is bound by the sugar-substituted ligand.
  • Step 1 For the DTPA-based ligands, the amino sugar is dissolved in chilled water, and the solid dianhydride of DTPA is added in small portions, with monitoring of pH, and sufficient NaOH is added to keep the pH above 8.
  • the synthesis of Gd(2-gal) 2 DT3A, Gd(2- glu) 2 DT3A, Gd(2-man) 2 DT3A are given.
  • One gram of the appropriate hexosamine hydrochloride (4.64 mmoles, available from Sigma Chemical Co.) is dissolved in 20 mL of water, chilled to 0°, and sufficient 6 M NaOH is added to bring the pH to 9.
  • caDPTA available from Sigma Chemical Co. 0.737 grams, 2.06 mmoles, ca. 2.25 moles of amino sugar per mole of caDTPA
  • Aqueous 6 M NaOH is added as needed to keep pH above 8.
  • Step 2 A portion of the production of Step 1 is placed in an NMR tube, and a small amount of D 2 O and 1,4- dioxane are added to provide a field-frequency lock and a chemical shift reference.
  • the C NMR spectrum is
  • the number of amino sugar groups on each DTPA ligand is determined by observing the carboxylate region of the
  • Figure 1 shows the C chemical shifts of the carboxylate carbons of model compounds (in which a 2-hydroxyethyl group replaces the sugar), as a function of pH. Similar chemical shifts are observed for all of the sugar derivatives.
  • Step 3 An aqueous solutio of the metal is added to the aqueous ligand solution, such that a slight excess of the ligand remains-
  • the gadolinium and dysprosium solutions are prepared by dissolving the chlorides MC1 3 in water, or the oxides M 2 O 3 in strong organic or mineral acids, or by other established methods.
  • a gadolinium chloride solution is prepared by dissolving 0.689 g of gadolinium trichloride hexahydrate (1.85 mmoles) in 10 mL of distilled water.
  • the GdCl 3 solution is added to the solution of the substituted DTPA ligand, and stirred for 15 min., to yield a solution of Gd(2-gal) 2 DT3A, Gd(2-glu)- 2 DT3A, Gd(2-man) 2 DT3A, which is diluted to the desired concentration, or lyophilized to a higher concentration.
  • the aqueous TC solutions are prepared by the reduction of the pertechnetate ion in an excess of a reducing agent such as stannous ion or dithionite. Mixing the metal solution with the ligand solution, with stirring at room temperature, for 15 min., produces the claimed complex.
  • the exact nature of the bond between the imaging agent (ligand) and the oligosaccharide-specific portion of the molecule is not critical, so long as the imaging-effective portion of the molecule is not inactivated, and the oligosaccharide-specif ic portion of the molecule is capable of interacting with the cell- surface of the biomodulator-stimulated aberrant cells when bound to the imaging agent, as in essentially all cases will be true.
  • a given mono- or oligosaccharide for use with a given biomodulator/tissue/imaging agent combination can be performed routinely, with a few orientation experiments.
  • essentially any mono- or oligosaccharide as described above will produce, for a given agent, a different biodistribution thereof vis-a-vis biomodulator-influenced tissue as compared with the biodistribution of the agent (with or without mono- or oligosaccharide modification) against non- biomodulator-influenced tissue.
  • this invention by modifying the agent's distributional characteristics, will compensate for deficiencies of the agent, such as side effects, imaging problems, therapeutic effect (in the related aspect of this invention) discussed herein.
  • An optimal oligosaccharide/agent/tissue combination can thus be chosen simply by comparing the beneficial effects achieved with candidate combinations.
  • Preferred biomodulator-induced effects will be those where the concentration of the oligosaccharide-modified agent is increased, thereby enhancing image contrast.
  • biomodulators of this invention will also affect the retention/clearance rates of the agent
  • oligosaccharides in place of the latter to modify the active agents of this invention is also an equivalent aspect of this invention where the chemical entity serves the function of binding to (interacting with)
  • the oligosaccharides can be bonded to any agents active for various imaging modalities, such as, for MRI paramagnetic substances, e.g., chelated metal ions, e.g., of atomic numbers 21-29, 42, 44 and 58-70, inter alia, particularly gadolinium, dysprosium, iron, manganese, etc., or magnetic particles; for X-ray imaging,
  • agents active for various imaging modalities such as, for MRI paramagnetic substances, e.g., chelated metal ions, e.g., of atomic numbers 21-29, 42, 44 and 58-70, inter alia, particularly gadolinium, dysprosium, iron, manganese, etc., or magnetic particles; for X-ray imaging,
  • iodinated-benzene-based compounds or chelated heavy metals, e.g., of atomic numbers 21-29, 42, 44 and 57-83, inter alia; for radionuclide, e.g., gamma camera imaging (or radiotherapy, also), to radioactive ions, e.g., in chelated form or bonded directly to a biomodulator, e.g., to its ring portion; suitable ions are cobalts,
  • radioactivity is the operative modality
  • any of the conventional techniques for radioactivity "tagging" chemical structures can be used, e.g., as described in Crockford et al., U.S.
  • biodistribution of these "active" moieties by means of the effect of the biomodulators will produce image enhancement and/or modification by the corresponding modality, MRI, X-ray, radioimaging, PET imaging, etc.
  • the oligosaccharide can be conjugated to the "active" moiety using any of the plethora of conventional techniques. Generally, where a metal is involved this can be accomplished by attachment to a metal binding molecule, typically a chelating agent.
  • the order of the binding reactions e.g., metal binding or oligosaccharide binding initially, is not critical.
  • an oligosaccharide can be bound by means of a substituent added to the agent on a non-critical portion. Typical such substituents include OH, COOH, NH 2 , CONH 2 , and many others.
  • Linking the oligosaccharide and the chelating agent can be any of a host of conventional linkers. For thorough descriptions of useful chelating agents, linking moieties, chemical methods for effecting the couplings, etc., see, e.g., U.S. Patent Nos.
  • Hoseman et al. J. Nuc. Med. 12, 455-460 (1986)); Meares et al. (Intl. J. Cancer [Suppl. ] U.S. 2 , 99-102 (1988); A.R. Fritzberg et al., "Specific and Stable Labeling of Antibodies with Technetium-99m with a Diamide Dithiolate Chelating Agent," Proc. Natl. Acad. Sci. 85:4025-4029 (1988); D.A. Scheinberg et al/, "Tumor Imaging with
  • Exemplary modified imaging agents include, e.g., (Sac) n -(CH 2 ) n -NH-Gd-DTPA,
  • biomodulators will be administered 15 minutes to 4 hours prior to administration of the imaging agent which will be administered in a normal time period prior to performing the imaging procedure, e.g., 15 minutes to 1 hour before.
  • the short time periods for biomodulator preadministration are derived from the advantage that they are localized rapidly at their target sites and then cleared rapidly therefrom, as discussed further below. Longer or shorter time periods are also applicable, as long as the effect of the biomodulator on the target tissue is still active when the active agent becomes bioavailable to such tissue.
  • interact any chemical or biological influence of one material on another, e.g., a bonding-type (weak or strong) relationship between two moieties, e.g., uptake of one moiety, e.g., an agent, by the other, e.g., tissue, or such as chemical attraction between a cellular oligosaccharide conformation (display) and an active agent in its vicinity or a different oligosaccharide in its vicinity, e.g., in contact
  • Example 1 Radionuclide Imaging of Tumor Using
  • mice C57/B1-6, 15-30 mg were injected with 6 ⁇ 10 5 of allogenic B-16 melanoma cells 7 days ( Figure 1) or 10 days ( Figure 2) prior to injection of 2 to 5 mCi of 99m Tc-labeled pokeweed mitogen (Tc-PWM). Images were obtained by positron - a gamma camera over the back of the animal and an image was acquired for 1 min. at four hours post injection. Visualization of the tumor
  • the pokeweed mitogen used in the tests of all examples herein was obtained by the method of Waxdal.
  • FIG. 4 shows a photograph of the rats bearing the tumors on 7 days post-implantation, unlabeled PWM was administered. NMR imaging was performed as above at 4 hours post injection. Visualization of the tumors ( Figure 5) was observed as bright areas in the flank regions of the rats, showing th'at the biomodulator lowers T 1 of the treated tissue image, thereby enhancing image contrast.
  • Example 3 Biodistribution Studies of Pokeweed
  • FIG. 6 shows that the T 1 measured on the tumor was enhanced tenfold by treatment with PWM, while the T 1 of normal muscle tissue remained at baseline levels, demonstrating that PWM is specific to the tumor, whereby the image of the latter is selectively enhanced.
  • Figure 7 shows that 125 I-labeled PWM is taken up very specifically by the canine glioma tumor cells in the nude rat, and is also washed out very quickly by 48 to 72 hours, whereby again the image of the cells is
  • mice were injected with B-16 melanoma cells 7 days prior to intravenous injection of 99m Tc-PWM or 99 T c-HSA (human serum albumin). Biodistribution studies were performed 2 and 4 hours later. At 2 hours post
  • the absolute percent uptake into the tumor was 0.41% for Tc-PWM, and 0.36% for Tc-HSA.
  • the absolute uptake decreased to 0.25% of the injected dose for both agents. Visualization of the tumor, however, was not observed for the Tc-HSA-labeled material, but was observed for the Tc-PWM-labeled
  • a mouse (0.20 kg) was injected with B-16 melanoma cells in acdordanee with Example 1. 7 days later, 10 ⁇ g of pokeweed mitogen was injected into the mouse. Four hours later 99m Tc-human serum albumin (HSA) was injected. The resultant posterior gamma camera image is obtained of the tumor grown in the mouse. Comparison with the control image (following identical procedures except without pokeweed mitogen) showed significant image enhancement demonstrating localization of the non- specific agent, Tc-99m HSA into the tumor.
  • Example 5 Effect of a Biomodulator on the
  • Adjuvant induced polyarthritis in rats is an animal model that has been extensively used to study the
  • This model resembles the human disease both clinically and pathologically.
  • the model was created by injection of 0. 1 mg of heat-killed Hycobacterium butrycium suspended in light mineral oil into the subplantar region of the right hindpaw. At the site of injection, an acute inflammation appears within 24 hours and reaches its maximum intensity approximately 4 days post induction and between days 10 to 12 a polyarthritis develops.
  • 125 I-PWM was labeled according to the iodobead method and injected into 4 rats 2 controls and 2 animals on day 15 post adjuvant
  • the animals were anesthetized with pentobarbital , the femoral vein was isolated and the 125 I-PWM was
  • Necrosis Factor (TNF- ⁇ ) and biomodulators Balb/c mice bearing xenografts of human
  • FIG. 2 shows the results of a similar experiment as in Example 1, except that the tumor-bearing rat was treated with pokeweed mitogen biomodulator for 10 days prior to imaging and the imaging agent was galactosamine-modified DTPA, Gal-Gad-DTPA.
  • the wash-out kinetics of the biomodulator-pretreated rat were linear ( Figure 2), indicating that there was a biomodulator-dependent enhancement of interaction of a specific agent to the tumor tissue.

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Abstract

Des biomodulateurs, liés facultativement à des fractions actives en imagerie, peuvent être administrés à un hôte afin d'améliorer les images de celui-ci, par exemple, des images prises aux rayons X, par RMN ou des images radio, en augmentant de préférence l'intensité du signal des tissus aberrants. Les biomodulateurs peuvent également conditionner les tissus afin d'améliorer la fixation d'agents d'imagerie autrement non-spécifiques. Lorsqu'ils sont liés à des médicaments, les biomodulateurs peuvent cibler les mêmes choses à des endroits particuliers du corps. Des biomodulateurs peuvent également être administrés avec un agent tel qu'un médicament ou un agent d'imagerie (spécifique ou non-spécifique) modifié dans sa structure pour exploiter les perturbations d'affichages d'oligosaccharides cellulaires provoquées par lesdits biomodulateurs, pour améliorer les images d'un hôte, par exemple, des images prises aux rayons X, par RMN ou des images radio, en augmentant de préférence l'intensité du signal de tissus aberrants. Les biomodulateurs conditionnent les tissus pour améliorer ou modifier la fixation du médicament ou de l'agent modifié dans sa structure.
PCT/US1992/003675 1991-05-01 1992-05-01 Biomodulateurs utilises comme agents de contraste universels WO1992019264A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996038184A2 (fr) * 1995-06-02 1996-12-05 Research Corporation Technologies, Inc. Agents d'imagerie par resonance magnetique pour la detection d'agents physiologiques
US5643549A (en) * 1992-02-20 1997-07-01 Rhomed Incorporated Leukostimulatory agent for in vivo leukocyte tagging
US5980862A (en) * 1995-06-02 1999-11-09 Research Corporation Technologies Magnetic resonance imaging agents for the detection of physiological agents
WO2001021219A2 (fr) * 1999-09-21 2001-03-29 The Government Of The United States Of America, As Represented By The Secretary Of Health And Human Services Imagerie d'accumulation de medicaments comme guide de therapie antitummorale
US6521209B1 (en) 1996-07-31 2003-02-18 California Institute Of Technology Bifunctional detection agents
US6656450B2 (en) 2000-07-17 2003-12-02 California Institute Of Technology, Inc. Macrocyclic magnetic resonance imaging contrast agents
US6673333B1 (en) 2000-05-04 2004-01-06 Research Corporation Technologies, Inc. Functional MRI agents for cancer imaging
US6713045B1 (en) 1995-06-02 2004-03-30 Research Corporation Technologies, Inc. Targeted magnetic resonance imaging agents for the detection of physiological processes
US6713046B1 (en) 1997-10-27 2004-03-30 Research Corporation Technologies Magnetic resonance imaging agents for the delivery of therapeutic agents
US6770261B2 (en) 1995-06-02 2004-08-03 Research Corporation Technologies Magnetic resonance imaging agents for the detection of physiological agents
US7029655B2 (en) 2000-10-04 2006-04-18 California Institute Of Technology Magnetic resonance imaging agents for in vivo labeling and detection of amyloid deposits
US7354568B1 (en) 1997-10-27 2008-04-08 California Institute Of Technology Magnetic resonance imaging agents for the detection of physiological agents
WO2010087612A1 (fr) * 2009-01-28 2010-08-05 Snu R&Db Foundation Complexe à agent(s) chélateur(s) bifonctionnel(s) et sérumalbumine humaine mannosylée
TWI553017B (zh) * 2012-12-28 2016-10-11 行政院原子能委員會核能研究所 新穎膽道掃描用造影劑及其製造方法

Citations (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4054645A (en) * 1976-08-24 1977-10-18 Minnesota Mining And Manufacturing Company Radiodiagnostic complexes employing fluorine-containing tin reducing agents
US4554925A (en) * 1982-07-07 1985-11-26 Picker International, Ltd. Nuclear magnetic resonance imaging method
US4564017A (en) * 1984-11-21 1986-01-14 General Electric Company Method and apparatus for respiration monitoring with an NMR scanner
US4586511A (en) * 1983-03-04 1986-05-06 Children's Hospital Medical Center Methods and compositions for detecting and imaging a gas in an animal by nuclear magnetic resonance
US4615879A (en) * 1983-11-14 1986-10-07 Vanderbilt University Particulate NMR contrast agents for gastrointestinal application
US4639365A (en) * 1984-10-18 1987-01-27 The Board Of Regents, The University Of Texas System Gadolinium chelates as NMR contrast agents
US4639364A (en) * 1984-11-14 1987-01-27 Mallinckrodt, Inc. Methods and compositions for enhancing magnetic resonance imaging
US4647567A (en) * 1984-04-05 1987-03-03 North Carolina State University Method of releasing growth hormones
US4656026A (en) * 1984-12-10 1987-04-07 University Of Iowa Research Foundation Magnetic resonance (MR) image enhancement compounds for specific areas of the brain
US4678667A (en) * 1985-07-02 1987-07-07 501 Regents of the University of California Macrocyclic bifunctional chelating agents
US4728575A (en) * 1984-04-27 1988-03-01 Vestar, Inc. Contrast agents for NMR imaging
US4731239A (en) * 1983-01-10 1988-03-15 Gordon Robert T Method for enhancing NMR imaging; and diagnostic use
US4749560A (en) * 1984-08-13 1988-06-07 Research Corporation Metal organo phosphorous compounds for NMR analysis
US4753927A (en) * 1983-08-12 1988-06-28 Immunetech Pharmaceuticals Method of blocking immune complex binding to immunoglobulin Fc receptors
US4755382A (en) * 1985-06-13 1988-07-05 Monsanto Company Immunostimulating method
US4822594A (en) * 1987-01-27 1989-04-18 Gibby Wendell A Contrast enhancing agents for magnetic resonance images
US4826673A (en) * 1985-01-09 1989-05-02 Mallinckrodt, Inc. Methods and compositions for enhancing magnetic resonance imaging
US4834964A (en) * 1986-03-07 1989-05-30 M.R.I., Inc. Use of charged nitroxides as NMR image enhancing agents for CSF
US4880008A (en) * 1985-05-08 1989-11-14 The General Hospital Corporation Vivo enhancement of NMR relaxivity
US4915933A (en) * 1986-06-26 1990-04-10 The University Of New Mexico Mixed complexes as shift and contrast reagents in NMR imaging and spectroscopy
US4925648A (en) * 1988-07-29 1990-05-15 Immunomedics, Inc. Detection and treatment of infectious and inflammatory lesions
US4926869A (en) * 1986-01-16 1990-05-22 The General Hospital Corporation Method for the diagnosis and treatment of inflammation
US4933441A (en) * 1987-01-27 1990-06-12 Gibby Wendell A Contrast enhancing agents for magnetic resonance images
US4957939A (en) * 1981-07-24 1990-09-18 Schering Aktiengesellschaft Sterile pharmaceutical compositions of gadolinium chelates useful enhancing NMR imaging
US4980148A (en) * 1985-02-06 1990-12-25 Mallinckrodt, Inc. Methods for enhancing magnetic resonance imaging
US5019368A (en) * 1989-02-23 1991-05-28 Cancer Biologics, Inc. Detection of necrotic malignant tissue and associated therapy
US5057301A (en) * 1988-04-06 1991-10-15 Neorx Corporation Modified cellular substrates used as linkers for increased cell retention of diagnostic and therapeutic agents
US5064849A (en) * 1987-10-22 1991-11-12 Pola Chemical Industries Inc. Heterocyclic derivatives useful as radiosensitizing agents and antiviral agents
US5068227A (en) * 1989-01-18 1991-11-26 Cyclex, Inc. Cyclodextrins as carriers
US5077037A (en) * 1990-08-03 1991-12-31 Mallinckrodt Medical, Inc. Novel compositions for magnetic resonance imaging
US5094837A (en) * 1990-01-22 1992-03-10 Wayne State University Method for use of magnetic resonance imaging to image pancreas using secretin
US5101827A (en) * 1985-07-05 1992-04-07 Immunomedics, Inc. Lymphographic and organ imaging method and kit

Patent Citations (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4054645A (en) * 1976-08-24 1977-10-18 Minnesota Mining And Manufacturing Company Radiodiagnostic complexes employing fluorine-containing tin reducing agents
US4957939A (en) * 1981-07-24 1990-09-18 Schering Aktiengesellschaft Sterile pharmaceutical compositions of gadolinium chelates useful enhancing NMR imaging
US4554925A (en) * 1982-07-07 1985-11-26 Picker International, Ltd. Nuclear magnetic resonance imaging method
US4731239A (en) * 1983-01-10 1988-03-15 Gordon Robert T Method for enhancing NMR imaging; and diagnostic use
US4586511A (en) * 1983-03-04 1986-05-06 Children's Hospital Medical Center Methods and compositions for detecting and imaging a gas in an animal by nuclear magnetic resonance
US4753927A (en) * 1983-08-12 1988-06-28 Immunetech Pharmaceuticals Method of blocking immune complex binding to immunoglobulin Fc receptors
US4615879A (en) * 1983-11-14 1986-10-07 Vanderbilt University Particulate NMR contrast agents for gastrointestinal application
US4647567A (en) * 1984-04-05 1987-03-03 North Carolina State University Method of releasing growth hormones
US4728575A (en) * 1984-04-27 1988-03-01 Vestar, Inc. Contrast agents for NMR imaging
US4749560A (en) * 1984-08-13 1988-06-07 Research Corporation Metal organo phosphorous compounds for NMR analysis
US4639365A (en) * 1984-10-18 1987-01-27 The Board Of Regents, The University Of Texas System Gadolinium chelates as NMR contrast agents
US4639364A (en) * 1984-11-14 1987-01-27 Mallinckrodt, Inc. Methods and compositions for enhancing magnetic resonance imaging
US4564017A (en) * 1984-11-21 1986-01-14 General Electric Company Method and apparatus for respiration monitoring with an NMR scanner
US4656026A (en) * 1984-12-10 1987-04-07 University Of Iowa Research Foundation Magnetic resonance (MR) image enhancement compounds for specific areas of the brain
US4826673A (en) * 1985-01-09 1989-05-02 Mallinckrodt, Inc. Methods and compositions for enhancing magnetic resonance imaging
US4980148A (en) * 1985-02-06 1990-12-25 Mallinckrodt, Inc. Methods for enhancing magnetic resonance imaging
US4880008A (en) * 1985-05-08 1989-11-14 The General Hospital Corporation Vivo enhancement of NMR relaxivity
US4755382A (en) * 1985-06-13 1988-07-05 Monsanto Company Immunostimulating method
US4678667A (en) * 1985-07-02 1987-07-07 501 Regents of the University of California Macrocyclic bifunctional chelating agents
US5101827A (en) * 1985-07-05 1992-04-07 Immunomedics, Inc. Lymphographic and organ imaging method and kit
US4926869A (en) * 1986-01-16 1990-05-22 The General Hospital Corporation Method for the diagnosis and treatment of inflammation
US4834964A (en) * 1986-03-07 1989-05-30 M.R.I., Inc. Use of charged nitroxides as NMR image enhancing agents for CSF
US4915933A (en) * 1986-06-26 1990-04-10 The University Of New Mexico Mixed complexes as shift and contrast reagents in NMR imaging and spectroscopy
US4933441A (en) * 1987-01-27 1990-06-12 Gibby Wendell A Contrast enhancing agents for magnetic resonance images
US4822594A (en) * 1987-01-27 1989-04-18 Gibby Wendell A Contrast enhancing agents for magnetic resonance images
US5064849A (en) * 1987-10-22 1991-11-12 Pola Chemical Industries Inc. Heterocyclic derivatives useful as radiosensitizing agents and antiviral agents
US5057301A (en) * 1988-04-06 1991-10-15 Neorx Corporation Modified cellular substrates used as linkers for increased cell retention of diagnostic and therapeutic agents
US4925648A (en) * 1988-07-29 1990-05-15 Immunomedics, Inc. Detection and treatment of infectious and inflammatory lesions
US5068227A (en) * 1989-01-18 1991-11-26 Cyclex, Inc. Cyclodextrins as carriers
US5019368A (en) * 1989-02-23 1991-05-28 Cancer Biologics, Inc. Detection of necrotic malignant tissue and associated therapy
US5094837A (en) * 1990-01-22 1992-03-10 Wayne State University Method for use of magnetic resonance imaging to image pancreas using secretin
US5077037A (en) * 1990-08-03 1991-12-31 Mallinckrodt Medical, Inc. Novel compositions for magnetic resonance imaging

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5643549A (en) * 1992-02-20 1997-07-01 Rhomed Incorporated Leukostimulatory agent for in vivo leukocyte tagging
US6770261B2 (en) 1995-06-02 2004-08-03 Research Corporation Technologies Magnetic resonance imaging agents for the detection of physiological agents
US5707605A (en) * 1995-06-02 1998-01-13 Research Corporation Technologies Magnetic resonance imaging agents for the detection of physiological agents
US6713045B1 (en) 1995-06-02 2004-03-30 Research Corporation Technologies, Inc. Targeted magnetic resonance imaging agents for the detection of physiological processes
WO1996038184A3 (fr) * 1995-06-02 1997-03-13 California Inst Of Techn Agents d'imagerie par resonance magnetique pour la detection d'agents physiologiques
WO1996038184A2 (fr) * 1995-06-02 1996-12-05 Research Corporation Technologies, Inc. Agents d'imagerie par resonance magnetique pour la detection d'agents physiologiques
US5980862A (en) * 1995-06-02 1999-11-09 Research Corporation Technologies Magnetic resonance imaging agents for the detection of physiological agents
US6521209B1 (en) 1996-07-31 2003-02-18 California Institute Of Technology Bifunctional detection agents
US6713046B1 (en) 1997-10-27 2004-03-30 Research Corporation Technologies Magnetic resonance imaging agents for the delivery of therapeutic agents
US7354568B1 (en) 1997-10-27 2008-04-08 California Institute Of Technology Magnetic resonance imaging agents for the detection of physiological agents
WO2001021219A3 (fr) * 1999-09-21 2002-03-07 Us Health Imagerie d'accumulation de medicaments comme guide de therapie antitummorale
US7141234B1 (en) 1999-09-21 2006-11-28 The United States Of America As Represented By The Department Of Health And Human Services Imaging of drug accumulation as a guide to antitumor therapy
US7175830B2 (en) 1999-09-21 2007-02-13 The United States Of America As Represented By The Secretary Of Health And Human Services Imaging of drug accumulation as a guide to antitumor therapy
WO2001021219A2 (fr) * 1999-09-21 2001-03-29 The Government Of The United States Of America, As Represented By The Secretary Of Health And Human Services Imagerie d'accumulation de medicaments comme guide de therapie antitummorale
US6673333B1 (en) 2000-05-04 2004-01-06 Research Corporation Technologies, Inc. Functional MRI agents for cancer imaging
US6656450B2 (en) 2000-07-17 2003-12-02 California Institute Of Technology, Inc. Macrocyclic magnetic resonance imaging contrast agents
US7029655B2 (en) 2000-10-04 2006-04-18 California Institute Of Technology Magnetic resonance imaging agents for in vivo labeling and detection of amyloid deposits
WO2010087612A1 (fr) * 2009-01-28 2010-08-05 Snu R&Db Foundation Complexe à agent(s) chélateur(s) bifonctionnel(s) et sérumalbumine humaine mannosylée
TWI553017B (zh) * 2012-12-28 2016-10-11 行政院原子能委員會核能研究所 新穎膽道掃描用造影劑及其製造方法

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