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WO1992007259A1 - Produits d'addition a base de polymere-deferoxamine-fer ferrique utilises en imagerie par resonance magnetique - Google Patents

Produits d'addition a base de polymere-deferoxamine-fer ferrique utilises en imagerie par resonance magnetique Download PDF

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Publication number
WO1992007259A1
WO1992007259A1 PCT/US1991/007546 US9107546W WO9207259A1 WO 1992007259 A1 WO1992007259 A1 WO 1992007259A1 US 9107546 W US9107546 W US 9107546W WO 9207259 A1 WO9207259 A1 WO 9207259A1
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Prior art keywords
deferoxamine
adduct
polymer
composition according
ferric iron
Prior art date
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PCT/US1991/007546
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English (en)
Inventor
Bo E. Hedlund
Phillip E. Hallaway
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Biomedical Frontiers, Inc.
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Publication date
Application filed by Biomedical Frontiers, Inc. filed Critical Biomedical Frontiers, Inc.
Priority to JP4500706A priority Critical patent/JPH06502177A/ja
Publication of WO1992007259A1 publication Critical patent/WO1992007259A1/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
    • A61K49/10—Organic compounds
    • A61K49/12—Macromolecular compounds
    • A61K49/126—Linear polymers, e.g. dextran, inulin, PEG
    • A61K49/128—Linear polymers, e.g. dextran, inulin, PEG comprising multiple complex or complex-forming groups, being either part of the linear polymeric backbone or being pending groups covalently linked to the linear polymeric backbone
    • 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
    • A61K49/14—Peptides, e.g. proteins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent

Definitions

  • the invention is directed to a composition for enhancing magnetic resonance (MR) imaging.
  • the composition comprises a ferric iron-chelator complex bound to a polymer moiety. More particularly, the composition comprises an adduct of deferoxamine moieties, ferric iron and polymer which may be water-soluble, as for example, a protein or polysaccharide, or water- insoluble, as for example, a cellulose or agarose.
  • the composition is capable of safely introducing large concentrations of ferric iron into the vascular system or gastrointestinal tract.
  • the invention is further directed to a pharmaceutical composition and method of using the composition in MR imaging.
  • Magnetic resonance imaging is a relatively new diagnostic technique in the field of medical imaging of the body's internal structure.
  • Magnetic resonance (MR) images of the human body are obtained by exposing the protons, that is, hydrogen atom nuclei, contained in the water in tissue to the combined action of high magnetic fields and radio frequency waves.
  • the MR image derived from the MR signals, depends on the density of the protons in a given tissue, and on the two relaxation parameters of these protons which are referred to as Tl and T2.
  • the most intense Tl signal is obtained from fatty tissue due to low concentrations of water whereas tissues containing high concentrations of water, as for example, cerebrospinal fluid and edematous tissue, provide a Tl signal of low intensity. Compartments containing high concentrations of proteins, such as the blood stream and muscle tissue, are associated with an intermediate Tl signal intensity.
  • the administration of a paramagnetic ion into a specific compartment will alter the Tl proton relaxation.
  • the introduction of the magnetic field associated with one or more unpaired electrons will alter the interactions between the protons and their environment. As a result, the Tl relaxation time of the protons will be shortened. The magnitude of this change is dependent on the relative concentration of both protons and the paramagnetic ion.
  • Iron and manganese although naturally occurring in biomolecules, are also intrinsically toxic ions. Their toxicity can also be reduced by chelation. In the case of iron, deferoxamine, has been employed to reduce toxicity ( orah, et al., Investiq. Radiol. 23: S281-S285 (1988)) .
  • Gadolinium has been detoxified by complexation with ethylenediaminetetraacetic acid (EDTA) and diethylenetria inepentacetic acid (DTPA) ( ein ann, et al., A.J.R. 142: 619-624 (1984)) .
  • EDTA ethylenediaminetetraacetic acid
  • DTPA diethylenetria inepentacetic acid
  • the Gd-DTPA chelate distributes within the extracellular fluid compartment, does not penetrate the blood-brain-barrier, and is rapidly eliminated by the kidney (Schmiedl, et al., A.J.R. 147: 1263-1270 (1986)). Accordingly, Gd-DTPA is useful as a contrast agent for urographic imaging, for detecting abnormal capillary permeability from inflammation and tumors, and for assessment of the integrity of the blood-brain-barrier.
  • Gd-DTPA is quickly eliminated from the intravascular compartment, about 50% being cleared from the vascular space into the extravascular fluid compartment on the initial pass through the capillaries (Schmiedl, et al., A.J.R. 147: 1263-1270 (1986)). As such, Gd-DTPA cannot provide selective enhancement of the intravascular space such that blood volume or tissue perfusion, for example, may be assessed.
  • macromolecular components such as proteins and polysaccharides, as for example, albumin, cellulose and molecular weight dextrans having molecular weights of about greater than 50,000 have been attached covalently to DTPA with subsequent chelation to gadolinium (Brasch, et al. , In Contrast and Contrast Agents in Magnetic Resonance Imaging. Special Topic Seminar, P.A. Rinck (ed.), European Workshop on Magnetic Resonance in Medicine, Belgium, pp. 74-93 (1989)).
  • Protein-(Gd-DTPA) conjugates have been prepared with human and bovine serum albumin, immunoglobulin G, and fibrinogen.
  • albumin-(Gd-DTPA) conjugates Another drawback of albumin-(Gd-DTPA) conjugates is that the relatively low coupling efficiency of albumin with DTPA requires the injection of a high quantity of human serum albumin. Concern has been expressed regarding the high potential for immunogenic reactions associated with its modified protein matrix.
  • Dextrans have been cross-linked with DTPA via a polymerization process to form molecules from small particles of 17,000 MW to large insoluble particles.
  • a typical process for cross-linking dextrans with DTPA utilizes the anhydride of DTPA to achieve ester cross ⁇ linking of DTPA to dextran (Gibby, et al., Invest. Radiol. 24: 302-309 (1989)).
  • the DTPA anhydride is a bifunctional cross-linking agent, this polymerization process can prove to be difficult and cumbersome.
  • that method leads to poorly defined products with broad distribution of molecular weights. Further, the solubility of the resulting compound is much lower than that of the starting dextran component.
  • a current focus in MR imaging is on binding paramagnetics to proteins to provide contrast agents which are tissue- or function-specific.
  • a protein-image contrast conjugate has been prepared by combining antibodies with Gd-DTPA. See for example, Shreve, P. and A.M. Aisen, Magn. Reson. Med. 3: 336-340 (1986).
  • gadolinium as the paramagnetic nucleus is the higher relaxivity as compared to ferric iron. As such, a lower concentration of gadolinium need be administered in order to obtain signal enhancement.
  • the loss of gadolinium from DTPA is a known occurrence especially in cases where the DTPA anhydride is utilized for polymer attachment.
  • association constant, or affinity, of gadolinium to DTPA is relatively low at neutral pH and, more importantly, rapidly decreases when the pH is lowered. This characteristic is a significant problem with in vivo administration, particularly during ischemic insults which lead to acidosis and a localized drop in pH to as much as a full pH unit.
  • contrast agents remain stable to ensure that the paramagnetic ion remains in a sequestered, nontoxic form within the body.
  • Contrast agents containing ferric iron have been used as an alternative to gadolinium. Like gadolinium, however, ferric iron, must be detoxified for internal administration such as by chelation with deferoxamine (desferrioxamine; DFO) . The acute and chronic toxicity of deferoxamine is relatively high, potentially causing hypotension when administered intravenously. Ferrioxamine is a stable complex of ferric iron (Fe +3 ) and deferoxamine, having a binding constant of about 10 "30 (Hallaway, et al., Proc. Natl. Acad. Sci. fUSA) 86: 10108-10112 (1989)).
  • Ferrioxamine is excreted primarily in the urine which makes it especially useful as an enhancing agent for the urinary tract. Further, it provides identification of local blood-brain-barrier defects and assessment of renal excretory functions (Wesbey, et al., Physiol. Chem. Phvs. and Med. NMR 16: 145-155 (1984); Weinman, et al. , A.J.R. 142: 619-624 (1984)).
  • FO clearance is biphasic, with an initial phase of about 128 minutes whereby about one-half of the dose is eliminated, followed by a prolonged elimination phase with a half-life of over 7 hours (Worah, et al., Investig. Radiol. 23: 5281-5285 (1988)) .
  • ferrioxamine as a paramagnetic contrast agent can be used only in very low concentrations and is limited to the urinary excreting system.
  • ferrioxamine at 20 MHz and at 37 degrees is 1.4 s "1 mM "1 , which is a factor of 3 lower than Gd-DTPA. Accordingly, ferrioxamine must be injected at a 2-3 times higher dose than gadolinium- containing chelates to produce the same relaxation effects.
  • Contrast agents comprising para- or ferromagnetic agents bound to proteins such as immunoglobulins, monoclonal antibodies and blood-pool markers have been suggested for use as tumor-specific MR agents (Paajanen, et al., Magn ⁇ Reson. Med. 13: 38-43 (1990)).
  • the metal chelator was initially attached to polyamino acids such as polylysine, polyglutamic acids, or other organic polymers such as polyacrylic acid
  • an object of the invention is to provide a macromolecular paramagnetic contrast agent composed of ferric iron for use in magnetic resonance imaging that will enhance proton relaxation times, be free of toxic effects in doses appropriate for contrast enhancement in vivo, remain stable in vivo, retain and/or increase its biological half-life in vivo, and be quickly eliminated from the body after completion of the desired imaging study.
  • Another object is to provide a ferric iron contrast agent which is capable of tissue-specific or compartment-specific distribution in a mammal.
  • Yet another object is to provide a pharmaceutical composition comprising the paramagnetic adduct of the invention and a method of using the composition to enhance magnetic resonance imaging.
  • compositions which comprise an adduct of a conjugate of deferoxamine moieties covalently bonded to a polymer, and ferric iron chelated to the deferoxamine moieties.
  • the polymer moiety according to the invention may be any macromolecular substance which is capable of decreasing the toxicity of the bound chelate component of the adduct.
  • the adducts may comprise water-soluble polymers such as polysaccharides, as for example, dextrans, starches, hyaluronic acid, inulin and celluloses, and proteins such as serum albumin and transferrin, or water-insoluble polymers such as celluloses, agaroses, and the like.
  • the contrast agent, or adduct is formed by saturating the binding sites on polymer-bound iron chelators with iron.
  • the deferoxamine moiety substantially retains its chelating ability after attachment to the polymer component.
  • the resulting polymer-(chelator-ferric iron) adducts are non-toxic and provide for the introduction of high concentrations of bound, non-toxic, ferric iron into the vascular system, or compartment, or gastrointestinal tract of a mammal. Concentrations greater than 1 mM of ferric iron may be introduced into the bloodstream without harmful side effects.
  • the adduct of the invention is capable of increasing the amount of ferric iron in the vascular compartment to about 5mM.
  • the amount of ferric iron in the vascular system provided by the adduct is about 0.5-2mM.
  • the ferric iron itself enhances the proton magnetic resonance signal. The magnetic signal is enhanced further by attaching the iron/chelator complex to the polymer.
  • the invention provides a composition suitable for in vivo administration for use in magnetic resonance imaging of a body feature of a patient.
  • the pharmaceutical composition according to the invention comprises a pharmaceutically-acceptable adduct in combination with a bioco patible, pharmaceutically- acceptable carrier. It is preferred that the adduct is present in an amount effective to enhance the body feature being imaged.
  • compositions of the invention are capable of selective magnetic resonance image enhancement of particular cells, tissues, and other features, particularly of the vascular system.
  • the adducts of the invention are useful in MR imaging to monitor circulatory insufficiency, tumor infiltration, vascular leak, or edema, and tissue injured by ischemia and reperfusion.
  • the invention includes MR image contrast agents with specificity for particular cells or tissues which are useful diagnostic tool, as for example, in cancer detection.
  • various neoplastic cell types including both vascular tumors, and solid tumors such as carcinoma of the breast, are associated with increased expression of the transferrin receptor.
  • transferrin an iron transporting protein, may be used as the polymer component of the adduct to enhance the distribution of such transferrin conjugates to cells and/or domains where the expression of binding sites, or receptors, for this protein are high.
  • the adducts provide for intravascular retention for the period of time required to provide effective contrast enhancement of the body feature being imaged, preferably 30-90 minutes.
  • the size of the adducts of the invention is effective to slow the rate of diffusion of the adduct from the vascular space into the extracellular fluid space so that the MR imaging of an organ, tissue or other feature of the vascular compartment can be achieved.
  • the adduct is preferably at least about 5,000 Daltons and less than 250,000 Daltons, more preferably about 10,000 to 50,000 Daltons. After the imaging process is completed, the adduct is rapidly eliminated from the body, preferably within 24 hours. It is preferred that the adduct is eliminated from the body through the urinary system.
  • a method of using the composition comprising the adduct in MR imaging comprises the steps of administering a composition composed of a contrast agent comprising a pharmaceutically-acceptable adduct according to the invention, such that the contrast agent is distributed to the body system being imaged, and determining the image of the system or a portion thereof according to an MR imaging technique.
  • the hatched and closed bars indicate the period of drug infusion and LAD occlusion, respectively. All values are the mean ⁇ SEM. * p ⁇ 0.05 vs control group.
  • the hatched and closed bars indicate the period of drug infusion and LAD occlusion, respectively. All values are the mean + SEM. * p ⁇ 0.05 vs DFO group.
  • the present invention is directed to magnetic resonance (MR) imaging of a mammal using an MR contrast agent which is an adduct of a ferric iron-chelator complex covalently bound to a polymer component.
  • MR contrast agent which is an adduct of a ferric iron-chelator complex covalently bound to a polymer component.
  • MR contrast agent which is an adduct of a ferric iron-chelator complex covalently bound to a polymer component.
  • the invention provides for enhancing the contrast of an MR image of the vascular compartment, that is, body features which are highly vascularized, as for example, the kidney, liver, heart, brain, and gastrointestinal tract.
  • the invention provides improved MR contrast agents which may be produced by saturating the binding sites on polymer-bound chelators, particularly deferoxamine, with iron.
  • the resulting compounds are non-toxic and provide for the introduction of high concentrations of bound, or sequestered, and thus non- toxic, ferric iron into body structures and systems,
  • the paramagnetic nature of ferric iron alone provides significant enhancement of the proton magnetic resonance signal by shortening the Tl relaxation time of protons. Additional enhancement of the magnetic signal is achieved by attaching a deferoxamine-ferric iron complex, or ferrioxamine, to a polymer component such as a protein or polysaccharide. Intravenous infusion of polymer-bound ferrioxamine provides a means for safely obtaining transient vascular concentrations of ferric iron at concentrations in excess of 1 mM.
  • the composition of the invention further provides a means for selective magnetic resonance image enhancement of particular sites within the vascular system.
  • the polymer moiety may be any macromolecular substance which may decrease the toxicity of the bound chelate component.
  • Suitable polymers according to the invention include water-soluble polymers such as polysaccharides, as for example, dextrans, starches, hyaluronic acid, inulin and celluloses, and proteins such as serum albumin and transferrin, and water-insoluble polymers such as celluloses and agaroses.
  • Polymers may be designed to provide an adduct for a particular clinical need with respect to particular physiological distribution and vascular retention within a body.
  • the water-insoluble polymers provide adducts for gastrointestinal tract imaging while the water-soluble polymers provide adducts for vascular imaging.
  • the adduct of the invention should be of a size effective to deter rapid diffusion of the adduct from the intravascular to the extracellular fluid space, such that the adduct is retained intravascularly to provide effective contrast enhancement of the organ or tissue being imaged. It is preferred that the adduct is retained within the vascular compartment for about 30-90 minutes.
  • the adduct has a molecular weight, as determined by gel permeation chro atography, of between 5,000 to 250,000 Daltons, more preferably about 10,000 to 50,000 Daltons.
  • the deferoxamine moiety is covalently bonded directly to a pharmaceutically-acceptable organic polymer and the conjugate is then saturated with ferric iron.
  • the deferoxamine-ferric iron complex in a prepared form may be bonded to the polymer moiety, and the conjugate saturated with ferric iron.
  • Methods for the preparation of deferoxamine N-[5-[3-[ (5-aminopentyl)hydroxycarbamoyl] propionamido]pentyl]-3-[ [5-(N-hydroxyacetamido) pentyl] carbamoyl]propionohydroxamic acid
  • deferoxamine N-[5-[3-[ (5-aminopentyl)hydroxycarbamoyl] propionamido]pentyl]-3-[ [5-(N-hydroxyacetamido) pentyl] carbamoyl]propionohydroxamic acid
  • pharmaceutically-acceptable salts have been disclosed, e.g., by Prelog, et al., in Helv. Chim. Acta.
  • Such salts include the acid addition salts of methane sulfonic acid, phosphoric acid, acetic acid, lactic acid, tartaric acid, citric acid and the like. It is preferred that the terminal amino (NH 2 ) group of deferoxamine is bound to a molecule of a pharmaceutically-acceptable organic polymer.
  • the amino group may be bonded directly to a carboxy-acid moiety on the polymer, e.g., to form an amide linkage.
  • the deferoxamine amino group will be directly bonded to an aldehyde (CHO) moiety on the polymer via the reaction sequence:
  • the terminal amino group on deferoxamine can also be bonded to an amino group on the polymer indirectly, by the use of a dialdehyde linking agent such as glutaraldehyde, followed by reduction, e.g., with sodium borohydride.
  • a dialdehyde linking agent such as glutaraldehyde
  • the mole ratios of deferoxamine:polymer attainable by these reactions will vary widely, depending on factors such as the number of reactive groups on the polymer, steric hindrance, rate and extent of Schiff base or amide formation, and the like. As an example, about 0.6-0.7 g of deferoxamine can be bonded to about 2.5 g of reacted Dextran 40, via reaction of the deferoxamine with aldehyde groups introduced into the dextran, followed by reduction.
  • Organic polymers used as a substrate material for reaction with deferoxamine may be either water- soluble or water-insoluble. Chelating agents formed from either will have utility in various applications, provided the polymer and chelating agent are pharmaceutically- and/or otherwise compatible with the physiological solutions with which they will have contact during use.
  • the chelating moiety of the agent must remain effective as a chelator after attachment to the polymer.
  • the deferoxamine moiety is anchored to the polymer moiety in such a manner that the chelating ability of the deferoxamine moiety in vitro remains substantial, preferably on the order of non-anchored deferoxamine.
  • the adduct should be sufficiently soluble for ease of introduction and should provide increased retention in the vascular compartment compared to ferrioxamine alone.
  • the adduct should be substantially non-toxic even when administered at concentrations 3 to 10 times higher than necessary for optimal contrast enhancement.
  • the polymeric substrate should not cause significant side reactions, and thus should be selected from polymers which are biocompatible.
  • polymers apparently useful for application according to an in vivo application of the present invention include polysaccharides such as the dextrans and hyaluronic acid, starch derivatives, and proteins such as serum albumin, transferrin and the like.
  • Polymer starting materials such as the dextrans, hydroxyethyl starch, human albumin and plasma protein fraction are commercially available. See Remington's Pharmaceutical Sciences. A. Osol., ed., Mack Publishing (16th ed. 1980) at pages 759-761, the disclosures of which are incorporated by reference herein.
  • insoluble synthetic and natural organic polymers can be bound to deferoxamine by the techniques described hereinabove, including water-
  • the ratio of deferoxamine to ferric iron in the adduct is about 1.2 to 1.01, most preferably 1.06 to 1.04. It is essential that a slight excess of deferoxamine is used in order to reduce and/or eliminate the occurrence of non-specifically bound iron which may be potentially toxic to the living system.
  • a preferred embodiment of the composition according to the invention comprises about 3-40 wt-% deferoxamine, more preferably about 10-25 wt-%, about 0.3-4 wt-% ferric iron, more preferably about 1.0-2.5 wt-%.
  • These synthetic iron chelator-polymer conjugates therefore contain a higher level of bound iron than transferrin, an iron transporting protein which, in its saturated form, contains approximately 0.15% of iron by weight.
  • the adduct of the invention exhibits substantial advantages, primarily relating to diminished toxicity of the deferoxamine-ferric iron moiety, and increased vascular retention time of the anchored deferoxamine-ferric iron moiety relative to non-anchored ferrioxamine. It will be understood from the below reported experimental results that behavior of the polymer bound deferoxamine-ferric iron adduct is not readily predictable from other polymer-bound MR contrast agents.
  • the polymer-(deferoxamine-ferric iron) adduct is capable of MR contrast enhancement in a mammal particularly of the vascular compartment, or, as in the case of oral administration, the gastro-intestinal system.
  • the adduct may enable MR detection of reperfusion of blood to damaged tissue upon restoration of arterial flow, enhance vascular tissues associated with the brain, or define tumors.
  • the adduct may enable the definition or detection by MR of hemorrhage sites such as a stroke, gradations in blood volume, extent of vascularity, or renal, intestinal, myocardial, or cerebral ischemia within minutes of onset.
  • deferoxamine-ferric iron complex conjugated to hydroxyethyl starch may be used to enhance the MR imaging of myocardial and brain blood vessels related to micro- and macrocirculation.
  • Such an agent is useful in the diagnosis of vascular lesions of several types in a variety of organs.
  • the composition of the invention may enhance tissues in multiple anatomic regions without reinjection.
  • the MR contrast composition of the invention provides for intravascular retention effective to accomplish MR imaging of a particular organ or tissue. It is preferred that the adduct has a vascular half-life of at least about 30-90 minutes. For example, a 20,000 molecular weight hydroxyethyl starch-deferoxamine adduct according to the invention may be retained within the vascular compartment for 2 to 3 hours. After completion of the imaging procedure, it is preferred that the adduct is eliminated from the body. Preferably, the adduct is completely eliminated within 24 hours post-administration of the magnetic resonance imaging procedure. It is further preferred that the adduct is eliminated through the urinary system. The adduct may also provide enhancement of other than the vascular compartment.
  • the adduct may be administered such as by injection, into the spinal cord to enhance structural details of cerebrospinal fluid circulation, the sinuses, the genito ⁇ urinary system, the lymphatic system, and any other systems which may be detected by MR procedures.
  • the adduct may provide enhancement of the lymphatic system by injection into lymph nodes such as the submandibular nodes, pre- and post-auricular nodes, superficial cervical nodes, axillary nodes, inguinal nodes, and the like.
  • the adduct may be injected into the synovial fluid of a joint, for example, a race horse, for image enhancement of the ligaments and other structures.
  • the invention includes MR image contrast agents with specificity for particular cells or tissues which are useful as diagnostic tools, as for example, in cancer detection.
  • Increased expression of transferrin receptors is a hallmark for a variety of neoplastic cell types, including both vascular tumors, and solid tumors such as carcinoma of the breast.
  • the adduct of the invention may incorporate transferrin, an iron transporting protein, to augment the distribution of contrast agent conjugates to cells and/or domains where the expression of binding sites, or receptors, for transferrin are high.
  • MR image contrast agents which possess a specificity for cells with increased expression of the transferrin receptor thus provide a means for the diagnosis of cancerous cells and/or tissues.
  • the invention further includes a pharmaceutically-acceptable adduct of deferoxamine, ferric iron and polymer for administration to a mammal.
  • the adduct of the invention may be combined with a pharmaceutically-acceptable vehicle such as a liquid or a powdered carrier, which is compatible with the adduct.
  • a pharmaceutically-acceptable vehicle such as a liquid or a powdered carrier, which is compatible with the adduct.
  • the adduct may be combined with hyaluronic acid for injection into the synovial fluid of the joint.
  • the pharmaceutical composition may be formulated as a powder, granules, solution, ointment, cream, aerosol, powder, or drops.
  • the solution or drops may contain appropriate adjuvants, buffers, preservatives and salts.
  • the powder or granular forms of the composition may be combined with a solution and with diluting, dispersing and/or surface active agents.
  • the composition may be administered orally, rectally, intravenously, parenterally, or by direct injection into the system being imaged.
  • composition of the invention is preferably administered in vivo as a solution, parenterally, e.g., by intramuscular or intravenous injection or infusion, or via oral, rectal or vaginal routes.
  • the composition may also be administered by direct injection into the system being imaged.
  • the appropriate dose will be adjusted in accord with appropriate clinical factors including the organ or tissue to be enhanced, the patient's age, size and weight, the mode of administration, and the like.
  • the optimal dose of a particular contrast agent is dependent on a number of factors, such as the rate of excretion of the adduct, the relaxivity of the adduct, or whether the adduct becomes distributed within the extracellular environment. Where the agent remains in the vascular compartment, lower doses are needed. However, the actual optimal dose will be dependent on any particular set of circumstances. It is preferred that the adduct is administered in an amount effective to enhance the resonance imaging of the organ being studied.
  • the dose of the polymer-(deferoxamine-ferric iron) conjugate is between about 0.01 and 0.1 millimoles/kg body weight, or about 6 to 60 mg/kg body weight ferrioxamine.
  • Formulations of polysaccharide- deferoxamine-ferric iron adducts preferably contain about 5-20 mg/ml of immobilized deferoxamine-ferric iron complex. Preferably between 0.5 to 6 ml/kg body weight deferoxamine-ferric iron, more preferably about 1 ml/kg body weight, is administered. For oral administration of the adduct for enhancement of the gastrointestinal tract, larger volumes may be administered.
  • the invention further includes a method for magnetic resonance imaging of the body of a mammal.
  • the method includes the steps of administering the composition containing the adduct of the invention to a patient such that the adduct is distributed to the body system being imaged, and determining the image of the body system or a portion thereof according to MR imaging techniques. See, for example, Niendorf & Haustein, In Contrast and Contrast Agents in Magnetic Resonance Imaging; Proc. Europ. Workshop on Magn. Reson. in Medic. (September 1988) , the disclosure of which is incorporated by reference herein.
  • composition which is administered according to the method of the invention comprises a pharmaceutically-acceptable adduct of deferoxamine, ferric iron, and polymer in combination with a pharmaceutically-acceptable carrier. It is preferred that the adduct is present in an amount effective to enhance a magnetic resonance image of the body system being imaged.
  • the method of the invention particularly provides for contrast enhancement of highly vascularized tissues in a mammal, although other systems such as the lymph system or the renal/urinary tract may also be enhanced according to the invention. To provide enhancement of the vascular system, it is preferred that the adduct is induced into the bloodstream.
  • the composition may be administered orally, rectally, intravenously, parenterally, or by direct injection into the system being imaged.
  • ferrioxamine-based adducts are the much higher affinity or binding constant of deferoxamine for ferric iron compared with that of DTPA for gadolinium ion. Accordingly, the adducts of the present invention will not degrade over the time required for the imaging study.
  • the loss of Gd from DTPA is a known occurrence especially in cases where the DTPA anhydride is utilized for polymer attachment.
  • the very high binding constant of ferric iron to deferoxamine ensures that the iron will not dissociate from the complex in vivo.
  • polysaccharide- deferoxamine conjugates of the present invention is that both water-soluble and water insoluble conjugates can be prepared. Attachment of DFO to biocompatible, water soluble polysaccharides and proteins provides adducts which are well suited for parenteral injection. Attachment of the chelator-iron complex to insoluble matrices, such as celluloses, agaroses, and the like, provide adducts which are well suited for oral or rectal administration.
  • Yet another advantage of the present invention is that since the amino group of the chelator is used for attachment to the polymer, there is no risk of polymer- polymer cross-linking. As a result, the conjugates of the invention remain very similar in character to the starting polymer component. In contrast, attachment of DTPA anhydride, a bifunctional cross-linking agent, to polymers is associated with polymer-polymer cross- linking, which leads to large complexes with poorly defined molecular weight.
  • Another advantage is that the attachment of deferoxamine to the polymer moiety, according to the invention, does not alter the iron binding properties of the chelator. See Hallaway, et al., Proc. Nat. Acad. Sci. USA 86: 10108-10112 (1989), the disclosures of which are incorporated by reference herein.
  • the polymer moiety of the invention are pharmaceutically-acceptable components. For example, hydroxyethyl starch, dextran, inulin and hyaluronic acid are used extensively in clinical treatment as plasma volume expanders.
  • a further advantage of the invention is that, unlike gadolinium conjugates, the ferrioxamine-containing compounds of the invention range in color from dark brown to orange and thus provide for enhanced visual detection of urinary excretion of the MR enhancing agent.
  • the adducts of the invention provide improved contrast agents for enhancement of various organs and tissues in MR imaging as compared to agents such as free Gd-DTPA, Gd-DTPA conjugates, or free deferoxamine-ferric iron complex.
  • This example describes attachment of deferoxamine (DFO) to the polysaccharide hydroxyethyl starch (HES) and saturation of the conjugate with ferric iron to synthesize a high molecular weight polysaccharide-deferoxamine-ferric iron adduct.
  • DFO deferoxamine
  • HES polysaccharide hydroxyethyl starch
  • HES Hydroxyethyl starch
  • HAS Hydroxyethyl starch
  • Cleavage of cis-diols to yield reactive aldehyde groups was accomplished by addition of solid sodium metaperiodate to a final concentration of 100 mM.
  • the solution was incubated for one hour at room temperature.
  • Low molecular weight reaction products were removed from the mixture by diafiltration (Pellicon system, Millipore Corporation, Bedford, Massachusetts) with depyrogenated water using a 100,000 molecular weight cut-off filter (Millipore Corporation) .
  • the polymer concentration was adjusted to 100 grams/liter based on refractive index of the solution.
  • Deferoxamine was added as the mesylate salt to a final concentration of 100 mM and allowed to fully dissolve at room temperature.
  • the resulting Schiff bases between the amino group of the deferoxamine and the aldehyde groups on the polymer were reduced by addition of sodium cyanoborohydride to a final concentration of 100 mM.
  • sodium borohydride was added to a final concentration of 100 mM to reduce any residual aldehyde groups. The reaction mixture was gently stirred for 16 hours at room temperature.
  • Concentration of the polymer-deferoxamine conjugate and removal of low molecular weight contaminants were accomplished by thorough diafiltration, using a 30,000 molecular weight cut-off filter and pyrogen-free water. The concentration of the polymer- deferoxamine conjugate was adjusted to 130 grams/liter based on refractive index.
  • the molecular weight distribution of the hydroxyethyl starch-deferoxamine-ferric iron adduct was determined by high pressure liquid chromatography and was unchanged from the distribution of the hydroxyethyl starch-deferoxamine conjugate.
  • adducts comprising inulin, hyaluronic acid or dextran as the polymer moiety.
  • inulin which is relatively insoluble in its native form, the inulin- deferoxamine conjugate becomes more soluble following attachment of chelator.
  • the resulting solution primarily contained the deferoxamine- glutaraldehyde conjugate with small amounts of deferoxamine-glutaraldehyde-deferoxamine conjugate, unreacted glutaraldehyde, and unreacted deferoxamine.
  • Human holotransferrin the iron saturated form of transferrin, was purchased from Sigma Chemical Co., St. Louis, MO.
  • a volume of 4.5 ml of a 10% solution of transferrin was reacted with an equal volume of the above-prepared solution containing deferoxamine- glutaraldehyde conjugate.
  • a control solution of transferrin mixed with an equal volume of saline was prepared as a control.
  • the concentration of the deferoxamine-glutaraldehyde adduct in the final mixture was 25 mM compared to 5% or 0.62 mM of the protein.
  • the final concentration of ferrous sulfate in solutions B and D was 10 mM; the absorbance of 10 mM ferrous sulfate at 429 nm is 0.010.
  • the increase in absorbance of 0.105 units upon addition of ferrous•sulfate to the control transferrin solutions represents non-specific binding of ferric iron to the protein.
  • the increase in optical density following addition of ferrous sulfate to reaction solution B containing transferrin- deferoxamine conjugate represents binding of ferric iron to deferoxamine.
  • Solution A containing transferrin- deferoxamine conjugate alone had an optical density of 0.536.
  • solution B the addition of ferric sulfate to the conjugate showed an optical density of 1.790, or an increase of 1.254 (solution B (1.790) minus control solution A (0.536)).
  • the optical density resulting from non-specific binding of ferric iron to transferrin protein (solutions D minus C, or 0.105) is then subtracted from the 1.254 figure to indicate a net increase in optical density of 1.149 for the transferrin- deferoxamine-ferrous sulfate solution B.
  • the observed value corresponds to 0.5 mM deferoxamine.
  • concentration of transferrin protein in the control and reaction solution was 0.125 mM. Therefore, each transferrin molecule carries, on the average, four bound deferoxamine molecules.
  • the material in solution B was precipitated with trichloroacetic acid. The supernatant was then neutralized and the optical density measured at 429 nm. This control experiment revealed that less than 10% of the deferoxamine remained in the supernatant. Therefore, more than 90% of the deferoxamine was bound to the protein.
  • larger quantities of the transferrin- deferoxamine-ferric iron adduct may be prepared by adding calculated quantities of an iron salt, such as ferric ammonium sulfate to the transferrin-deferoxamine solution. Following diafiltration against normal saline, the preparation is sterile filtered, and either lyophilized or used directly as a 5% solution.
  • an iron salt such as ferric ammonium sulfate
  • the ratio of deferoxamine- glutaraldehyde to protein By altering the ratio of deferoxamine- glutaraldehyde to protein, as many as 10 moles of deferoxamine may be added per mole of protein. However, such preparations show a significant amount of cross- linked protein when analyzed by polyacrylamide gel electrophoresis.
  • the ratio of deferoxamine to protein is about 4-6 moles deferoxamine:1 mole protein.
  • the transferrin-deferoxamine-ferric deferoxamine iron adduct is also capable of unaltered affinity for binding to human transferrin receptor on HeLa cells.
  • the retention of specific receptor binding affinity which may be characteristic of the unaltered protein component by the modified protein-deferoxamine conjugate is an important parameter for achieving binding and the subsequent'image enhancement of those cells and tissues containing high concentrations of the transferrin receptor. Accordingly, it is preferred that the adduct of the invention retain the receptor binding affinity of its protein moiety.
  • the effect on myocardial function was determined using deferoxamine (DFO) , a conjugate of deferoxamine attached to a low molecular weight form of hydroxyethyl starch (HES-DFO) , and a hydroxyethyl starch-deferoxamine conjugate (HES-DFO) in which 90-95% of the iron sites had been saturated with ferric iron.
  • DFO deferoxamine
  • HES-DFO a conjugate of deferoxamine attached to a low molecular weight form of hydroxyethyl starch
  • HES-DFO a hydroxyethyl starch-deferoxamine conjugate
  • the physiological effects of HES-DFO-ferric iron in relation to DFO and HES-DFO were studied to determine the suitability of the hydroxyethyl starch-deferoxamine- ferric iron adduct as an MR image contrast agent.
  • Aortic blood pressure and left ventricular pressure were monitored by inserting a double pressure transducer-tipped catheter into the aorta and left ventricle via the carotid artery.
  • Left ventricular dP/dt was determined by electronic differentiation of the left ventricular pressure pulse.
  • the left jugular vein was cannulated for the administration of deferoxamine (DFO) , hydroxyethyl starch-deferoxamine conjugate (HES-DFO) and hydroxyethyl starch-deferoxamine-ferric iron adduct (HES-DFO-ferric iron) .
  • DFO deferoxamine
  • HES-DFO hydroxyethyl starch-deferoxamine conjugate
  • HES-DFO-ferric iron hydroxyethyl starch-deferoxamine-ferric iron adduct
  • a left thoracotomy was performed at the fifth intercostal space, the pericardium incised and the heart suspended in a cradle.
  • a portion of the left anterior descending coronary artery (LAD) was isolated distal to the first diagonal branch and a electromagnetic flow probe was placed around the vessel.
  • LAD blood flow was measured with a flow meter.
  • a micrometer driven mechanical occluder was placed to produce a total occlusion of the LAD and to subsequently allow reperfusion.
  • the heart was paced at 150 beats/min.
  • Myocardial segment function expressed as percent segment shortening, or %SS, as a measure of altered myocardial function following ischemia/reperfusion, was measured in the regions perfused by the LAD and the left circumflex coronary artery by using two sets of piezoelectric crystals. The precalibrated crystals were inserted into the subendocardium. The leads of each crystals were connected to an ultrasonic amplifier which transformed the sound pulse transmitted between the two crystals into an electrical signal proportional to the distance between them. These tracings were monitored with an oscilloscope. The %SS was calculated according to the following equation:
  • %SS (DL - SL)/DL X 100 where DL is the diastolic segment length, and SL is the systolic segment length.
  • Regional myocardial blood flow was determined by the use of the microsphere technique.
  • the left atrial appendage and the right femoral artery were cannulated for the administration of microspheres and for the withdrawal of a reference blood flow sample, respectively.
  • Radioactive microspheres (15 ⁇ 3 diameter) were injected into the left atrium followed by a 6 ml saline wash. Before administration of the microspheres, a reference blood flow sample was withdrawn from the femoral artery at a constant rate for 2-3 minutes.
  • Blood levels of DFO, HES-DFO and HES-DFO-ferric iron were obtained before, during and after coronary occlusion in blood samples obtained from the femoral artery. Blood samples were centrifuged and plasma samples stored at -70 ⁇ C for later analysis. The methodology for these measurements are described in Hallaway, et al., Proc. Nat. Acad. Sci. USA. 86: 10108-10112 (1989) , the disclosures of which are incorporated by reference herein. After surgical preparation and stabilization, control measurements of hemodynamics were obtained and radioactive microspheres administered to determine regional myocardial blood flow. Four groups of dogs were used.
  • One group received saline, the other groups received 50 mg/kg of deferoxamine or deferoxamine-ferric iron (ferrioxamine) equivalents at 30 minutes prior to and during the 15 minute period of occlusion.
  • the solutions were infused at a rate of 2.3 ml/min.
  • the occluder was released slowly and the LAD reperfused for three hours. Hemodynamics were continuously recorded during this period. Radioactive microspheres were infused at 12 minutes of occlusion and at 30 and 180 minutes of reperfusion.
  • HES-DFO-ferric iron was prepared by addition of 0.95 equivalents of ferric iron as ferric chloride, based on the measured content of available iron building sites, to a solution containing HES-DFO. The resulting acidic solution was neutralized with sodium hydroxide and filtered before use.
  • Myocardial Function Myocardial segment function is expressed as present segment shortening, or %SS. No differences in the subendocardial wall function in the non-ischemic (LCX) area was observed in the four groups. In the ischemic LAD region, there was a similar reduction in %SS in all four groups which is an indication of passive systolic lengthening.
  • HES-DFO can be assigned to the iron chelating properties of the HES-DFO conjugate.
  • Plasma Levels of Chelator Conjugates The plasma levels of DFO, HES-DFO and HES-DFO-ferric iron are illustrated in Figure 2. The infusion of 50 mg/kg of HES-DFO or HES-DFO-ferric iron over 45 minutes yielded a plasma concentration of approximately 1.0 mM. The maximal plasma concentration of DFO reached about 0.4 mM and then rapidly decreased.
  • the hydroxyethyl starch-deferoxamine- ferric iron adduct did not cause any observable toxicity when infused intravenously at a dose equivalent to 50 mg/kg deferoxamine-ferric iron (ferrioxamine) .
  • the effect of the HES-deferoxamine-ferric iron adduct on myocardial function is indistinguishable from that of a similar volume of saline, indicating that there is neither a protective nor adverse effect on the heart. Plasma concentrations in the millimolar range were maintained over a 30 minute period following the termination of infusion of the adduct.

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Abstract

Compositions comprenant un produit d'addition fixé de manière covalente de déféroxamine, de fer ferrique et de polymère servant à améliorer les images en imagerie par résonance magnétique (RM). L'invention concerne également une composition pharmaceutique comprenant le produit d'addition ainsi qu'un procédé d'utilisation de la composition en imagerie par résonance magnétique.
PCT/US1991/007546 1990-10-16 1991-10-15 Produits d'addition a base de polymere-deferoxamine-fer ferrique utilises en imagerie par resonance magnetique WO1992007259A1 (fr)

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WO1995005611A1 (fr) * 1993-08-12 1995-02-23 The Trustees Of Dartmouth College Appareil et methodologie de determination de la concentration d'oxygene dans des systemes biologiques
WO1995014491A3 (fr) * 1993-11-29 1995-07-06 Access Pharma Inc Chelates d'ions de metaux avec des saccharides et glycosaminoglycanes acides
US5707604A (en) * 1986-11-18 1998-01-13 Access Pharmaceuticals, Inc. Vivo agents comprising metal-ion chelates with acidic saccharides and glycosaminoglycans, giving improved site-selective localization, uptake mechanism, sensitivity and kinetic-spatial profiles
WO1999042139A3 (fr) * 1998-02-20 1999-09-30 Schering Ag Conjugues d'amidon hydroxyethyle, leur procede de production et produits pharmaceutiques les contenant
WO2000036422A1 (fr) * 1998-12-17 2000-06-22 Yissum Research Development Company Of The Hebrew University Of Jerusalem Mesure du fer lie hors transferine
US6106866A (en) * 1995-07-31 2000-08-22 Access Pharmaceuticals, Inc. In vivo agents comprising cationic drugs, peptides and metal chelators with acidic saccharides and glycosaminoglycans, giving improved site-selective localization, uptake mechanism, sensitivity and kinetic-spatial profiles, including tumor sites
AT409929B (de) * 1997-03-07 2002-12-27 Tritthart Helmut A Dr Polymere-infusionslösung zur anwendung bei der diagnose von tumoren, gegebenenfalls zu deren behandlung
WO2004011036A1 (fr) * 2002-07-31 2004-02-05 General Electric Company Procede destine a evaluer la permeabilite de capillaires
WO2004010841A3 (fr) * 2002-07-31 2004-04-29 Gen Electric Technique d'evaluation pour angiogenese du myocarde
WO2004052401A3 (fr) * 2002-12-09 2005-02-17 American Bioscience Inc Compositions et methodes d'administration d'agents pharmacologiques
AU2003299590B2 (en) * 2002-12-09 2010-03-04 Abraxis Bioscience, Llc Compositions and methods of delivery of pharmacological agents
CN114460163A (zh) * 2022-02-11 2022-05-10 河北师范大学 一种检测生物组织铁含量的maldi质谱成像方法

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DE69306250T2 (de) * 1992-01-15 1997-03-20 Univ Washington Ein verfahren zur bestimmung des biologischen potentials eines ausgenählten karzinoms von einem patienten
JP2004532245A (ja) * 2001-05-15 2004-10-21 ページ ダブル フォーク 癌を治療するための生体影響性化合物の標的送達

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US5707604A (en) * 1986-11-18 1998-01-13 Access Pharmaceuticals, Inc. Vivo agents comprising metal-ion chelates with acidic saccharides and glycosaminoglycans, giving improved site-selective localization, uptake mechanism, sensitivity and kinetic-spatial profiles
WO1995005611A1 (fr) * 1993-08-12 1995-02-23 The Trustees Of Dartmouth College Appareil et methodologie de determination de la concentration d'oxygene dans des systemes biologiques
US5494030A (en) * 1993-08-12 1996-02-27 Trustees Of Dartmouth College Apparatus and methodology for determining oxygen in biological systems
US5833601A (en) * 1993-08-12 1998-11-10 Trustees Of Dartmouth College Methodology for determining oxygen in biological systems
WO1995014491A3 (fr) * 1993-11-29 1995-07-06 Access Pharma Inc Chelates d'ions de metaux avec des saccharides et glycosaminoglycanes acides
US6106866A (en) * 1995-07-31 2000-08-22 Access Pharmaceuticals, Inc. In vivo agents comprising cationic drugs, peptides and metal chelators with acidic saccharides and glycosaminoglycans, giving improved site-selective localization, uptake mechanism, sensitivity and kinetic-spatial profiles, including tumor sites
AT409929B (de) * 1997-03-07 2002-12-27 Tritthart Helmut A Dr Polymere-infusionslösung zur anwendung bei der diagnose von tumoren, gegebenenfalls zu deren behandlung
WO1999042139A3 (fr) * 1998-02-20 1999-09-30 Schering Ag Conjugues d'amidon hydroxyethyle, leur procede de production et produits pharmaceutiques les contenant
WO2000036422A1 (fr) * 1998-12-17 2000-06-22 Yissum Research Development Company Of The Hebrew University Of Jerusalem Mesure du fer lie hors transferine
WO2004010841A3 (fr) * 2002-07-31 2004-04-29 Gen Electric Technique d'evaluation pour angiogenese du myocarde
WO2004011036A1 (fr) * 2002-07-31 2004-02-05 General Electric Company Procede destine a evaluer la permeabilite de capillaires
US6961607B2 (en) 2002-07-31 2005-11-01 Uzgiris Egidijus E Method for assessing myocardial angiogenesis
WO2004052401A3 (fr) * 2002-12-09 2005-02-17 American Bioscience Inc Compositions et methodes d'administration d'agents pharmacologiques
AU2003299590B2 (en) * 2002-12-09 2010-03-04 Abraxis Bioscience, Llc Compositions and methods of delivery of pharmacological agents
AU2003299590B8 (en) * 2002-12-09 2010-04-08 Abraxis Bioscience, Llc Compositions and methods of delivery of pharmacological agents
US7820788B2 (en) 2002-12-09 2010-10-26 Abraxis Bioscience, Llc Compositions and methods of delivery of pharmacological agents
US8846771B2 (en) 2002-12-09 2014-09-30 Abraxis Bioscience, Llc Compositions and methods of delivery of pharmacological agents
US9012519B2 (en) 2002-12-09 2015-04-21 Abraxis Bioscience, Llc Compositions and methods of delivery of pharmacological agents
US9012518B2 (en) 2002-12-09 2015-04-21 Abraxis Bioscience, Llc Compositions and methods of delivery of pharmacological agents
EP3470084A1 (fr) * 2002-12-09 2019-04-17 Abraxis BioScience, LLC Compositions comprenant des nanoparticules d'albumine et méthodes pour la libération de principes actifs
CN114460163A (zh) * 2022-02-11 2022-05-10 河北师范大学 一种检测生物组织铁含量的maldi质谱成像方法
CN114460163B (zh) * 2022-02-11 2023-03-03 河北师范大学 一种检测生物组织铁含量的maldi质谱成像方法

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EP0553273A4 (en) 1998-04-22
EP0553273A1 (fr) 1993-08-04

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