Disclosed are compounds that include two or more haptens conjugated by a spacer or a carrier. The haptens may include diethylenetriaminepentaacetate (DTPA), histimine-succinyl-glutamine (HSG), or combinations of DTPA and HSG. The compound also includes an effector molecule which may be conjugated to one or more of the haptens, the spacer/carrier, or both. The effector molecule may be conjugated by a number of linkages including an ester linkage, an imino linkage, an amino linkage, a sulfide linkage, a thiosemicarbazone linkage, a semicarbazone linkage, an oxime linkage, an ether linkage, or combinations of these linkages. Also disclosed are methods of synthesizing the compounds and/or precursors of the compounds.

Description of the Invention

SUMMARY

Disclosed herein are reagents for therapeutic use, for example, in radioimmunotherapy (RAIT), and diagnostic use, for example, in radioimmunodetection (RAID) and magnetic resonance imaging (MRI). In particular, disclosed herein are targetable molecules for use with binding molecules (i.e. targeting molecules), such as bi-specific antibodies (bsAb) and bi-specific antibody fragments (bsFab) that have at least one arm that specifically binds the targetable construct and at least one other arm that specifically binds a targeted tissue.

The compounds described herein include two or more haptens conjugated by a spacer. The haptens may include diethylenetriaminepentaacetate (DTPA), histimine-succinyl-glutamine (HSG), or combinations of DTPA and HSG. Preferably, the compound includes DTPA. In one embodiment, the compound includes DTPA and HSG. The compounds may be multivalent to facilitate crosslinking of one or more binding molecules on the surface of a targeted tissue to facilitate internalization of the crosslinked complex. The compounds may also include one or more moieties that facilitate internalization by binding to an internalized receptor on the surface of the targeted tissue (e.g., the folate receptor).

The compound also includes an effector molecule which may be conjugated to one or more of the haptens, the spacer, or both. As such, the haptens and/or the spacer may function as carrier molecules for the effector. The effector molecule may be conjugated by a number of linkages, and preferably, the linkage is stable under, physiological conditions in serum, but the linkage is sensitive to hydrolysis when the compounds are localized to target cells or internalized by target cells. For example, the linkages may be subject to acid hydrolysis under the physiological conditions present within lysosomes. Alternatively, hydrolysis of a particular linkage may be catalyzed by one or more enzymes localized at the target cells or internal to the target cells. Suitable linkages may include an ester linkage, an imino linkage, an amino linkage, a sulfide linkage, a thiosemicarbazone linkage, a semicarbazone linkage, an oxime linkage, an ether linkage, or combinations of these linkages.

The compound may also include metal ions. Preferably, the compound includes indium cations. In one embodiment, metal ions, such as indium, are chelated by a hapten such as DTPA.

The spacer may include one or more amino acids, and preferably the spacer includes three or more amino acids. In one embodiment, the peptide may include one or more D-amino acids, (e.g., to create a more stable molecule that is not easily metabolized in serum).

In one particular embodiment the spacer includes a peptide with one or more lysine residues and one or more cysteine residues. In another embodiment, the spacer includes a penicillamine moiety or a moiety that is a derivative of penicillamine. In a further embodiment, the spacer includes a thiolactic acid moiety or a moiety that is a derivative of thiolactic acid.

The haptens and/or effectors may be conjugated to one or more residues of the spacer. For example, the haptens may be conjugated to an .epsilon.-nitrogen atom of a lysine residue, or a sulfur atom of a cysteine residue. In another example, the effector is conjugated to a penicillamine moiety or a derivative thereof, or a thiolactic acid moiety or a derivative thereof. Preferably, the effector molecule is linked by an ester linkage, or another linkage which may be hydrolyzed under physiological conditions after being administered to a subject.

As used herein, an effector molecule includes any molecule that brings about a desirable result. As such, an effector molecule many include drugs, prodrugs, toxins, enzymes, radioisotopes, immunomodulators, cytokines, hormones, nucleotide sequences (e.g., antisense nucleotides or interference RNAs), binding molecules (e.g., antibodies), or combinations of these types of molecules. Examples of antisense oligonucleotides and interference RNAs are disclosed in Kalota et al., Cancer Biol. Ther. 2004 January; 3(1); Tong et al., Clin. Lung Cancer 2001 February; 2(3): 220-6; Dean et al., Oncogene 2003 Dec. 8; 22(56): 9087-96; Nahta et al., Semin. Oncol. 2003 October; 30(5 Suppl 16): 143-9; Patry et al., Cancer Res. 2003 Nov. 15; 63(22): 7679-88; Duxbury et al., Biochem Biophys Res Commun. 2003 Nov. 21; 311 (3) 786-92; Crnkovic-Mertens et al., Oncogene 2003 Nov. 13; 22(51): 8330-6; Lipscomb et al., Clin Exp Metastasis 2003; 20(6): 569-76; Wall et al., Lancet 2003 Oct. 25; 362(9393): 1401-3; Bedford et al., Semin Cancer Biol 2003 August; 13(40): 301-8; Damm-Welk et al., Semin Cancer Biol. 2003 August; 13(4): 283-92; Duursma et al., Semin Cancer Biol. 2003 August; 13(4): 267-73, all of which are incorporated herein by reference in their entireties.

An effector may also include a lipid or a polymer, which may be capable of forming a higher-ordered structure, (e.g., a micelle, liposome, or polymeric structure), which may incorporate other effectors as described herein. Alternatively, the effector may be a higher-ordered structure itself (e.g., a micelle, liposome, polymeric structure, and/or a nanoparticle). Where the effector is a lipid, the lipid-conjugated compound may form an emulsion that is associated with any of the effectors as described herein.

Therapeutic effector molecules may include cytotoxic drugs, such as aplidin, azaribine, anastrozole, azacytidine, bleomycin, bortezomib, bryostatin-1, busulfan, calicheamycin, camptothecin, 10-hydroxycamptothecin, carmustine, celebrex, chlorambucil, cisplatin, irinotecan (CPT-11), SN-38, carboplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunomycin glucuronide, daunorubicin, dexamethasone, diethylstilbestrol, doxorubicin, 2-pyrrolinodoxorubicin (2P-DOX), cyano-morpholino doxorubicin, doxorubicin glucuronide, epirubicin glucuronide, ethinyl estradiol, estramustine, etoposide, etoposide glucuronide, etoposide phosphate, floxuridine (FUdR), 3',5'-O-dioleoyl-FudR (FUdR-dO), fludarabine, flutamide, fluorouracil, fluoxymesterone, gemcitabine, hydroxyprogesterone caproate, hydroxyurea, idarubicin, ifosfamide, L-asparaginase, leucovorin, lomustine, mechlorethamine, medroprogesterone acetate, megestrol acetate, melphalan, mercaptopurine, 6-mercaptopurine, methotrexate, mitoxantrone, mithramycin, mitomycin, mitotane, phenyl butyrate, prednisone, procarbazine, paclitaxel, pentostatin, PSI-341, semustine streptozocin, tamoxifen, taxanes, taxol, testosterone propionate, thalidomide, thioguanine, thiotepa, teniposide, topotecan, uracil mustard, velcade, vinblastine, vinorelbine, vincristine, ricin, abrin, ribonuclease, onconase, rapLR1, DNase I, Staphylococcal enterotoxin-A, pokeweed antiviral protein, gelonin, diphtheria toxin, Pseudomonas exotoxin, Pseudomonas endotoxin, or combinations of these.

In one embodiment, the effector molecule may be a prodrug that is activated after the compound is administered to a subject. For example, a prodrug may be activated after it is localized to a targeted cell and/or internalized by the targeted cell. In particular, the prodrug may be activated by physiological conditions in the cell (e.g., the acidic environment of lysosomes). Alternatively, the prodrug may be activated by one or more enzymes, (e.g., carboxylesterase can activate prodrugs such as irinotecan (CPT-11). Preferably, the effector molecule includes camptothecin, doxorubicin, or derivatives and/or analogs thereof, and preferably the effector molecule is conjugated by an ester linkage. Doxorubicin derivatives and/or analogs include 2-pyrrolinodoxorubicin (2P-DOX) and cyano-morpholino doxorubicin.

Where an effector molecule is not water soluble, preferably one or more of the haptens, the spacer (e.g., a peptide), and/or the linkage makes the effector molecule more water soluble. In one embodiment, an insoluble effector molecule may be administered as part of an emulsion or liposome, wherein the lipid that forms the emulsion or liposome may be conjugated to one or more of the administered compounds (e.g., the targetable construct). In another embodiment, one or more of the haptens, the spacer, and/or the linkage may reduce the toxicity of the effector molecule. In a further embodiment, one or more of the haptens, the spacer, and/or the linkage facilitate localization of the compound (which includes the effector molecule) to a targeted tissue, while non-targeted compounds (and/or effector molecules) can be rapidly excreted. As such, the biodistribution of the effector molecule may be altered by conjugating the effector to one or more of the haptens, the spacer, and/or the linkage.

The compound may also include an isotope. Examples include .sup.18F, .sup.32P, .sup.33P, .sup.45Ti, .sup.47Sc, .sup.52Fe, .sup.59Fe, .sup.62Cu, .sup.64Cu, .sup.67Cu, .sup.67Ga, .sup.68Ga, .sup.75Se, .sup.77As, .sup.86Y, .sup.89Sr, .sup.89Zr, .sup.90Y, .sup.94Tc, .sup.94mTc, .sup.99Mo, .sup.99mTc, .sup.105Pd, .sup.105Rh, .sup.111Ag, .sup.111In, .sup.123I, .sup.124I, .sup.125I, .sup.131I, .sup.142Pr, .sup.143Pr, .sup.149 Pm, .sup.153Sm, .sup.154-158Gd, .sup.161Tb, .sup.166Dy, .sup.166Ho, .sup.169Er, .sup.175Lu, .sup.177Lu, .sup.186Re, .sup.188Re, .sup.189Re, .sup.194Ir, .sup.198Au, .sup.199Au, .sup.211At, .sup.211Pb .sup.212Bi, .sup.212Pb, .sup.213Bi, .sup.223Ra, or .sup.225Ac. The isotope may be covalently linked to the compound or the isotope may be chelated by a chelating moiety present in the compound (e.g., DTPA).

In particular embodiments, the compound includes a peptide, one or more haptens, and one or more effector molecules. Further, the peptide may include one or more sequences R.sup.1-Lys(X)-R.sup.2-Lys(Y) or Lys(X)-R.sup.2-Lys(Y)-R.sup.1, where R.sup.1 and R.sup.2 include one or more amino acids, and where (X) and (Y) include one or more conjugated moieties selected from antigenic molecules, haptens, hard acid chelators, and soft acid chelators. The effector molecule, as described herein, may be conjugated by a linkage to the haptens and/or one or more amino acids present in R.sup.1 or R.sup.2. Desirably, the linkage is stable in physiological conditions in serum, but the linkage is susceptible to hydrolysis when the compound is internalized in a cell. For example, the linkage may be susceptible to hydrolysis under the acidic conditions in a lysosome or the linkage may be susceptible to hydrolysis as facilitated by an enzyme (e.g., carboxylesterase). Linkages may include an ester linkage, an imino linkage, an amino linkage, a sulfide linkage, a thiosemicarbazone linkage, a semicarbazone linkage, an oxime linkage, an ether linkage, an amide, and combinations of these linkages. As noted herein, the effector molecule may include drugs, prodrugs, toxins, enzymes, radioisotopes, immunomodulators, cytokines, hormones, nucleotide sequences, binding molecules, or combinations of these.

The moiety may be a hard acid chelator, and where the compound includes a hard acid chelator, preferably the compound further includes a cation selected from the group consisting of Group IIa and Group IIIa metal cations. The compound may also include one or more isotopes as described above.

In one embodiment, the moiety includes DTPA, HSG, DOTA, NOTA, TETA, Tscg-Cys, Tsca-Cys, nitroloacetic acid, or combinations of these moieties. Preferably, the compound includes DTPA, HSG, or combinations of DTPA and HSG. Most preferably, the compound includes DTPA. The moieties, designated by (X) and (Y), may be the same or different.

The compound may also include a soft acid chelator. Where the compound includes a soft acid chelator, the compound may also include a cation selected from the group consisting of transition metals, Bi, lanthanides, and actinides. For example, the compound may include Tc, Re, Bi, or combinations of these cations.

It may be desirable to synthesis peptides that include particular amino acids or types of amino acids. For example, in one embodiment the group designated by R.sup.2 may include tyrosine. Also, it may be desirable to create a peptide that includes one or more D-amino acids.

Also disclosed herein is a method of treating and/or diagnosing a disease or condition that may lead to a disease in a patient, which may include: (1) administering a binding molecule to the patient, where the binding molecule has at least one arm that binds a targeted tissue and at least one other arm that binds a targetable construct; (2) optionally, administering a clearing composition to the patient and allowing the composition to clear non-localized binding molecules from circulation; and (3) administering to the patient one or more targetable constructs that include one or more of the above-described compounds. For example, the targetable construct may include one or more compounds that include: (1) two or more haptens linked by a spacer, where one or more haptens are DTPA or HSG; and (2) one or more effector molecules conjugated to one or more of the haptens, the spacer, or both. In one embodiment the targetable construct includes a compound that includes: (1) a peptide having one or more of the sequences R.sup.1-Lys(X)-R.sup.2-Lys(Y) or Lys(X)-R.sup.2-Lys(Y)-R.sup.1, where R.sup.1 and R.sup.2 include one or more amino acids and where (X) and (Y) include a conjugated moiety; and (2) an effector molecule conjugated to the peptide. The moiety may include an antigenic molecule, a hapten, a hard acid chelator, a soft acid chelator or combinations of these types of moieties.

As used herein, a binding molecule (i.e., a targeting molecule) may include an antibody or a fragment of an antibody. Particular suitable antibodies or binding molecules may be multivalent and multispecific (e.g., bi-specific antibodies). The binding molecule may include a monoclonal antibody or a fragment of a monoclonal antibody. The antibody or antibody fragment (e.g., monoclonal) may include a human, chimeric or humanized antibody or a fragment of a human, chimeric or humanized antibody. Examples of particular suitable antibodies include MAb 679, MAb 734, MAb Mu-9, MN-14, RS-7, 679, 734, or combinations of these antibodies. The binding molecule or antibody may include a fusion protein. In some embodiments, it may be desirable to use antibodies, fragments thereof, or binding molecules that include the CDRs of Mab 679, Mab 734, Mab Mu-9, MN-14, RS-7, 679, or 734.

As noted herein, the targetable construct may include a peptide including the sequence R.sup.1-Lys(X)-R.sup.2-Lys(Y) or Lys(X)-R.sup.2-Lys(Y)-R.sup.1, and an effector molecule conjugated to an amino acid present in R.sup.1 or R.sup.2 and/or to one or more of the conjugated moieties (X) and/or (Y). Preferably the effector molecule is conjugated by an ester linkage, an amido linkage, and/or a hydrazone linkage.

Also, as noted herein, the effector molecule may include any molecule that brings about a desirable result. For example, the effector molecule may include one or more drugs, prodrugs, toxins, enzymes, radioisotopes, immunomodulators, cytokines, hormones, nucleotide sequences (e.g., antisense oligonucleotide or interference RNAs), binding molecules, or molecules that facilitate administration of the foregoing categories of molecules (e.g., a lipid or polymer capable of forming a higher-ordered structure, or a higher-ordered structure itself, such as a micelle, liposome, polymeric structure, and/or nanoparticle), which may be useful as drug carriers. Specific examples of effector molecules are exemplified herein. In particular, the effector molecule may include camptothecin or a derivative of camptothecin, (e.g., SN-38, 10-hydroxy-CPT, 9-amino-CPT, irinotecan (CPT-11), etc.). Doxorubicin, or derivatives and/or analogs thereof, may also be a particularly suitable effector molecule. Doxorubicin derivatives are described in Nagy et al., Proc. Natl. Acad. Sci. USA, 1996, 93:2464-9. Antitumor anthracyclines may also be particularly suitable effector molecules, as described in Monneret, Eur. J. Med. Chem. 2001 36:483-93. The effector molecule, (e.g., camptothecin and/or doxorubicin), may be conjugated to the targetable construct and/or associated with a drug-carrier such as a micelle/liposome or an emulsion, wherein the drug-carrier is conjugated to the targetable construct.

In regard to selected enzymes as effector molecules, particularly suitable enzymes may include carboxylesterases, glucuronidases, carboxypeptidases, beta-lactamases, phosphatases, or mixtures of these enzymes.

The methods of treating and/or diagnosing diseases or conditions may be used to treat/diagnose a variety of diseases or conditions. For example, a malignant disease, a cardiovascular disease, an infectious disease, an inflammatory disease, an autoimmune disease, a metabolic disease, a neurological disease, or combinations of these diseases or conditions.

Where the disease or condition is a malignant disease, the binding molecule may specifically bind to a targeted tissue that includes an antigen selected from the group consisting of carcinoembryonic antigen, tenascin, epidermal growth factor receptor, platelet derived growth factor receptor, fibroblast growth factor receptors, vascular endothelial growth factor receptors, gangliosides, HER/2neu receptors and mixtures of these antigens. The targeted tissue may also include a tumor. The binding molecule may specifically bind to antigens produced by or associated with the tumor including colon-specific antigen-p (CSAp), carcinoembryonic antigen (CEA), CD4, CD5, CD8, CD14, CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD30, CD45, CD74, CD80, HLA-DR, Ia, Ii, MUC 1, MUC 2, MUC 3, MUC 4, NCA, EGFR, HER 2/neu, PAM-4, TAG-72, EGP-1, EGP-2, A3, KS-1, Le(y), S100, PSMA, PSA, tenascin, folate receptor, VEGF, PIGF, ILGF-1, necrosis antigens, IL-2, IL-6, T101, MAGE, and combinations of these antigens. Particularly useful antigens include CD74 and EGP-1, which may facilitate internalization of the bound antibody. Antibodies that recognize CD74 include LL1, the use of which is described in U.S. Pat. Nos. 6,458,933; 6,395,276; 6,083,477; and U.S. 2003-0103982. Antibodies that recognize EGP-1 include RS7, which is described in U.S. Ser. No. 10/377,121; U.S. Pat. No. 5,635,603; and Stein et al., 1990, Cancer Res., 50, 1330-1336.

The targeted tissue may include a multiple myleoma, a B-cell malignancy, or a T-cell malignancy. Specific B-cell malignancies may include indolent forms of B-cell lymphomas, aggressive forms of B-cell lymphomas, chronic leukemias, multiple myeloma, and acute lymphatic leukemias. The targeted tissue may also include a lymphoma such as a non-Hodgkin's lymphoma or a Hodgkin's lymphoma.

In addition, the targeted tissue(s) may include a solid tumor, such as a melanoma, a carcinoma, a sarcoma, a glioma, or combinations of these malignancies. Particular carcinomas may include esophageal, gastric, colonic, rectal, pancreatic, lung, breast, ovarian, urinary bladder, endometrial, cervical, testicular, renal, adrenal, liver cancer, or combinations of these carcinomas.

The disease or condition may also include a cardiovascular disease that is associated with granulocytes, lymphocytes, monocytes, D-dimer, and/or fibrin deposits. As such, the binding molecule (i.e., targeting molecule) may specifically bind to antigens that are present on granulocytes, lymphocytes, monocytes, and/or fibrin. Particular cardiovascular diseases or conditions may include a myocardial infarction, ischemic heart disease, atherosclerotic plaques, fibrin clots, emboli, or a combinations of these disease or conditions.

The method may also be used to treat and/or diagnose infectious diseases, for example, bacterial disease, fungal disease, parasitic disease, viral disease, protozoan disease, mycoplasmal, and combinations of these infectious diseases. In particular, the infectious disease may be caused by a pathogen selected from the group consisting of Microsporum, Trichophyton, Epidermophyton, Sporothrix schenckii, Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis, Candida albicans, human immunodeficiency virus (HIV), herpes virus, cytomegalovirus, rabies virus, influenza virus, hepatitis B virus, Sendai virus, feline leukemia virus, Reovirus, poliovirus, human serum parvo-like virus, simian virus 40, respiratory syncytial virus, mouse mammary tumor virus, Varicella-Zoster virus, Dengue virus, rubella virus, measles virus, adenovirus, human T-cell leukemia viruses, Epstein-Barr virus, murine leukemia virus, mumps virus, vesicular stomatitis virus, Sindbis virus, lymphocytic choriomeningitis virus, wart virus, blue tongue virus, Anthrax bacillus, Streptococcus agalactiae, Legionella pneumophilia, Streptococcus pyogenes, Escherichia coli, Neisseria gonorrhoeae, Neisseria meningitidis, Pneumococcus, Hemophilis influenzae B, Treponema pallidum, Lyme disease spirochetes, Pseudomonas aeruginosa, Mycobacterium leprae, Brucella abortus, Mycobacterium tuberculosis, Tetanus, a helminth, a malaria parasite, Plasmodium falciparum, Plasmodium vivax, Toxoplasma gondii, Trypanosoma rangeli, Trypanosoma cruzi, Trypanosoma rhodesiensei, Trypanosoma brucei, Schistosoma mansoni, Schistosoma japanicum, Babesia bovis, Elmeria tenella, Onchocerca volvulus, Leishmania tropica, Trichinella spiralis, Onchocerca volvulus, Theileria parva, Taenia hydatigena, Taenia ovis, Taenia saginata, Echinococcus granulosus, Mesocestoides corti, Mycoplasma arthritidis, Mycoplasma hyorhinis, Mycoplasma orale, Mycoplasma arginini, Acholeplasma laidlawii, Mycoplasma salivarum, Mycoplasma pneumoniae, and combinations of these pathogens.

The method may also be used to treat and/or diagnose autoimmune diseases or conditions, such as acute idiopathic thrombocytopenic purpura, chronic idiopathic thrombocytopenic purpura, dermatomyositis, Sydenham's chorea, myasthenia gravis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, polyglandular syndromes, bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcalnephritis, erythema nodosurn, Takayasu's arteritis, Addison's disease, rheumatoid arthritis, multiple sclerosis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa, ankylosing spondylitis, Goodpasture's syndrome, thromboangitisubiterans, Sjogren's syndrome, primary biliary cirrhosis, Hashimoto's thyroiditis, thyrotoxicosis, scleroderma, chronic active hepatitis, polymyositis/dermatomyositis, polychondritis, parnphigus vulgaris, Wegener's granulomatosis, membranous nephropathy, amyotrophic lateral sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, perniciousanemia, rapidly progressive glomerulonephritis, psoriasis, fibrosing alveolitis, and combinations of these diseases or conditions.

Neurological diseases may also be treated or diagnosed by using the method. For example, a neurological disease characterized by a metabolic disorder, such as amyloidosis, may be treated or diagnosed by the method where the targeted tissue includes an amyloid deposit.

In addition to administering the binding molecule, optionally the clearing agent, and the targetable molecule, the method may also include administering one or more additional therapeutic or diagnostic agents. Suitable therapeutic or diagnostic agents may include binding molecules (e.g., antibodies or fragments thereof), drugs, prodrugs, toxins, enzymes, enzyme-inhibitors, nucleases, hormones, hormone antagonists, immunomodulators, cytokines, chelators, boron compounds, uranium atoms, photoactive agents, radionuclides, and combinations of these agents. The agents may be administering before, simultaneously, or after administration of the binding molecule, the optional clearing agent, and the targetable molecule. Further, the agents may be conjugated to one or more of the binding molecule, clearing agent, and/or the targetable construct. The agents may also be administered in combination with an emulsion or liposome, which may be conjugated to a compound such as the targetable construct.

In one embodiment, the therapeutic agent includes a cytokine selected from the group consisting of IL-1, IL-2, IL-3, IL-6, IL-10, IL-12, IL-18, IL-21, interferon-.alpha., interferon-.beta., interferon-.gamma., G-CSF, and GM-CSF, and mixtures of these cytokines. In another embodiment, the therapeutic agent includes an anti-angiogenic agent selected from the group consisting of angiostatin, endostatin, basculostatin, canstatin, maspin, anti-VEGF antibodies, anti-placental growth factor antibodies, anti-vascular growth factor antibodies, and mixtures of these anti-angiogenic agents.

The method may include administering a diagnostic agent selected from radioisotopes, dyes, radioopaque materials, contrast agents, fluorescent compounds, enhancing agents, and combinations of these diagnostic agents.

It may be desirable to further administer a metal as a therapeutic or diagnostic agent. For example, zinc, aluminum, gallium, lutetium, palladium, boron, gandolinium, uranium, manganese, iron, chrominum, copper, cobalt, nickel, dysprosium, rhenium, europium, terbium, holmium, neodymium, and combinations of these metals may be administered.

Paramagnetic ions, useful for diagnostic procedures, may also be administered. Examples of paramagnetic ions include chromium (III), manganese (II), iron (III), iron (II), cobalt (II), nickel (II), copper (II), neodymium (III), samarium (III), ytterbium (III), gadolinium (III), vanadium (II), terbium (III), dysprosium (III), holmium (III), erbium (III), or combinations of these paramagnetic ions.

The therapeutic and/or diagnostic agent may include one or more agents for photodynamic therapy, (e.g., a photosensitizer). Photosensitizers may include a benzoporphyrin monoacid ring A (BDP-MA), tin etiopurpurin (SnET2), sulfonated aluminum phthalocyanine (AISPc) and lutetium texaphyrin (Lutex).

Therapeutic or diagnostic nuclides may also be administered, including .sup.18F, .sup.32P, .sup.33P, .sup.45Ti, .sup.47Sc, .sup.52Fe, .sup.59Fe, .sup.62Cu, .sup.64Cu, .sup.67Cu, .sup.67Ga, .sup.68G, .sup.75Se, .sup.77 As, .sup.86Y, .sup.89Sr, .sup.89Zr, .sup.90Y, .sup.94Tc, .sup.94mTc, .sup.99Mo, .sup.99mTc, .sup.105Pd, .sup.105Rh, .sup.111Ag, .sup.111In, .sup.123I, .sup.124I, .sup.125I, .sup.131I, .sup.142Pr, .sup.143Pr, .sup.149Pm, .sup.153Sm, .sup.154-158Gd, .sup.161Tb, .sup.166Dy, .sup.166Ho, .sup.169Er, .sup.175Lu, .sup.177Lu, .sup.186Re, .sup.188Re, .sup.189Re, .sup.194Ir, .sup.198Au, .sup.199Au, .sup.211At, .sup.211Pb .sup.212Bi, .sup.212Pb, .sup.213Bi, .sup.223Ra, .sup.225Ac, and mixtures of these nuclides. Particularly suitable therapeutic nuclides may include .sup.32P, .sup.33P, .sup.47Sc, .sup.64Cu, .sup.67Cu, .sup.67Ga, .sup.90Y, .sup.111Ag, .sup.111In, .sup.123I, .sup.131I, .sup.142Pr, .sup.153Sm, .sup.161Tb, .sup.166Dy, .sup.166Ho, .sup.177Lu, .sup.186Re, .sup.188Re, .sup.189Re, .sup.211At, .sup.212Pb, .sup.212Bi, .sup.213Bi, .sup.223Ra, .sup.225Ac, or mixtures of these nuclides. Therapeutic nuclides may emit gamma particles and/or positrons that have an energy of about 70 to about 700 keV.

Particularly suitable diagnostic nuclides may include .sup.18F, .sup.52Fe, .sup.62Cu, .sup.64Cu, .sup.67Cu, .sup.67Ga, .sup.68Ga, .sup.86Y, .sup.89Zr, .sup.94Tc, .sup.94mTc, .sup.99mTc, .sup.111In, .sup.123I, .sup.124I, .sup.125I, .sup.131I, or mixtures of these nuclides. Diagnostic nuclides may emit gamma particles and/or positrons that have an energy of between about 25 to about 4000 keV.

The diagnostic agent may be useful when imaging methods are performed. For example, nuclides such as .sup.18F may be included to perform positron emission tomography (PET). Alternatively, image enhancing agents useful for performing magnetic resonance imaging (MRI) may be included. Image enhancing agents may include gadolinium ions, lanthanum ions, manganese ions, iron, chromium, copper, cobalt, nickel, fluorine, dysprosium, rhenium, europium, terbium, holmium, neodymium, or mixtures of these agents. In another embodiment, one or more radiopaque agents or contrast agents for X-ray or computed tomography (CT) may be included. Radiopaque or contrast agents may include barium, diatrizoate, ethiodized oil, gallium citrate, iocarmic acid, iocetamic acid, iodamide, iodipamide, iodoxamic acid, iogulamide, iohexol, iopamidol, iopanoic acid, ioprocemic acid, iosefamic acid, ioseric acid, iosulamide meglumine, iosemetic acid, iotasul, iotetric acid, iothalamic acid, iotroxic acid, ioxaglic acid, ioxotrizoic acid, ipodate, meglumine, metrizamide, metrizoate, propyliodone, thallous chloride, or combinations of these agents.

The method may also include administering one or more ultrasound contrast agents such as a liposome or dextran. Liposomes may be gas-filled.

The therapeutic and/or diagnostic method may also include performing an operative, intravascular, laparoscopic, or endoscopic procedure, either before, simultaneously, or after the therapeutic and/or diagnostic method.
 

Claim 1 of 15 Claims

1. A method of preparing a polyalkylene polyamine substituted at one or more nitrogen positions with an alkyl carboxylate group, comprising: reacting a polyalkylene polyamine having a formula NH.sub.2--R with a molecule having a formula Z-X.sup.1 to form a molecule (I) having a formula Z-NH--R, wherein R is a straight chain or branched alkyl group that has between 1 and 20 carbon atoms and includes one or more nitrogen atoms, Z is a protecting group, and X.sup.1 is a leaving group; reacting molecule (I) with a molecule (II) having a formula -- see Original Patent.
 

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