WO2002042318A2 - Conjugues fixant les recepteurs de transcobalamine pour therapie par capture de neutrons - Google Patents
Conjugues fixant les recepteurs de transcobalamine pour therapie par capture de neutrons Download PDFInfo
- Publication number
- WO2002042318A2 WO2002042318A2 PCT/US2001/050782 US0150782W WO0242318A2 WO 2002042318 A2 WO2002042318 A2 WO 2002042318A2 US 0150782 W US0150782 W US 0150782W WO 0242318 A2 WO0242318 A2 WO 0242318A2
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- WO
- WIPO (PCT)
- Prior art keywords
- independently
- pharmaceutically acceptable
- compound
- alkyl
- hydrogen
- Prior art date
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical class FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 1
- 229960003962 trifluridine Drugs 0.000 description 1
- YFHICDDUDORKJB-UHFFFAOYSA-N trimethylene carbonate Chemical compound O=C1OCCCO1 YFHICDDUDORKJB-UHFFFAOYSA-N 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- WFKWXMTUELFFGS-OUBTZVSYSA-N tungsten-185 Chemical compound [185W] WFKWXMTUELFFGS-OUBTZVSYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 150000003668 tyrosines Chemical class 0.000 description 1
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 229940096973 urethral suppository Drugs 0.000 description 1
- 239000006217 urethral suppository Substances 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- LEONUFNNVUYDNQ-OIOBTWANSA-N vanadium-48 Chemical compound [48V] LEONUFNNVUYDNQ-OIOBTWANSA-N 0.000 description 1
- LEONUFNNVUYDNQ-YPZZEJLDSA-N vanadium-49 Chemical compound [49V] LEONUFNNVUYDNQ-YPZZEJLDSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000000982 vasogenic effect Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- NAWDYIZEMPQZHO-AHCXROLUSA-N ytterbium-169 Chemical compound [169Yb] NAWDYIZEMPQZHO-AHCXROLUSA-N 0.000 description 1
- VWQVUPCCIRVNHF-BJUDXGSMSA-N yttrium-88 Chemical compound [88Y] VWQVUPCCIRVNHF-BJUDXGSMSA-N 0.000 description 1
- VWQVUPCCIRVNHF-NJFSPNSNSA-N yttrium-91 Chemical compound [91Y] VWQVUPCCIRVNHF-NJFSPNSNSA-N 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- QCWXUUIWCKQGHC-RNFDNDRNSA-N zirconium-95 Chemical compound [95Zr] QCWXUUIWCKQGHC-RNFDNDRNSA-N 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention includes compounds and methods for the treatment of abnormal cellular proliferation.
- Cellular differentiation, growth, function and death are regulated by a complex network of mechanisms at the molecular level in a multicellular organism. In the healthy animal or human, these mechanisms allow the cell to carry out its designed function and then die at a programmed rate.
- Abnonnal cellular proliferation can occur as a result of a wide variety of factors, including genetic mutation, infection, exposure to toxins, autoimmune disorders, and benign or malignant tumor induction.
- Psoriasis is a benign disease of human skin generally characterized by plaques covered by thickened scales. The disease is caused by increased proliferation of epidermal cells of unknown cause. In normal skin the time required for a cell to move from the basal layer to the upper granular layer is about five weeks. In psoriasis, this time is only 6 to 9 days, partially due to an increase in the number of proliferating cells and an increase in the proportion of cells which are dividing (G. Grove, Int. J. Dermatol. 18:111, 1979).
- hyperproliferative cell disorders include blood vessel proliferation disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors and cancers.
- Blood vessel proliferative disorders include angiogenic and vasculogenic disorders.
- Proliferation of smooth muscle cells in the course of development of plaques in vascular tissue cause, for example, restenosis, retinopathies and atherosclerosis.
- the advanced lesions of atherosclerosis result from an excessive inflammatory-proliferative response to an insult to the endotheliu and smooth muscle of the artery wall (Ross R., Nature 362:801-809 (1993). Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.
- Fibrotic disorders are often due to the abnormal formation of an extracellular matrix.
- fibrotic disorders include hepatic cirrhosis and mesangial proliferative cell disorders.
- Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar.
- Hepatic cirrhosis can cause diseases such as cirrhosis of the liver.
- An increased extracellular matrix resulting in a hepatic scar can also be caused by viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic cirrhosis.
- Mesangial disorders are brought about by abnormal proliferation of mesangial cells.
- Mesangial hyperproliferative cell disorders include various human renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection, and glomerulopathies.
- Another disease with a proliferative component is rheumatoid arthritis.
- Rheumatoid arthritis is generally considered an autoimmune disease that is thought to be associated with activity of autoreactive T cells (See, e.g., Harris, E. D., Jr., The New
- a tumor also called a neoplasm
- a benign tumor is one that lacks the properties of invasion and metastasis and is usually surrounded by a fibrous capsule.
- a malignant tumor i.e., cancer
- Malignant tumors also show a greater degree of anaplasia (i.e., loss of differentiation of cells and of their orientation to one another and to their axial framework) than benign tumors.
- Proliferative disorders are currently treated by a variety of classes of compounds including alkylating agents, antimetabolites, natural products, enzymes, biological response modifiers, miscellaneous agents, radiopharmaceuticals (for example, Yt 90 tagged to hormones or antibodies), hormones and antagonists, such as those listed below.
- alkylating agents for example, alkylating agents, antimetabolites, natural products, enzymes, biological response modifiers, miscellaneous agents, radiopharmaceuticals (for example, Yt 90 tagged to hormones or antibodies), hormones and antagonists, such as those listed below.
- Boron neutron capture therapy is based on the nuclear reaction that occurs when a stable isotope, 10 B, is irradiated with low energy (0.025 eV) or thermal neutrons to yield helium nuclei ( ⁇ -particles) and 7 Li nuclei.
- BNCT is a two component or binary system, consisting of 10 B and thermal neutrons, which when combined together generate high linear energy transfer (LET) radiation capable of selectively destroying tumor cells without significant damage to normal tissues.
- LET linear energy transfer
- 10 B is the most attractive for the following reasons: (a) it is nonradioactive and readily available, comprising approximately 20% of naturally occurring boron; (b) the particles emitted by the capture reaction ( B(n, ⁇ ) Li) are largely high LET; and (c) their path lengths are approximately 1 cell diameter (10-14 ⁇ m), theoretically limiting the radiation effect to those tumor cells that have taken up a sufficient amount of 10 B and simultaneously sparing normal cells and (d) the extensive chemistry of boron is such that it can be incorporated into a multitude of different chemical structures.
- Li and ⁇ -particles are the primary fission product of the neutron capture reaction with 10 B.
- ⁇ -Particles are relatively slow and give rise to closely spaced ionizing events that consist of tracks of sharply defined columns. They have a path length of approximately 10 ⁇ m, are high LET, and destroy a wide variety of biologically active molecules including DNA, RNA and proteins. For these reasons there is little, if any, cellular repair from ⁇ -particle-induced radiation injury.
- boron compounds to be used for BNCT should have a high specificity for malignant cells with concomitantly low concentrations in adjacent normal tissues and blood. Since it is desirable to confine the radiation solely to these cells, an intracellular and optimally intranuclear localization of boron would be preferred.
- Tumor localization has been demonstrated following IN. administration by means of whole body autoradiography (Coderre, J. A. et al., Cancer Res., 48, 6313-6316 (1988)) and in several patients with cutaneous melanoma following perilesional injection (Mishima, Y. et al, Sthralenther. Onkol., 165, 251-254 (1989)). Stimulated by Mishima's experience, a number of other boron-containing amino acids have been synthesized that potentially could be incorporated in larger amounts into proteins of malignant cells (Hall, I. H. et al., J. Pharm. Sci., 68, 685-688 (1979).
- porphyrins Two other classes of compounds with a propensity for localizing in malignant tumors are the porphyrins and the related phthalocyanines.
- the biochemical basis by which these compounds achieve elevated concentration in malignant tumors is unknown, but this observation has served as the rationale for the use of hematoporphyrin derivative in the photodynamic therapy of cancer (Dougherty, T. J. et al., Porphyrin
- boron-containing purines and pyrimidines and their nucleosides are boron-containing purines and pyrimidines and their nucleosides.
- the rationale for their development is that such compounds may be selectively incorporated into rapidly proliferating tumor cells and trapped within the cell following their conversion to the corresponding nucleotide.
- these bases and their nucleosides may function as analogues of naturally occurring precursors of nucleic acids and become incorporated into nuclear DNA.
- Cytoplasmic or preferably a nuclear localization of all of these boron compounds would be advantageous since the heavy particles resulting from the capture reaction would deliver a greater proportion of their energy to intranuclear targets, thereby permitting lower boron concentrations than would have been required if the compounds were located extracellularly (Gabel, D. et al., Radiat. Res., Ill, 14-25 (1987); Fairchild, R. G. et al., Int.
- the immunoconjugates contained only 0.2% natural boron by weight, which was equal to 6 atoms of 10 B/molecule of antibody. In retrospect, it appears that there must have been some other explanation for the reduced cell viability that was observed. Sneath et al. (Sneath, R. L., Jr., J. Medicinal Chem., 17, 796-799 (1974)) showed that water- solubilizing groups had to be incorporated into protein-binding polyhedral boranes if protein solubility in aqueous systems was to be maintained.
- encapsulating complexes such as liposomes, microspheres and low density lipoproteins (Kahl, S. B. et al, Strahlenther. Onkol., 165, 137-139 (1989)).
- encapsulating complexes such as liposomes, microspheres and low density lipoproteins (Kahl, S. B. et al, Strahlenther. Onkol., 165, 137-139 (1989)).
- encapsulating complexes such as liposomes, microspheres and low density lipoproteins
- Co-59 is has weakly paramagnetic quadrapolar nucleus in the 2 oxidation state
- Co-59 exists in the 3 + oxidation state within the corrin ring of vitamin B 12 and is diamagnetic. Therefore, insertion of either a radioactive or paramagnetic metal ion other than cobalt into the corrin ring does not seem feasible at tins time.
- FIG. 1 The structure of various forms of vitamin B 12 is shown in Figure 1, wherein X is CN, OH, CH 3 or 5'-deoxyadenosyl, respectively.
- cobalamin is sometimes used to refer to the entire molecule except the X group.
- the fundamental ring system without cobalt (Co) or side chains is called corrin and the octadehydrocorrin is called corrole.
- Figure 1 is adapted from The Merck Index, Merck & Co. (11th ed. 1989), wherein X is above the plane defined by the corrin ring and the nucleotide is below the plane of the ring.
- the corrin ring has attached seven amidoalkyl (H 2 NC(O)Alk) substituents, at the 2, 3, 7, 8, 13, 18 and 23 positions, which can be designated a-g respectively. See D. L.
- Vitamin B 12 (adenosyl-, cyano-, hydroxo-, or methylcobalamin) must be bound by the transport protein Transcobalamin I, II, or III ("TC") to be biologically active, and by Intrinsic Factor ("IF") if administered orally.
- TC transport protein Transcobalamin I, II, or III
- IF Intrinsic Factor
- Gastrointestinal absorption of vitamin B 12 occurs when the intrinsic factor- vitamin B 1 complex is bound to the intrinsic factor receptor in the terminal ileum.
- intravascular transport and subsequent cellular uptake of vitamin B 12 throughout the body typically occurs through the transcobalamin transport protein (I, II or III) and the cell membrane transcobalamin receptors, respectively.
- the transport protein undergoes lysozymal degradation, which releases vitamin B 12 into the cytoplasm. All forms of vitamin B 12 can then be interconverted into adenosyl-, hydroxo- or methylcobalamin depending upon cellular demand. See, for example, A. E. Finkler et al, Arch. Biochem.
- vitamin B 12 is first subjected to mild hydrolysis to form a mixture of monocarboxylic acids, which Houts, infra, disclosed to contain mostly the (e)-isomer.
- the mixture is then reacted with a p-(aminoalkyl)phenol to introduce a phenol group into the B 12 acids (via reaction with one of the free carboxylic acid groups).
- the mixed substituent B 12 derivatives are then iodinated in the phenol-group substituent.
- This U.S. patent teaches that the mixed 125 I-B 12 derivatives so made are useful in the radioimmunoassay of B ⁇ 2 , using antibodies raised against the mixture.
- U.S. Patent Nos. 5,739,313; 6,004,533; 6,096,290 and PCT Publication WO 97/18231 listing Collins and Hogenkamp as inventors disclose radionuclide labeling of vitamin B 12 through the propionamide moieties on naturally occurring vitamin B 12 .
- the inventors converted the propionamide moieties at the b-, d-, and e- positions of the corrole ring to monocarboxylic acids, through a mild hydrolysis, and separated the carboxylic acids by column chromatography.
- the chelating moiety was then used to attach a radionuclide to the vitamin that can be used for therapeutic and/or diagnostic purposes. See also PCT Publications WO 00/62808; WO 01/28595 and WO 01/28592.
- PCT Publication WO 98/08859 listing Grissom et al as inventors discloses conjugates containing a bioactive agent and an organocobalt complex in which the bioactive agent is covalently bound directly or indirectly, via a spacer, to the cobalt atom.
- the organocobalt complex can be cobalamin and the bioactive agent can be a chemotherapeutic agent.
- chemotherapeutic agent only one bioactive agent (i.e., chemotherapeutic agent) is attached to the organocobalt complex (i.e., cobalamin) and the attachment is solely through the cobalt atom (i.e., the 6-position of cobalamin).
- the bioactive agent is released from the bioconjugate by the cleavage of the weak covalent bond between the bioactive agent and the cobalt atom as a result of normal displacement by cellular nucleophiles or enzymatic action, or by application of an external signal (e.g., light, photoexcitation, ultrasound, or the presence of a magnetic field).
- an external signal e.g., light, photoexcitation, ultrasound, or the presence of a magnetic field.
- U.S. Patent Nos. 5,428,023; 5,589,463 and 5,807,823 to Russell-Jones et al discloses a vitamin B 1 conjugate for delivering oral hormone formulations.
- Russell- Jones teaches that the vitamin B 12 conjugate must be capable of binding in vivo to intrinsic factor, enabling uptake and transport of the complex from the intestinal lumen of a vertebrate host to the systemic circulation of the host.
- the hormones are attached to the vitamin B 12 through a hydrolyzed propionamide linkage on the vitamin.
- the patent states that the method is useful for orally administering hormones, bioactive peptides, therapeutic agents, antigens, and haptens, and lists as therapeutic agents neomycin, salbutamol cloridine, pyrimethamine, penicillin G, methicillin, carbenicillin, pethidine, xylazine, ketamine hydrochloride, mephanesin and iron dextran.
- U.S. Patent No. 5,449,720 to Russell- Jones et al discloses vitamin B i2 linked through a polymer to various active agents wherein the conjugate is capable of binding to intrinsic factor for systemic delivery.
- the document discloses the attachment of various polymeric linkers to the propionamide positions of the vitamin B 12 molecule, and the attachment of various bioactive agents to the polymeric linker.
- bioactive agents include hormones, bioactive peptides and polypeptides, antitumor agents, antibiotics, antipyretics, analgesics, antiinflammatories, and haemostatic agents.
- Exemplary polymers include carbohydrates and branched chain amino acid polymers.
- the linkers used in '720 are polymeric.
- linkers are described as exhibiting a mixture of molecular weights, due to the polymerization process by which they are made. See in particular, page 11, lines 25-26 wherein it is stated that the polymer used in that invention is of uncertain size and/or structure.
- PCT Publication WO 99/65930 to Russell- Jones et al. discloses the attachment of various agents to the 5'-OH position on the vitamin B 12 ribose ring.
- the publication indicates that the system can be used to attach polymers, nanoparticles, therapeutic agents, proteins and peptides to the vitamin. See also, U.S. Patent Nos.
- U.S. Patent No. 5,574,018 to Habberfield et al. discloses conjugates of vitamin B ⁇ 2 in which a therapeutically useful protein is attached to the primary hydroxyl site of the ribose moiety.
- the patent lists erythropoietin, granulocyte-colony stimulating factor and human intrinsic factor as therapeutically useful proteins, and indicates that the conjugates are particularly well adapted for oral administration.
- U.S. Patent No. 5,840,880 to Morgan, Jr. et al. discloses vitamin B 12 conjugates to which are linked receptor modulating agents, which affect receptor trafficking pathways that govern the cellular uptake and metabolism of vitamin B 12 .
- the receptor modulating agents are linked to the vitamin at the b-, d-, or e- position.
- Vitamin B ⁇ 2 Vitamin B ⁇ 2
- U.S. Patent No. 4,283,342 to YoUees Anticancer Agents and Methods of Manufacture
- U.S. Patent No. 4,301,140 to Franlc et al Radiopharmaceutical Method for Monitoring Kidneys
- U.S. Patent No. 4,465,775 to Houts Vehicle et al
- U.S. Patent No. 5,308,606 to Wilson et al Methodhod of Treating and/or Diagnosing Soft Tissue Tumors
- U.S. Patent No. 5,405,839 Vitamin B 12 Derivative, Preparation Process Thereof, and Use Thereof
- Russell- Jones et al. (Amplification of the Vitamin B 12 Uptake System Using Polymers); U.S. Patent No. 5,589,463 to Russell Jones (Oral Delivery of Biologically Active Substances Bound to Vitamin B 1 2); U.S. Patent No. 5,608,060 to Axworthy et al (Biotinidase-Resistant Biotin-DOTA Conjugates); U.S. Patent No. 5,807,832 to Russell- Jones et al (Oral Delivery of Biologically Active Substances Bound to Vitamin B 12 ); U.S.
- Patent No. 5,869,465 to Morgan et al Method of Receptor Modulation and Uses Therefor
- U.S. Patent No. 5,869,466 to Russell- Jones et al vitamin B 12 Mediated Oral Delivery systems for GCSF.
- a neutron capture agent such as a molecule comprising Boron- 10, for the treatment of a proliferative disorder, is highly and effectively absorbed into a site of unwanted proliferation by direct or indirect attachment to a compound that binds to a transport protein for vitamin B 12 , i.e. transcobalamin I, II or III, or intrinsic factor, (the TC- or IF-binding carrier) in a manner that allows binding to a transcobalamin receptor (TR).
- transcobalamin I, II or III i.e. transcobalamin I, II or III, or intrinsic factor
- TR transcobalamin receptor
- the TC-or IE-binding carrier and neutron capture agent useful to treat or image sites of proliferative disease in the body, such as cancerous tumors can optionally be joined by means of a di- or multi- valent linking moiety.
- the linker used to join the TC- or IF-binding carrier and the active agent preferably has a single molecular weight, and does not exhibit a molecular weight distribution, for example as found in most polymers.
- the linker can range in size from small to large molecular weight, as long as there is not a distribution of weights in the linker. It is important to strictly control the uniformity of size of the conjugate for predictability of therapeutic performance.
- the linkers preferably have a molecular weight below about 2000, more preferably below about 1900 or 1800, and even more preferably below about 1500 or 1000.
- the invention provides a neutron capture conjugate having a high specificity for abnormally proliferative cells, comprising (1) a TC- or IF- binding carrier, and (2) a neutron capture agent linked directly or through a linker to the TC- or IF-binding carrier, wherein the linker has either (i) a unimodal (i.e., single) and defined molecular weight, or (ii) a molecular weight less than about 2000, and preferably, below 1900, 1800, or 1500.
- the TC- or IE-binding carrier is any moiety that will bind to a transcobalamin receptor and is able to be linked to a neutron capture agent.
- Methods for the assessment of whether a moiety binds the TC receptor are known, and include those described by Pathare, et al., (1996) Bioconjugate Chem. 7, 217-232; and Pathare, et al.,
- TC- or IF-binding carrier is represented by formula (I).
- the wavy line in the chemical structure indicates either a dative or covalent bond such that there are three dative Co-N bonds and one covalent Co-N bond, wherein, in the case of the dative bond, the valance of nitrogen is completed either with a double bond with an adjacent ring carbon or with a hydrogen;
- the dotted line in the chemical structure indicates either a double or single bond such that the double bond does not over-extend the valence of the element (i.e. to give pentavalent carbons) and, in the case of a single bond, the valence is completed with hydrogen; and preferably, the bonding and stereochemistry of the compound is the same as that of vitamin B 12 as it exists in nature;
- X is hydrogen, cyano, halogen (CI. F, Br or I), haloalkyl (including CF , CF 2 CF 3 , CH 2 CF 3 and CF 2 C1), NO 2 , NO 3 , PR 15 R 16 R 17 , NH 2 , NR 15 R 16 , OH, OR 15 , SR 15 , SCN, N 3 , OC(O)R 15 , C(O) 2 R 15 , C(O)R 15 , OC(O)NR 15 R 16 ,
- M is a monovalent heterocycle or heteroaromatic, which is capable of binding to the adjacent sugar ring and forming a dative bond with Co +3 , and is preferably a benzimidazole, a 5- and/or 6- substituted benzimidazole, such as 5,6-dimethylbenzimidazole, 5-methyl-benzimidazole, 5-hydroxybenzimid- azole, 5-methoxy-benzimidazole, naphth-imidazole, 5-hydroxy-6-methyl- benzimidazole or 5-methoxy-6-methyl-benz-imidazole; or a purine or pyrimidine including but not limited to adenine, 2-methyladenine, 2- methylmercaptoadenine, e-methylsulfmyladenine, 2-methyl-sulfonyladenine and guanine; or a phenol, such as phenol or p-cresol;
- (v) K is O, S, NJ 1 , C(OH)H, CR 100 R 101 or C(R 100 )V 8 Z 8 ;
- E is O or S
- G 1 is hydrogen, alkyl, acyl, silyl, phosphate or L-T;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 independently are O, S or NJ 2 ;
- V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 and V 8 independently are O, S, NJ 3 , CR 102 R 103 or a direct bond;
- (x) Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 7 and Z 8 independently are R 104 or L-T;
- each L is independently a direct bond or a linker to one or more T moieties, and that does not significantly impair the ability of the TC- or IF- binding carrier to bind to a transcobalamin receptor, optionally via a transport protein;
- each T independently comprises the residue of one or more molecules neutron capture agents such as a molecule comprising B-10 (in one embodiment T is for the treatment of a proliferative disorder other than cancer);
- J , J and J independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl, heterocycle, heteroaryl, hydroxyl, alkoxy or amine;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, heteroalkyl, heterocyclic, lower alkoxy, azido, amino, lower alkylamino, halogen, thiol, SO 2 , SO 3 , carboxylic acid, carboxyl, hydroxyl, nitro, cyano, oxime or hydrazine;
- R 13 and R 14 optionally can form a double bond
- R 15 , R 16 and R 17 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl or aralkyl group, heteroalkyl, heterocycle or heteroaromatic;
- R 100 , R 101 , R 102 , R 103 , and R 104 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl, heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO 2 , SO 3 , thioalkyl, or amino.
- vitamin B 12 In naturally occurring vitamin B 12 , there is an ⁇ -D-5,6-dimethylbenzimidazolyl ribose 3 '-phosphate that is bound through the phosphate to the B 12 moiety and coordinated to the cobalt ion.
- the M- sugar component In a modified vitamin B 12 TC- or IF- binding carrier, the M- sugar component is likewise in an ⁇ -D configuration, although other configurations (i.e., ⁇ -L, ⁇ -D and ⁇ -L) are possible.
- Vitamin B 12 In the X position, the biologically active form of vitamin B 12 has a 5'- deoxyadenosyl moiety. Vitamin B 12 catalysis occurs via the detachment and reattachment of the methylene radical at the 5'-deoxy position of the adenosyl moiety.
- the selected substituent in the X position is capable of similar catalysis.
- the molecule comprising B-10 of the present invention comprises the residue of an o-, m-, or p- carborane.
- X comprises the residue of 5'-deoxyadenosine.
- the TC- or IF-binding carrier comprises one or more neutron capture agents at each of one or more of the b-, d-, or e- cobalamin positions, linked directly or through a linker, and preferably through the b-position.
- the TC- or IF-binding carrier of the present invention comprises one or more neutron capture agents at M, K or G 1 .
- the compounds of the present invention exclude compounds (and therapeutic and imaging methods using such compounds) in which:
- X is cyano, hydroxyl, methyl, adenosine or L-T,
- A is C(OH)H
- G 1 is hydrogen
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 are O
- L is a direct bond or a multivalent linker derived from a dicarboxylic acid (C(O)OH-alkylene-C(O)OH), a diamine (NH 2 -alkylene-NH 2 ), an amino-carboxylic acid (C(O)OH-alkylene-NH 2 ), an amino acid, a peptide or a polymer of one or amino acids,
- the molecule(s) comprising B-10 is linked to the vitamin B 12 structure through Z 2 ,
- J 1 , J 2 and J 3 are all hydrogen
- R 1 , R 2 , R 4 , R 5 , R 8 , R 9 , R 11 , R 12 and R 15 are methyl and all of R 3 , R 6 , R 7 , R 10 , R 13 and R 14 are hydrogen, and/or
- V r Z ! , V 3 Z 3 , V°Z 6 and V 7 Z 7 are amino.
- the invention also provides intermediates disclosed herein that are useful in the preparation of the compounds of the present invention as well as synthetic methods useful for preparing the compounds of the invention.
- the present invention also provides a method of treating a disorder characterized by abnormal cell proliferation in an animal, preferably a human, comprising administering to the animal an effective amount of a cobalamin conjugate of the present invention.
- the invention also provides a method for treating and imaging a proliferative disorder in an animal, again preferably a human, comprising administering to the animal a detectable or therapeutic amount of a cobalamin conjugate of the present invention which comprises a neutron capture and imaging agent; and detecting the presence of the compound.
- the invention also provides the use of a compound of the present invention for the manufacture of a medicament for treating a disorder characterized by abnormal cellular proliferation in an animal (e.g., a human).
- the invention also provides a method for imaging and treating a proliferative disease (especially cancer) in a mammal (especially a human) comprising administering to the mammal a detectable amount of a cobalamin conjugate of the present invention which comprises a radionuclide; and detecting the presence of the compound.
- the invention also provides the use of a compound of the present invention for the manufacture of a medicament for treating a proliferative cell disease in a mammal (e.g., a human).
- a mammal e.g., a human
- the invention also provides the use of a compound of the present invention for the manufacture of a medicament for treating and imaging a proliferative disease in a mammal (e.g., a human).
- a mammal e.g., a human
- the neutron capture agent and the TC- or IF-binding carrier, or a pharmaceutically acceptable salt or prodrug thereof is delivered to the site of unwanted proliferation in a manner that bypasses, or at least does not rely on, the gastrointestinal route of absorption via the vitamin B12 intrinsic factor binding protein.
- Preferred modes of administration are parenteral, intraperitoneal, intravenous, intradermal, epidural, intraspinal, intrasternal, intra-articular, intra-synovial, intrathecal, intra-arterial, intracardiac, intramuscular, intranasal, subcutaneous, intraorbital, intracapsular, topical, transdermal patch, via rectal, vaginal or urethral administration including via suppository, percutaneous, nasal spray, surgical implant, internal surgical paint, infusion pump, or via catheter, h one embodiment, the agent and carrier are administered in a slow release formulation such as a direct tissue injection or bolus, implant, microparticle, microsphere, nanoparticle or nanosphere.
- a slow release formulation such as a direct tissue injection or bolus, implant, microparticle, microsphere, nanoparticle or nanosphere.
- a neutron capture agent can be highly and effectively absorbed into a site of unwanted proliferation by direct or indirect attachment to a compound that binds to the intrinsic factor (IF-binding carrier), wherein the IF-binding carrier and neutron capture agent are administered parenterally, for example, using any of the methods listed above.
- IF-binding carrier intrinsic factor
- the TC- or IF-binding carrier and the neutron capture agent, or a pharmaceutically acceptable salt or prodrug thereof can be administered in the course of surgical or medical treatment of the afflicted site.
- the TC- or IF-binding carrier and active agent can be positioned directly at the site of proliferation during the course of surgery either by painting the formulation (with or without a controlled release matrix) onto the surface of the afflicted area or by depositing a bolus of material in a suitable matrix that is released into the afflicted area over time.
- the TC- or IF-binding carrier and the active agent are administered directly into the proliferative mass via injection or catheter.
- the TC- or IF-binding carrier and the neutron capture agent is combined with either intrinsic factor or a transcobalamin carrier protein, or both, and administered parenterally, for example, via intravenous, intramuscular, direct injection or catheter, to the afflicted location.
- the TC- or IF-binding carrier and the neutron capture agent be administered parenterally and not orally to increase the effectiveness of the agent.
- the ileal receptor for intrinsic factor-bound cobalamin is present in the gastrointestinal tract in only very small quantities, and on oral delivery of vitamin B 12 into the alimentary system the ileal receptor can only absorb approximately two micrograms per day of vitamin B ⁇ for systemic delivery. Even assuming a small amount of systemic absorption via passive transport of a large oral dose, this level of administration is insufficient for the treatment of a proliferative disorder.
- the TC- or IF-binding carrier and the neutron capture agent is combined with either intrinsic factor or a transcobalamin carrier protein, or both, and administered parenterally, for example, via intravenous, intramuscular, direct injection or catheter, to the afflicted location.
- Figure 1 depicts the structure of cobalamin wherein X is CN (cyano), OH, CH 3 or adenosyl.
- Figure 2 illustrates the synthesis of a cyanocobalamin-nido-carborane conjugate.
- FIG. 3 illustrates the synthesis of representative compounds of the present invention.
- a neutron capture agent such as a molecule comprising Boron- 10, for the treatment of a proliferative disorder, is highly and effectively absorbed into a site of unwanted proliferation by direct or indirect attachment to a compound that binds to a transport protein for vitamin B 12 , i.e. transcobalamin I, II or III, or intrinsic factor, (the TC- or IF-binding carrier) in a manner that allows binding to a transcobalamin receptor (TR). Subsequent initiation of neutron capture therapy will selectively destroy abnormally proliferating cells.
- a transport protein for vitamin B 12 i.e. transcobalamin I, II or III, or intrinsic factor
- the TC- or IF-binding carrier and the neutron capture agent is combined with either intrinsic factor or a transcobalamin carrier protein, or both, and administered parenterally, for example, via intravenous, intramuscular, direct injection or catheter, to the afflicted location.
- the present invention includes at least the following:
- a TC- or IF-binding carrier of the present invention linked directly or via a linker to one or more therapeutic and/or diagnostic agent(s), including at least one neutron capture agent, or the pharmaceutically acceptable salt or prodrug thereof, for the treatment, prophylaxis and/or diagnosis of a proliferative disorder;
- a pharmaceutical composition for the treatment, prophylaxis and/or diagnosis of a proliferative disorder comprising an effective amount of a TC- or IF-binding carriers of the present invention linked directly or via a linker to one or more therapeutic and/or diagnostic agent(s), including at least one neutron capture agent, or the pharmaceutically acceptable salt or prodrug thereof, in combination with a pharmaceutically acceptable carrier of diluent;
- a pharmaceutical composition for the treatment, prophylaxis and/or diagnosis of a proliferative disorder comprising an effective amount of a TC- or IF-binding carrier of the present invention linked directly or via a linker to one or more therapeutic and/or diagnostic agent(s), including at least one neutron capture agent, or the pharmaceutically acceptable salt or prodrug thereof, optionally with a pharmaceutically acceptable carrier or diluent, in combination with one or more other effective therapeutic and/or diagnostic agent(s), or the pharmaceutically acceptable salt or prodrug thereof;
- a method for the treatment, prophylaxis and/or diagnosis of a proliferative disorder in a host, and in particular a human comprising administering an effective amount of a TC- or IF-binding carrier of the present invention linked directly or via a linker to one or more therapeutic and/or diagnostic agent(s), including at least one neutron capture agent, or the pharmaceutically acceptable salt or prodrug thereof, optionally with a pharmaceutically acceptable carrier or diluent;
- a method for the treatment, prophylaxis and/or diagnosis of a proliferative disorder in a host, and in particular a human comprising administering an effective amount of a TC- or lF-binding carrier of the present invention linked directly or via a linker to one or more therapeutic and/or diagnostic agent(s), including at least one neutron capture agent, or the pharmaceutically acceptable salt or prodrug thereof, optionally with a pharmaceutically acceptable carrier or diluent in combination or alternation with one or more other effective therapeutic and/or diagnostic agent(s), or its pharmaceutically acceptable salt or prodrug thereof;
- a TC- or IF-binding carrier of the present invention linked directly or via a linker to one or more therapeutic and/or diagnostic agent(s), including at least one neutron capture agent, or the pharmaceutically acceptable salt or prodrug thereof, optionally with a pharmaceutically acceptable carrier or diluent, for the treatment, prophylaxis and/or diagnosis of a proliferative disorder in a host, and in particular a human;
- the invention provides a non-oral or oral pharmaceutical formulation comprising a neutron capture conjugate having a high specificity for abnormally proliferative cells, comprising (1) a transcobalamin binding carrier or an intrinsic factor binding carrier, and (2) a neutron capture agent linked directly or through a linker to the TC binding carrier or intrinsic factor binding carrier.
- the invention provides a neutron capture conjugate having a high specificity for abnormally proliferative cells, comprising (1) a transcobalamin binding carrier or an intrinsic factor binding carrier, and (2) a neutron capture agent linked directly or through a linker to the TC binding carrier or intrinsic factor binding carrier, wherein the linker has either (i) a unimodal (i.e., single) and defined molecular weight, or
- Halo is fluoro, chloro, bromo or iodo.
- Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as “propyl” embraces only the straight chain radical, a branched chain isomer such as “isopropyl” being specifically referred to.
- heterocycle or heterocyclic as used herein except where noted represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S; and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
- the heterocyclic ring may be attached at any heteroatom or carbon atom that results in the creation of a stable structure.
- alkyl refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon of Ci to C ⁇ 0 , and specifically includes methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexymiethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.
- the term includes both substituted and unsubstituted alkyl groups.
- Moieties with which the alkyl group can be substituted are selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.
- lower alkyl refers to a to C 4 saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group, including both substituted and unsubstituted forms. Unless otherwise specifically stated in this application, when alkyl is a suitable moiety, lower alkyl is preferred. Similarly, when alkyl or lower alkyl is a suitable moiety, unsubstituted alkyl or lower alkyl is preferred.
- alkenyl and alkynyl refer to alkyl moieties wherein at least one saturated C-C bond is replaced by a double or triple bond.
- (C 2 -C 6 )alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5- hexenyl.
- (C 2 -C 6 )alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3 -hexynyl, 4-hexynyl, or 5 -hexynyl.
- alkylene refers to a saturated, straight chain, divalent alkyl radical of the formula -(CH 2 ) n -, wherein n can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
- aryl is intended to mean any stable monocyclic, bicyclic or tricyclic carbon ring of up to 8 members in each ring, wherein at least one ring is aromatic as defined by the Huckel 4n+2 rule.
- aryl ring systems include phenyl, naphthyl, tetrahydronaphthyl and biphenyl.
- the aryl group can be substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, Protective
- purine or pyrimidine base includes, but is not limited to, adenine, N 6 - alkylpurines, N 6 -acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 - benzylpurine, N 6 -halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 -hydroxyalkyl purine, N 6 -thioalkyl purine, N 2 -alkylpurines, N 2 -alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6- azacytosine, 2- and/or 4-mercapto-pyrimidine, uracil, 5-halouracil, including 5- fluorouracil, C 5 -alkylpyrimidines, C
- Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diamino-purine and 6- chloropurine. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl and t- butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
- heteroalkyl refers to an alkyl group that contains a heteroatom in the alkyl chain, including O, S, N, or P, and wherein the heteroatom can be attached to other substituents (including R 15 ) to complete the valence.
- heteroalkyl moieties include polyoxyalkylene, and when divalent, -(CH 2 O)n- wherein n is an integer offrom 0 to 20
- acyl refers to a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from straight, branched, or cyclic alkyl or lower alkyl, alkoxyalkyl including methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as phenoxymethyl, aryl including phenyl optionally substituted with halogen, Ci to C 4 alkyl or Ci to C 4 alkoxy, sulfonate esters such as alkyl or ar alkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g.
- esters dimethyl-t-butylsilyl or diphenylmethylsilyl.
- Aryl groups in the esters optimally comprise a phenyl group.
- lower acyl refers to an acyl group in which the non-carbonyl moiety is lower alkyl.
- heteroaryl or heteroaromatic refers to an aromatic moiety that includes at least one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring.
- heterocyclic refers to a nonaromatic cyclic group wherein there is at least one heteroatom, such as oxygen, sulfrir, nitrogen or phosphorus in the ring.
- heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazofyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazo
- heteroaromatic and heterocyclic moieties can be optionally substituted as described above for aryl, including substituted with one or more substituent selected from halogen, haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, amido, amino, alkylamino, dialkylamino.
- the heteroaromatic can be partially or totally hydrogenated as desired.
- dihydropyridine can be used in place of pyridine. Functional oxygen and nitrogen groups on the heteroaryl group can be protected as necessary or desired.
- Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldi-methylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
- aralkyl refers to an aryl group as defined above linked to the molecule through an alkyl group as defined above.
- alkaryl refers to an alkyl group as defined above linked to the molecule through an aryl group as defined above.
- alkoxy refers to a moiety of the structure -O-alkyl, wherein alkyl is as defined above.
- amino refers to a moiety represented by the structure - NR 2 , and includes primary amines, and secondary, and tertiary amines substituted by alkyl
- R 2 may represent two hydrogens, two alkyl moieties, or one hydrogen and one alkyl moiety.
- amido refers to a moiety represented by the structure - C(O)NR2, wherein R2 is as defined for amino.
- amino acid is a natural amino acid residue (e.g. Ala, Arg,
- phosphoserine phosphothreonine; phosphotyrosine; gamma-carboxyglutamate; hippuric acid; octahydroindole-2-carboxylic acid; statine; l,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid; penicillamine; ornithine; citrulline; ⁇ -methyl-alanine; para-benzoylphenylalanine; phenylglycine; propargyl-glycine; sarcosine; and tert-butylglycine) residue having one or more open valences.
- the term also comprises natural and unnatural amino acids bearing amino protecting groups such as acetyl, acyl, trifluoroacetyl, and benzyloxycarbonyl), as well as natural and unnatural amino acids protected at carboxy with protecting groups such as a d-C 6 alkyl, phenyl or benzyl ester and amide.
- amino protecting groups such as acetyl, acyl, trifluoroacetyl, and benzyloxycarbonyl
- suitable amino and carboxy protecting groups are known to those skilled in the art. See for example, T. W. Greene, Protecting Groups in Organic Synthesis; Wiley: New York, 1981; D. Voet, Biochemistry,
- a "peptide” is a sequence of 2 to 25 amino acids (e.g. as defined hereinabove) or peptidic residues having one or more open valences.
- the sequence may be linear or cyclic.
- a cyclic peptide can be prepared or may result from the formation of disulfide bridges between two cysteine residues in a sequence.
- a "molecule comprising B-10" can be any compound that contains at least one B-10 atom.
- the nature of the molecule that includes B-10 is not critical. The compound, however, must be nontoxic and must be able to enter the tumor cell or locate near the tumor cell when the molecule comprising B-10 is attached.
- a "residue of a molecule comprising B-10" is a radical of a molecule comprising B-10 having one or more open valences. Any synthetically feasible atom or atoms of the molecule comprising B-10 may be removed to provide the open valence, provided bioactivity is substantially retained. Based on the linkage that is desired, one skilled in the art can select suitably functionalized starting materials that can be derived from a molecule comprising B-10 using procedures that are known in the art.
- a "residue of o-carborane,” a “residue of m-carborane,” or a “residue of p-carborane” is a radical of o-carborane, m-carborane or p-carborane, respectively, having one or more open valences. Any synthetically feasible atom or atoms of o-carborane, m-carborane or p-carborane may be removed to provide the open valence, provided bioactivity is substantially retained. Based on the linkage that is desired, one skilled in the art can select suitably functionalized starting materials that can be derived from o-carborane, m-carborane or p-carborane using procedures that are known in the art.
- a pharmaceutically acceptable residue of an active agent is one that is modified to facilitate binding to the TC- or IF-binding agent, covalently, ionically or through a chelating agent, such that the modification does not inhibit the biological action of the active agent, in that it does not inhibit the drugs ability to modulate abnormal cellular proliferation.
- the residue refers to the active agent with an open valence state such that covalent bonding to the compound is possible. This open valence state can be achieved by any means known in the art, including the methodology described herein. In a preferred embodiment, the open valence state is achieved through the removal of an atom, such as hydrogen, to activate a functional group.
- the term “substantially free of or “substantially in the absence of refers to a composition that includes at least 85 or 90% by weight, preferably 95% to 98 % by weight, and even more preferably 99% to 100% by weight, of the designated enantiomer of that TC- or IF-binding agent.
- the compounds are substantially free their enantiomers.
- isolated refers to a composition that includes at least 85 or 90% by weight, preferably 95% to 98 % by weight, and even more preferably 99%> to 100% by weight, of the TC- or IF-binding agent, the remainder comprising other chemical species, including diastereomers or enantiomers.
- host refers to a multicellular organism in which proliferative disorders can occur, including animals, and preferably a human. Alternatively, the host is any abnormally proliferating cell, whose replication or function can be altered by the compounds of the present invention. The term host specifically refers to any cell line that abnormally proliferates, either from natural or unnatural causes
- the TC- or IF-binding carrier is any ligand that will bind effectively to a Vitamin B 12 transport protein (i.e. transcobalamin I, II or III or intrinsic factor) and which when appropriately linked to a neutron capture agent and bound to a transport protein, will fit into a transcobalamin receptor.
- Suitable carriers may be ascertained using any one of several means known in the art, including competitive binding assays with the receptor modulating agent competing with native vitamin B ⁇ 2 . Methods for the assessment of whether a moiety binds the TC receptor are known, and include those described by Pathare, et al., Bioconjugate Chem. 1996, 7, 217-232; and Pathare, et al., Bioconjugate Chem.
- the ligand preferably displays a binding affinity of at least 50% of the binding affinity displayed by vitamin B 12 , more preferably at least 75% and even more preferably at least 90%.
- the neutron capture agent is preferably bound directly or indirectly through an amide residue at the b-position, as illustrated in Figure 1.
- TC- or IF-binding carrier is represented by formula (I).
- the wavy line in the chemical structure indicates either a dative or covalent bond such that there are three dative Co-N bonds and one covalent Co-N bond, wherein, in the case of the dative bond, the valance of nitrogen is completed either with a double bond with an adjacent ring carbon or with a hydrogen;
- the dotted line in the chemical structure indicates either a double or single bond such that the double bond does not over-extend the valence of the element (i.e. to give pentavalent carbons) and, in the case of a single bond, the valence is completed with hydrogen; and preferably, the bonding and stereochemistry of the compound is the same as that of vitamin B 12 as it exists in nature;
- X is hydrogen, cyano, halogen (CI. F, Br or I), haloalkyl (including CF , CF 2 CF 3 , CH 2 CF 3 and CF 2 C1), NO 2 , NO 3 , PR 15 R 16 R 17 , NH 2 , NR 15 R 16 , OH, OR 15 , SR 15 , SCN, N 3 , OC(O)R 15 , C(O) 2 R 15 , C(O)R 15 , OC(O)NR 15 R 16 ,
- M is a monovalent heterocycle or heteroaromatic, which is capable of binding to the adjacent sugar ring and forming a dative bond with Co +3 , and is preferably a benzimidazole, a 5- and/or 6- substituted benzimidazole, such as 5,6-dimethylbenzimidazole, 5-methyl-benzimidazole, 5-hydroxybenzimid- azole, 5-methoxy-benzimidazole, naphth-imidazole, 5-hydroxy-6-methyl- benzimidazole or 5-methoxy-6-methyl-benz-imidazole; or a purine or pyrimidine including but not limited to adenine, 2-methyladenine, 2- methylmercaptoadenine, e-methylsulfinyladenine, 2-methyl-sulfonyladenine and guanine; or a phenol, such as phenol or p-cresol;
- (v) K is O, S, NJ 1 , C(OH)H, CR 100 R 101 or C(R 100 )V 8 Z 8 ;
- E is O or S
- G 1 is hydrogen, alkyl, acyl, silyl, phosphate or L-T;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 independently are O, S or NJ 2 ;
- V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 and V 8 independently are O, S, NJ 3 , CR 102 R 103 or a direct bond;
- (x) Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 7 and Z 8 independently are R 104 or L-T;
- each L is independently a direct bond or a linker to one or more T moieties, and that does not significantly impair the ability of the TC- or IF- binding carrier to bind to a transcobalamin receptor, optionally via a transport protein;
- each T independently comprises the residue of one or more molecules neutron capture agents such as a molecule comprising B-10 (in one embodiment T is for the treatment of a proliferative disorder other than cancer);
- J 1 , J 2 and J 3 independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl, heterocycle, heteroaryl, hydroxyl, alkoxy or amine;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, heteroalkyl, heterocyclic, lower alkoxy, azido, amino, lower alkylamino, halogen, thiol, SO 2 , SO , carboxylic acid, C ⁇ - 6 carboxyl, hydroxyl, nitro, cyano, oxime or hydrazine;
- R 13 and R 14 optionally can form a double bond
- R 15 , R 16 and R 17 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl or aralkyl group, heteroalkyl, heterocycle or heteroaromatic;
- R 100 , R 101 , R 102 , R 103 , and R 104 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl, heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO 2 , SO 3 , thioalkyl, or amino.
- vitamin B ⁇ 2 In naturally occurring vitamin B ⁇ 2 , there is an ⁇ -D-5,6-dimethylbenzimidazolyl ribose 3 '-phosphate that is bound through the phosphate to the B 12 moiety and coordinated to the cobalt ion.
- the M- sugar component In a modified vitamin Bi 2 TC- or IF- binding carrier, the M- sugar component is likewise in an ⁇ -D configuration, although other configurations (i.e., ⁇ -L, ⁇ -D and ⁇ -L) are possible.
- Vitamin B 12 has a 5'- deoxyadenosyl moiety.
- Vitamin B 12 catalysis occurs via the detachment and reattachment of the methylene radical at the 5'-deoxy position of the vitamin.
- L is preferably a direct bond, in which the molecule comprising B-10 is directly linked to the TC carrier.
- the molecule comprising B-10 can also be linked through one of many suitable linkers.
- a neutron capture agent capable of absorbing low energy or thermal neutrons is suitable for practicing the invention.
- a preferred neutron capture agent is B-10.
- a variety of molecules comprising B-10 known in the art are useful in the present invention. The molecules vary considerably in structure but are suitable to practice the present invention. Acceptable species include boron containing amino acids, carbohydrates, and nucleosides, as well as carboranes.
- a variety of molecules comprising B-10 are commercially available from Boron Biologicals, Inc., Raleigh, North Carolina and RysCor Science, Inc.,
- At least one molecule comprising B-10 can be o-carborane, m- carborane or p-carborane. More specifically, at least one molecule comprising B-10 is o- carborane.
- o-Carborane [l,2-dicarbadodecaborane(12)]; m-carborane [1,7-dicarbadode- caborane(12)]; and p-carborane [l,12-dicarbadodecaborane(12)] are commercially available from Aldrich, Milwaukee, WI.
- the TC- or IF-binding carrier/active agent of the present invention provides a delivery system capable of targeting abnormally proliferative cells, and selectively destroying a greater proportion of such cells in relation to healthy cells.
- a wide range of analogs and derivatives are capable of attaining these properties, as reflected by the above referenced chemical structure and variables.
- the TC- or IF-binding carrier can be modified in any manner that does not interfere with its fundamental ability to bind a transcobalamin transport protein, and thereafter bind the TC receptor.
- each variable on the vitamm B 12 structure independently either (i) retains its natural vitamin B12 structure, (ii) imparts imaging and/or anti-proliferative properties to the cobalamin conjugate, (iii) renders the cobalamin conjugate more water soluble, or more stable, (iv) increases the bioavailability of the carrier; (v) increases or at least does not decrease the binding affinity of the carrier for the TC-binding or IF-binding protein over vitamin Bj 2; or (vi) imparts another characteristic that is desired for pharmaceutical or diagnostic performance.
- the neutron capture agent can be linked to the TC-binding or IF-binding moiety through a number of positions, including any of the V-Z moieties, the X moiety, the M moiety, the K moiety and/or the G 1 moiety, though as mentioned above at least one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 7 , Z 8 , M, K and G 1 moieties comprises a neutron capture agent.
- a neutron capture agent is linked to the TC- or IF-binding carrier through Z 2 ,
- Z 4 , and/or Z 5 i.e. one or more of Z 2 , Z 4 , and Z 5 is L-T, and T is a neutron capture agent).
- a neutron capture agent is linked to the TC- or IE-binding carrier through the Z 2 moiety (i.e. Z 2 is L-T, and T is a neutron capture agent).
- the Z moiety or moieties not containing a neutron capture agent preferably retain its natural vitamin B12 configuration, in which VZ is NH 2 .
- the Z moieties not containing a neutron capture agent may comprise a secondary or tertiary amino analog of NH 2 substituted by one or two of J 1 .
- each T can independently comprise the residue of one or more neutron capture agents bound to L through one or more chelating moieties. More specifically, in a series of embodiments, each T can comprise 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 neutron capture agents bound through one or more chelating moieties.
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13 independently represent moieties that do not interfere with binding between the compound and the transcobalamin transport protein or receptor.
- Vitamin B 12 can be modified through these moieties to modulate physical properties of the molecule, such as water solubility, stability or ⁇ max .
- Preferred groups for enhancing water solubility include heteroalkyl, amino, C1- 6 alkylamino, C ⁇ - 6 alcohol, C ⁇ _ 6 carboxylic acid and SO " .
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 are independently selected from the group consisting of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 ,
- R 11 , R 12 , and R 13 independently assume their natural roles in vitamin B 12 .
- R 1 , R 2 , R 4 , R 5 , R 8 , R 9 , R 11 , R 12 and R 15 are independently methyl in one embodiment, and one, some, or all of R 3 , R 6 , R 7 , R 10 , R 13 and R 14 are independently hydrogen.
- one, some, or all of Y , Y , Y , Y , Y and Y assume their natural roles in vitamin B 12 , and are O.
- V assumes its natural role in vitamin B1 2 , and is NH, or a primary amine analog thereof substituted by J 1 .
- position X assumes its natural role in vitamin Bn, i.e. as cyano, hydroxyl, methyl or 5'-deoxyadenosyl, most preferably 5'-deoxyadenosyl.
- M is the radical of a purine or pyrimidine base.
- M is the radical of adenosine, guanine, cytosine, uridine or thymine.
- M is the radical of 5,6-dimethylbenzimidazole.
- K is CH(OH).
- E is O.
- G 1 is OH.
- all constituents of the conjugate assume their natural roles in vitamin B 12 , except for the moieties through which any neutron capture agents are linked.
- the neutron capture agent(s) are preferably linked to the vitamin B1 2 structure through Z 2 , Z 4 and/or Z 5 , and even more preferably through the Z 2 moieties.
- the metallic radionuclide Gadolinium-157 is an especially useful ion for conducting magnetic resonance imaging. It is also a useful target ion for neutron capture therapy. Applicants have discovered that incorporation of Gd-157 into the cobalamin conjugate of the present invention (wherein the Gd-157 supplements or replaces B-10) provides a compound that is not only particularly useful for conducting magnetic resonance imaging, but also a compound that can be used in conjunction with neutron capture therapy, to treat tumors.
- the invention provides a method of perforating neutron capture therapy using a Gd-157 conjugate having a high specificity for abnormally proliferative cells, or an enantiomer, diastereomer, salt or pro-drug thereof, comprising (1) a TC- or IF-binding carrier, and (2) a Gd-157 molecule linked directly or through a linker to the carrier.
- the method comprises administering the Gd-157 conjugate to a mammal (preferably a human), and initiating neutron capture.
- suitable ligands may be ascertained using any one of several means known in the art, including competitive binding assays with the receptor modulating agent competing with native vitamin B1 2 .
- the neutron capture agent is preferably bound directly or indirectly through an amide residue at the b-position, as illustrated in Figure 1.
- the Gd-157 conjugate is a compound of fo ⁇ nula (II), or an enantiomer, diastereomer, salt or pro-drug thereof:
- the wavy line in the chemical structure indicates either a dative or covalent bond such that there are three dative Co-N bonds and one covalent Co-N bond, wherein, in the case of the dative bond, the valance of nitrogen is completed either with a double bond with an adjacent ring carbon or with a hydrogen;
- the dotted line in the chemical structure indicates either a double or single bond such that the double bond does not over-extend the valence of the element (i.e. to give pentavalent carbons) and, in the case of a single bond, the valence is completed with hydrogen; and preferably, the bonding and stereochemistry of the compound is the same as that of vitamin B 12 as it exists in nature;
- X is hydrogen, cyano, halogen (CI. F, Br or I), haloalkyl (including CF 3 , CF 2 CF 3 , CH 2 CF 3 and CF 2 C1), NO 2 , NO 3 , PR 15 R 16 R 17 , NH 2 , NR 15 R 16 , OH, OR 15 , SR 15 , SCN, N 3 , OC(O)R 15 , C(O) 2 R 15 , C(O)R 15 , OC(O)NR 15 R 16 , C(O) 2 NR 15 R 16 , C(O)NR 15 R 16 , P(O) 2 OR 15 , S(O) 2 OR 15 , a purine or pyrimidine nucleoside or nucleoside analog, including adenosyl (preferably linked through a 5'-deoxy linkage), alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, amino
- M is a monovalent heterocycle or heteroaromatic, which is capable of binding to the adjacent sugar ring and forming a dative bond with Co +3 , and is preferably a benzimidazole, a 5- and/or 6- substituted benzimidazole, such as 5,6-dimethylbenzimidazole, 5-methyl-benzimidazole, 5-hydroxybenzimid- azole, 5-methoxy-benzimidazole, naphth-imidazole, 5-hydroxy-6-methyl- benzimidazole or 5-methoxy-6-methyl-benz-imidazole; or a purine or pyrimidine including but not limited to adenine, 2-methyladenine, 2- methylmercaptoadenine, e-methylsulfinyladenine, 2-methyl-sulfonyladenine and guanine; or a phenol, such as phenol or p-cresol;
- (v) K is O, S, NJ 1 , C(OH)H, CR 100 R 101 or C(R 100 )V 8 Z 8 ;
- E is O or S;
- G 1 is hydrogen, alkyl, acyl, silyl, phosphate or L-T;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 independently are O, S or NJ 2 ;
- V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 and V 8 independently are O, S, NJ 3 , CR 102 R 103 or a direct bond;
- (x) Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 7 and Z 8 independently are R 104 or L-T;
- each L is independently a direct bond or a linker to one or more T moieties, and that does not significantly impair the ability of the TC- or IF- binding carrier to bind to a transcobalamin receptor, optionally via a transport protein;
- each T independently comprises the residue of one or more molecules comprising Gd-157 or one or more radionuclides bound to L through a chelating moiety (in one embodiment T is for the treatment of a proliferative disorder other than cancer);
- J 1 , J 2 and J 3 independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heteroalkyl, heterocycle, heteroaryl, hydroxyl, alkoxy or amine;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, heteroalkyl, heterocyclic, lower alkoxy, azido, amino, lower alkylamino, halogen, thiol, SO 2 , SO , carboxylic acid, C ⁇ - 6 carboxyl, hydroxyl, nitro, cyano, oxime or hydrazine;
- R 13 and R 14 optionally can form a double bond
- R 15 , R 16 and R 17 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, alkaryl or aralkyl group, heteroalkyl, heterocycle or heteroaromatic;
- R 100 , R 101 , R 102 , R 103 , and R 104 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, heteroaromatic, heteroaryl, heteroalkyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO 2 , SO 3 , thioalkyl, or amino.
- Preferred and more specific embodiments of the Gd-157 conjugate are the same as those set forth above for neutron capture agents such as B-10.
- the TC- or IF-binding carrier and neutron capture agent useful to treat and optionally image sites of proliferative disease in the body, such as cancerous tumors can be combined by means of a di- or multi-valent linking moiety.
- the linker used to join the TC binding carrier and the neutron capture agent preferably has a single molecular weight, and does not exhibit a molecular weight distribution, for example as found in most polymers.
- the linker can range in size from small to large molecular weight, as long as there is not a distribution of weights in the linker. It is important to strictly control the uniformity of size of the conjugate for predictability of therapeutic performance.
- L is the residue of a linker molecule that conjugates one or more neutron capture agents to the TC ligand.
- the structure of the linker from which L is derived is not crucial, provided it does not significantly impair the ability of the conjugate to bind to the transcobalamin or IF transport protein or receptor.
- L is preferably any multivalent molecule (divalent or greater) that does not significantly impair the ability of the TC carrier to bind to the transcobalamin transport protein or receptor.
- vitamin B 12 or any other TC-binding or IF-binding carrier to bind to the transcobalamin transport protein or receptor is "significantly impaired" when attaching a linking moiety to the B ⁇ 2 or TC-binding or IF-binding carrier lessens the affinity of the vitamin B1 2 or the TC- binding or IF-binding carrier for the transcobalamin transport protein to which the vitamin B1 2 or TC-binding or IF-binding carrier is most readily bound by 50%) or more.
- the unsaturated vitamin Bj 2 binding capacity (UBBC) assay described by D. A. Collins and H. P. C. Hogenkamp in J. Nuclear Medicine, 1997, 55, 717-723 can be used to compare the relative affinities of ligands for this receptor .
- the linker is of precise molecular weight and does not posses a molecular weight distribution. In one embodiment, the linker has a molecular weight less than about 2,500, 2,000, 1900, 1800, 1,500, 1,000 or 500.
- the linlcers preferably have a molecular weight below about 2000, more preferably below about 1000, and even more preferably below about 500.
- a particularly preferred linker is one having multiple sites for conjugation to one or more neutron capture agents, wherein the linker has a unimodal molecular weight.
- Recombinant protein production techniques can be employed to obtain poly(amino acid) linkers of substantially constant molecular weight.
- the linker is an amino acid, or a polymer or peptide formed from a plurality of amino acids.
- the polymer or peptide can be derived from one or more amino acids.
- the amino acid, poly(amino acid) or peptide can link T to V through the carboxy temiinus or the amino terminus.
- ether e.g.
- Peptide derivatives can be prepared as disclosed in U.S. Patent Numbers
- Peptide sequences specifically recited herein are written with the amino terminus on the left and the carboxy teraiinus on the right, but are meant to also include the opposite flow.
- Particularly suitable peptides and poly(amino acids) comprise from 2 to about 20 amino acids, from 2 to about 15 amino acids, or from 2 to about 12 amino acids.
- poly(amino acid) is poly-L-lysine ((-NHCH((CH2) 4 -NH 2 )CO-) m -Q, wherein Q is H, (C ⁇ -C 14 )alkyl, or a suitable carboxy protecting group, and m is from 2 to about 20, from about 5 to about 15, or from about 8 to about 11.
- the polylysme offers multiple primary amine sites to which anti-proliferative agents can be readily attached.
- the linkers can be formed with multiple cysteines, to provide free thiols, or multiple glutamates or aspartates, to provide free carboxyls for conjugation using suitable carbodiimides.
- the linker can contain multiple histidines or tyrosines for conjugation.
- poly(amino acid) linkers are poly-L-glutamic acid, poly-L- aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L- tyrosine, poly-L-lysine-L-phenylalanine or poly-L-lysine-L-tyrosine.
- the linker is derived from a ⁇ oly(amino acid) other than polylysme, the linker is, in a series of embodiments, prepared from 2 to about 30 amino acids, 5 to about 20 amino acids, or 8 to about 15 amino acids.
- L is a polyamine residue (having at least three amino moieties) of the following chemical structure: NR' (alley lene-NR') n alkyleneNR', wherein n is from 1 to 20, the carbon length of alkylene can vary within the n units, and each R' is independently hydrogen, lower alkyl, or T.
- N is preferably from 1 to 10.
- L preferably has a backbone along its longest length of no more than 100, 75, 50, 40, 30, 20 or 15 atoms.
- Exemplary polyamines from which L can be derived include spermine (H 2 N(CH2)3NH(CH 2 ) 4 NH(CH2) 3 NH2), spermidine (H2N(CH 2 )3NH(CH2) 4 NH 2 ), decamethylene tetraamine, and pentamethylene hexamine. These linkers are a definite size and thus provide consistent and predictable targeting by the cobalamin conjugate, in addition to multiple binding sites for the neutron capture agent.
- L is a diamine represented by the formula NH 2 (CH 2 ) X NH 2 , in which x is 2-20, and preferably 2-12.
- the linker can be prepared from 1,6- diaminohexane, 1,5-diaminopentane, 1,4-diaminobutane and 1,3-diaminopropane.
- linkers are formed from the covalent linkage of various water soluble molecules with amino acids, peptides, poly(amino acids), polyamines, polyoxyalkylenes, polyanhydrides, polyesters, polyamides, polyglycolides and diamines.
- Suitable water soluble molecules include, for example, polyethylene glycol, and dicarboxylic monosaccharides such as glucaric acid, galactaric acid and xylaric acid.
- linkers include those represented by the formula HO(O)C(CH 2 ) x C(O)OH, in which x is 2-20, and preferably 2-12.
- the linker can be prepared from succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid or maleic acid.
- Still other suitable linkers comprise carboxylic acid derivatives that yield an amide upon reaction with an amine.
- Such reactive groups include, by way of example, carboxylic acid halides such as acid chlorides and bromides; carboxylic acid anhydrides such as acetic anhydrides and trifluoroacetic anhydrides; esters such as p- nitrophenyl esters and N-hydroxysuccinimide esters; and imidazolides. Techniques for using such linkers are described in detail in Bodanszky, Principles of Peptide Synthesis, Springer Verlag, Berlin, 1984.
- the linker is modified to facilitate its conjugation either to V or T.
- Suitable molecules for modifying the linker include: disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl) suberate (BSS), ethylene glycolbis(succinimidylsuccinate) (EGS), ethylene glycolbis(sulfosuccinimidyl-succinate) (Sulfo-EGS), p-aminophenylacetic acid, dithiobis(succinimidyl-propionate) (DSP), 3,3 '-dithiobis-(sulfosuccinimidylpropionate) (DTSSP), disuccinimidyl tartarate (DST), disulfosuccinimidyl tartarate (Sulfo-DST), bis- (2-(succinimidooxycarbonyloxy)-ethylene)sulfone (BSOCOES), bis(2-(succ
- Various degradable linkers can be used to link the TC-binding or IF-binding moiety to the neutron capture agent.
- the desired linkers can degrade under biological conditions such as by enzymatic cleavage or by systemic pH or temperature.
- these linkers can be induced to degrade by external manipulation such as changes in pH, temperature, ultrasound, magnetic field, radiation (i.e. UV radiation) or light.
- Patent No. 5,296,483 entitled “Brain-specific analogues of centrally acting amines;” U.S. Patent No. 5,258,388 entitled “Anticholmergic compounds, compositions and methods of treatment;” U.S. Patent No. 5,231,089 entitled “Method of improving oral bioavailability of carbamazepine;” U.S. Patent No. 5,223,528 entitled “Anticholmergic compounds, compositions and methods of treatment;” U.S. Patent No. 5,187,158 Brain-specific drug delivery;” U.S. Patent No. 5,177,064 entitled “Targeted drug delivery via phosphonate derivatives;” U.S. Patent No.
- 4,479,932 entitled "Brain-specific drug delivery" to Nicholas S. Bodor, et al. disclose several biodegradable linkers that target the brain.
- a lipoidal form of dihydropyridine pyridinium salt redox carrier, DHC linked to a centrally acting drug which can be reduced and biooxidized to pass through the blood brain barrier.
- the dihydropyridine nucleus readily and easily penetrates the blood brain barrier in increased concentrations; furthermore, the in vivo oxidation of the dihydropyridine moiety to the ionic pyridinium salts thereby prevents its elimination from the brain, while elimination from the general circulation is accelerated, resulting in a prolongedly sustained brain-specific drug activity.
- This dihydropyridine can be incorporated into the linkers set forth above for biodegradation.
- U.S. Patent No. 4,622,218 entitled “Testicular-specific drug delivery,” discloses linkers that can specifically deliver drugs to the testes in much the same manner, and which can be used in the linkers of the present invention.
- the lipoidal form [D--DHC] of a dihydropyridine pyridinium salt redox carrier, e.g. 1,4- dihydrotrigonelline penetrates the blood-testis barrier. Oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salt type drug/carrier entity [D--QC] prevents elimination thereof from the testes, while elimination from the general circulation is accelerated, resulting in significant and prolongedly sustained testicular-specific drug activity.
- Margerum, et al. in U.S. Patent No. 5,976,493 discloses the use of polychelant compounds which are degradable in vivo to release excretable fragments for diagnostic imaging which also are suitable in the linkers of the present invention. These compounds contain a linker moiety which is metabolically cleavable to release macrocyclic monochelant fragments, wherein the macrocyclic skeleton preferably has 9 to 25 ring members, and a biotolerable polymer, preferably a substantially monodisperse polymer.
- Other suitable linkers are disclosed, for example, in Krejcarek et al. (Biochemical and Biophysical Research Communications 77: 581 (1977)) (mixed anhydrides), Hnatowich et al. (Science 220: 613 (1983))(cyclic anhydrides), United States Patent 5,637,684 to Cook, et al (Phosphoramidate and phosphorothioamidate oligomeric compounds).
- linker can be formed from the polyanhydrides and polyorthoesters, which take advantage of labile backbone linkages (see: Domb et al. Macromolecules, 22, 3200, 1989; and Heller et al. Biodegradable Polymers as Drug Delivery Systems, Dekker, NY: 1990).
- linker materials include hydrogels, such as the PEG-oligoglycolyl-acrylates disclosed in U.S. Patent No. 5,626,863 to Hubbell et al..
- Other biodegradable linkers are formed from oligoglycolic acid is a poly(a-hydroxy acid), polylactic acid, polycaprolactone, polyorthoesters, polyanhydrides and polypeptides.
- U.S. Patents that describe controlled release formulations suitable for use as linking agents are: U.S. Patent No. 5,356,630 to Laurencin et al. (Delivery System for Controlled Release of Bioactive Factors); U.S. Patent No. 5,797,898 to Santini, Jr. et al. (Microchip Drug Delivery Devices); U.S. Patent No. 5,874,064 to Edwards et al. (Aerodynamically Light Particles for Pulmonary Drug Delivery); U.S. Patent No. 5,548,035 to Kim et al. (Biodegradable Copolymer as Drug Delivery Matrix Comprising Polyethyleneoxide and Aliphatic Polyester Blocks); U.S. Patent No. 5,532,287 to Savage et al. (Radiation Cured Drug Release Controlling Membrane); U.S.
- Patent No. 5,284,831 to Kahl et al (Drug Delivery Porphyrin Composition and Methods); U.S. Patent No. 5,741,329 to Agrawal et al. (Methods of Controlling the pH in the Vicinity of Biodegradable Implants); U.S. Patent No. 5,820,883 to Tice et al. (Methods for Delivering Bioactive Agents into and Through the Mucosally-Associated Lymphoid Tissues and Controlling Their Release);U.S. Patent No. 5,955,068 to Gouin et al.
- Patent No. 5,356,630 Delivery system for controlled release of bioactive factors U.S. Patent No. 5,330,768 Controlled drug delivery using polymer/pluronic blends; U.S. Patent No. 5,286,763 Bioerodible polymers for drug delivery in bone; U.S. Patent No. 5,149,543 Ionically cross-linked polymeric microcapsules; U.S. Patent No. 5,128,420 Method of making hydroxamic acid polymers from primary amide polymers; U.S. Patent No. 5,122,367 Polyanhydride bioerodible controlled release implants for administration of stabilized growth hormone;
- Nonmetallic radioisotopes can conveniently be linked to the vitamin B 12 structure through a residue of a peptide having the following formula:
- each M is independently a non-metallic radionuclide; each R is independently (C ⁇ -C 14 )alkyl, (C 2 -C 1 )alkenyl, (C2-C 1 )alkynyl, (Ci-C 14 )alkoxy, hydroxy, cyano, nitro, halo, trifluoromethyl, N(R a )(R b ), (C ⁇ -C 14 )alkanoyl, (C 2 -C 14 )alkanoyloxy, (C 6 -C ⁇ 0 )aryl, or (C 3 -C 8 )cycloalkyl wherein R a and R are each independently H or (C ⁇ -C 14 )alkyl; P; Q is H, (C ⁇ -C 1 )alkyl, or a suitable carboxy protecting group; n is 2 to.
- i can be 1
- j can be 0
- M can be a positron emitter such as Fluorine-18, Bromine-76, Iodine-124 or a gamma emitter such as Iodine-123 or Iodine-131
- n can be about 6 to about 12.
- X is 5'-deoxyadenosyl
- M is a monovalent heterocycle that is capable of binding to the adjacent sugar ring, and forming a dative bond with Co +3 , optionally substituted by L-T
- K is O, S, NJ 1 , CR 100 R 101 , or C(R 100 )V 8 Z 8
- E is O or S
- G 1 is hydrogen, alkyl, acyl, silyl, phosphate, or L-T
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 independently are O, S or NJ 2
- V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 and V 8 independently are O, S or NJ 3
- CR 102 R 103 or a direct bond
- ⁇ Z 2 , Z 3 , Z 4 , Z 5 , Z 7 and Z 8 independently are R 104 or L
- X is 5'-deoxyadenosyl
- M, K, E and G 1 retain their natural vitamin B12 configuration
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 independently are O, S or NJ 2 ;
- V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 and V 8 independently are O, S or NJ 3 ; CR 102 R 103 , or a direct bond; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 7 and Z 8 independently are R 104 or L-T; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each T independently comprises the residue of one or more molecules comprising B-10 or one or more radionuclides; at least one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 7 and Z 8 , M, K, E, or G 1 comprises a molecule comprising B-10; J 1 , J 2 and J 3 independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heterocycle,
- R 13 and R 14 optionally can come together to form a double bond; and R 100 , R 101 , R 102 , R 103 , and R 104 are independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO 2 , SO 3 , thioalkyl, or amino.
- X is 5'-deoxyadenosyl
- M is a monovalent heterocycle that is capable of binding to the adjacent sugar ring, and forming a dative bond with Co +3 , optionally substituted by L-T
- K is O, S, NJ 1 , CR 100 R 101 , or C(R 100 )V 8 Z 8
- E is O or S
- G 1 is hydrogen, alkyl, acyl, silyl, phosphate, or L-T
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 independently are O, S or NJ 2
- V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 and V 8 independently are O, S or NJ 3
- CR 102 R 103 or a direct bond
- Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 7 and Z 8 independently are R 104
- R , R , R , R and R independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, heterocyclic, lower alkoxy, azido, amino, lower alkylamino, halogen, thiol, SO 2 , SO 3 , carboxylic acid, Ci- 6 carboxyl, hydroxyl, nitro, cyano, oxime or hydrazine; R 13 and R 14 optionally can come together to form a double bond; and R 100 , R 101 , R 102 , R 103 , and R 104 are independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO 2 , SO 3 , thioalkyl, or amino.
- X is hydrogen, cyano, amino, amido, hydroxyl, 5'- deoxyadenosyl, L-T, alkyl, alkenyl, alkynyl, cylcoalkyl, aryl, aralkyl, heterocycle, or heteroaryl, or alkylheteroaryl;
- M, K, E and G 1 retain their natural vitamin B 12 configuration;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 independently are O, S or NJ 2 ;
- V 4 , V 5 , V 6 , V 7 and V 8 independently are O, S or NJ 3 ; CR 102 R 103 , or a direct bond; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 7 and Z 8 independently are R 104 or L-T; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each T independently comprises the residue of one or more molecules comprising B-10 or one or more radionuclides; at least one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 7 and Z 8 , M, K, E or G 1 comprises a molecule comprising B-10; J 2 and J 3 independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl
- R 13 , R 14 and R 15 retain their natural vitamin B 12 configuration; and R 100 , R 101 , R 102 , R 103 , and R 104 are independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO 2 , SO 3 , thioalkyl, or amino.
- X is hydrogen, cyano, amino, amido, hydroxyl, 5'- deoxyadenosyl, L-T, alkyl, alkenyl, alkynyl, cylcoalkyl, aryl, aralkyl, heterocycle, or heteroaryl, or alkylheteroaryl;
- B, K, E and G 1 retain their natural vitamin B 12 configuration;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 independently are O, S or NJ 2 ;
- V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 and V 8 independently are O, S or NJ 3 ;
- CR 102 R 103 or a direct bond;
- z Z 2 is hydrogen, cyano, amino, amido, hydroxyl, 5'- deoxyadenosyl, L-T, alkyl, alkenyl, alkyn
- Z 3 , Z 4 , Z 5 , Z 7 and Z 8 independently are R 104 or L-T; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each T independently comprises the residue of one or more
- J 1 , J 2 and J 3 independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heterocycle, heteroaryl, hydroxyl, alkoxy, or amine;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R n , R 12 , R 13 , R 14 and R 15 independently are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, heterocyclic, lower alkoxy, azido, amino, lower alkylamino, halogen, thiol, SO 2 , SO 3 , carboxylic acid
- R 13 and R 14 optionally can come together to form a double bond; and R 100 , R 101 , R 102 , R 103 , and R 104 are independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO 2 ,
- X is hydrogen, cyano, amino, amido, hydroxyl, 5'- deoxyadenosyl, L-T, alkyl, alkenyl, alkynyl, cylcoalkyl, aryl, aralkyl, heterocycle, or heteroaryl, or alkylheteroaryl;
- M, K, E and G 1 retain their natural vitamin B 12 configuration;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 independently are O, S or NJ 2 ;
- V 4 , V 5 , V 6 , V 7 and V 8 independently are O, S or NJ 3 ; CR 102 R 103 , or a direct bond; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 7 and Z 8 independently are R 104 or L-T; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each T independently comprises the residue of one or more molecules comprising B-10 or one or more radionuclides; at least one of Z 2 , Z 4 , or Z 5 comprises a molecule comprising B-10, the remaining Z moieties retaining their natural 1 9 vitamm B 12 configuration; J , J and J independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl, cyclo
- X is 5'-deoxyadenosyl; M, K, E and G 1 retain their natural vitamin B 12 configuration; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 independently are O, S or NJ 2 ; V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 and V s independently are O, S or NJ 3 ; CR 102 R 103 , or a direct bond; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 7 and Z 8 independently are R 104 or L-T; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each T independently comprises the residue of one
- Z , Z , Z , Z and Z , M, K, E or G compnses a molecule comprising B-10;
- J and J independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl, cycloalkyl, aryl, cycloaryl, heterocycle, heteroaryl, hydroxyl, alkoxy, or amine;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 retain their natural vitamin B 12 configuration;
- R 100 , R 101 , R 102 , R 103 , and R 104 are independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxy, cyano, azido, halogen, nitro, SO 2 , SO 3 , thioalkyl, or amino.
- X is 5'-deoxyadenosyl; M, K, E and G 1 retain their natural vitamin B 12 configuration; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 independently are O, S or NJ 2 ; V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 and V 8 independently are O, S or NJ 3 ; CR 102 R 103 , or a direct bond; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 7 and Z 8 independently are R 104 or L-T; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each T independently comprises the residue of one or
- X is hydrogen, cyano, amino, amido, hydroxyl, 5'- deoxyadenosyl, L-T, alkyl, alkenyl, alkynyl, cylcoalkyl, aryl, aralkyl, heterocycle, or heteroaryl, or alkylheteroaryl;
- M, K, E and G 1 retain their natural vitamin B 12 configuration;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 independently are O, S or NJ 2 ;
- V 4 , V 5 , V 6 , V 7 and V 8 independently are O, S or NJ 3 ; CR 102 R 103 , or a direct bond; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 7 and Z 8 independently are R 104 or L-T; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each T independently comprises the residue of one or more molecules comprising B-10 or one or more radionuclides; at least one of Z 2 , Z 4 , or Z 5 comprises a molecule comprising B-10, the remaining Z moieties retaining their natural vitamin B 12 configuration; J 1 , J 2 and J 3 independently are hydrogen, alkyl, alkenyl, alkynyl, alkaryl, cycloal
- X is 5'-deoxyadenosyl; M, K, E and G 1 retain their natural vitamin B 12 configuration; Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 and Y 7 independently are O, S or NJ 2 ; V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 and V 8 independently are O, S or NJ 3 ; CR 102 R 103 , or a direct bond; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 7 and Z 8 independently are R 104 or L-T; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each L is independently a direct bond or the residue of a multivalent moiety that does not significantly impair the ability of the compound to bind transcobalamin II; each T independently comprises the residue of one or
- Subembodiments 11-20 Any one of subembodiments 1-10, wherein L is a direct bond and the molecule comprising B-10 comprises an o-carborane, an m-carborane or a p- carborane.
- Chelating groups can be used to link radionuclides to the cobalamm conjugate of the present invention. Any suitable chelating group can be employed. Suitable chelating groups include those disclosed in U.S. Patent Number 5,739,313. Other suitable chelating groups are the thiazoline derivatives disclosed in U.S. Patent No. 6,083,966, the pyridinones disclosed in U.S. Patent No. 5,892,029, and the catecholaurates disclosed in U.S. Patent No. 5,514,695.
- the chelating group can be NT A, HEDTA, DCTA, RP414, MDP, DOTATOC, CDTA, HYNIC, EDTA, DTP A, TETA, DOTA, DOTMP, DCTA,
- the chelating group is DTP A.
- DTPA diethylenetriaminepentaacetic acid
- TETA 1,4,8,11-tetraaza-cyclo- tetradecane-N,N',N",N"'-tetraacetic acid
- DOTA is 1,4,7, 10-tetraaza-cyclododecane- N,N',N",N'"-tetraacetic acid
- 15N4 is l,4,8,12-tetraazacyclo- ⁇ entadecane-N,N',N",N'"- tetra-acetic acid
- 9N3 is l,4,7-triazacyclononane-N,N',N"-triacetic acid
- 12N3 is 1,5,9- triazacyclo-dodecane-N,N',N"-triacetic acid
- polyaminoacid chelators, such as MAG3 is (N-(N-(N-((benzoylthio)acetyl)glycyl)gly
- R 3 may by (C 1 -C )alkyl or CH 2 CO2-, which may be attached through positions 4 or 5, or through the group R 3 and which carries from 1 to 4 detectable metal or nonmetal cations (M), monovalent cations, or the alkaline earth metals.
- M metal or nonmetal cations
- each individual cyclohexane-based molecule may carry up to 4 metal cations (where both R 3 groups are CH 2 COOM).
- R 3 groups are CH 2 COOM
- NTA, HEDTA, and DCTA are disclosed in Poster Sessions, Proceedings of the 46th Annual Meeting, J. Nuc. Med., p. 316, No. 1386.
- RP414 is disclosed in Scientific Papers, Proceedings of the 46th Annual Meeting, J. Nuc. Med., p. 123, No. 499.
- MDP is disclosed in Scientific Papers, Proceedings of the 46th Annual Meeting, J. Nuc. Med., p.
- DOTATOC is disclosed in Scientific Papers, Proceedings of the 46th Annual Meeting, J. Nuc. Med., p. 102, No. 414 and Scientific Papers, Proceedings of the 46th Annual Meeting, J. Nuc. Med., p. 103, No. 415.
- CDTA is disclosed in Poster Sessions, Proceedings of the 46th Annual Meeting, J. Nuc. Med., p. 318, No. 1396.
- HYNIC is disclosed in Poster Sessions, Proceedings of the 46th Annual Meeting, J. Nuc.
- Bifunctional chelators i.e., chelating groups
- macrocyclic ligands in which conjugation is via an activated arm attached to the carbon backbone of the ligand can also be employed as a chelating group, as described by M. Moi et al, J. Amer. Chem., Soc, 49, 2639 (1989) (2-p-nitrobenzyl-l,4,7,10-tetraazacyclododecane-N,N',N",N'"- tetraacetic acid); S. V. Deshpande et al, J. Nucl. Med., 31, 473 (1990); G. Kuser et al, Bioconj. Chem., 1, 345 (1990); C. J.
- the chelator or chelating group can be any of the chelating groups disclosed in Scientific Papers, Proceedings of the 46th Annual Meeting, J. Nuc. Med., Wednesday, June 9, 1999, p. 124, No. 500.
- the chelating group can be any one of the carbonyl complexes disclosed in Waibel et al, Nature Biotechnology, 897-901, Vol. 17, September 1999; or
- the detectable chelating group can be any one of the carbonyl complexes disclosed in Waibel et al, Nature Biotechnology, 897-901, Vol. 17, September 1999; or Sattelberger et al, Nature Biotechnology, 849-850, Vol. 17, September 1999, further comprising a metallic radionuclide. More specifically, the detectable chelating group can be any one of the carbonyl complexes disclosed in Waibel et al, Nature Biotechnology, 897-901, Vol. 17, September 1999; or Sattelberger et al, Nature Biotechnology, 849-850, Vol. 17, September 1999, further comprising Technetium-99m, Rhenium- 186, or Rhenium- 188.
- the TC- or EF-binding carrier of the present invention is also linked to a detectable radionuclide or other imaging agent.
- a detectable radionuclide is any suitable radionuclide (i.e., radioisotope) capable of being detected in a diagnostic procedure in vivo or in vitro.
- Suitable detectable radionuclides include metallic radionuclides (i.e., metallic radioisotopes) and non-metallic radionuclides (i.e., non- metallic radioisotopes).
- Suitable metallic radionuclides include Antimony-124, Antimony-125, Arsenic-74, Barium-103,
- the compounds of the invention can also comprise one or more (e.g., 1, 2, 3, or 4) non-metallic radionuclide which can be directly linked to a residue of the compound of formula I at any synthetically feasible site, or can be linked to a residue of the compound of formula I, by a linker, at any synthetically feasible site.
- Suitable linkers are described herein.
- suitable points of attachment of the compound of formula I for the non-metallic radionuclide, either directly or by a linker are also described herein.
- the invention also provides compounds having more than one non-metallic radionuclide attached to a compound of formula I, either directly, or by a linker.
- the non-metallic radionuclide can be a non-metallic paramagnetic atom (e.g., Fluorine-19); or non-metallic positron emitting radionuclide (e.g., Carbon-11, Fluorine- 18, Iodine- 12, or Bromine-76), or a nonmetallic gamma emitting radionuclide such as Iodine- 123 or Iodine-131.
- Fluorine-19 is a suitable non-metallic paramagnetic for use the compounds of the present invention in part because there is typically little or no background noise associated with the diagnostic use of fluorine in the body of a mammal (e.g., human).
- a "therapeutic chelating group” is a chelating group comprising a metallic radionuclide (e.g., a metallic radioisotope) that possesses therapeutic efficacy against cancer or other neoplastic cells in vivo or in vitro.
- a metallic radionuclide e.g., a metallic radioisotope
- Any suitable chelating group can be employed.
- the therapeutic chelating group can be any of the carbonyl complexes disclosed in Waibel et al., Nature Biotechnology, 897-901, Vol. 17, September 1999; or Sattelberger et al., Nature Biotechnology, 849-850, Vol. 17, September 1999, further comprising a metallic radionuclide.
- the therapeutic chelating group can be any of the carbonyl complexes disclosed in Waibel et al., Nature Biotechnology, 897-
- Tumors treatable with the compounds and methods of the invention can be located in any part of the mammal.
- the tumor can be located in the breast, lung, thyroid, lymph node, genitourinary system (e.g., kidney, ureter, bladder, ovary, teste, or prostate), musculoskeletal system (e.g., bones, skeletal muscle, or bone marrow), gastrointestinal tract (e.g., stomach, esophagus, small bowel, colon, rectum, pancreas, liver, or smooth muscle), central or peripheral nervous system (e.g., brain, spinal cord, or nerves), head and neck tumors (e.g., ears, eyes, nasopharynx, oropharynx, or salivary glands), or the heart.
- genitourinary system e.g., kidney, ureter, bladder, ovary, teste, or prostate
- musculoskeletal system e.g., bones, skeletal muscle, or bone m
- pharmaceutically acceptable salt or prodrug is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester, mono-, di- or tri-phosphate ester, salt of an ester or a related group) of a TC- or IF- binding carrier, which, upon administration to a patient, provides the active compound.
- Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.
- Pharmaceutically acceptable prodrags refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention. Typical examples of prodrags include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
- Prodrags include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.
- the compounds of this invention possess activity against infectious disease or are metabolized to a compound that exhibits such activity.
- pharmaceutically acceptable salts are organic acid addition salts formed with acids, which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate and ⁇ -glycerophosphate.
- Suitable inorganic salts may also be formed, including, sulfate, nitrate, bicarbonate and carbonate salts.
- salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
- a sufficiently basic compound such as an amine
- a suitable acid affording a physiologically acceptable anion.
- Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
- any of the TC- or IF-binding carriers described herein can be administered as a prodrug to increase the activity, bioavailability, stability or otherwise alter the properties of the carrier.
- a number of prodrug ligands are known, h general, alkylation, acylation or other lipophilic modification of the mono, di or triphosphate of the G 1 substituent on the five-membered "sugar-ring" moiety will increase the stability of the carrier.
- substituent groups that can replace one or more hydrogens on the phosphate moiety are alkyl, aryl, steroids, carbohydrates, including sugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jones and N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can be used in combination with the disclosed carriers to achieve a desired effect.
- the G 1 substituent of the active carrier can also be provided as a 5'-phosphoether lipid or a 5 '-ether lipid, as disclosed in the following references, which are incorporated by reference herein: Kucera, L.S., N. Iyer, E. Leake, A. Raben, Modest E. K., D. L. W., and C. Piantadosi. 1990. "Novel membrane-interactive ether lipid analogs that inhibit infectious H1N-1 production and induce defective virus formation.” AIDS Res. Hum.
- Nonlimiting examples of U.S. patents that disclose suitable lipopbilic substituents that can be covalently incorporated into the TC- or IF-binding agent, preferably at the G 1 position of the carrier or lipophilic preparations include U.S. Patent Nos. 5,149,794 (Sep. 22, 1992, Yatvin et al); 5,194,654 (Mar. 16, 1993, Hosteller et al, 5,223,263 (June 29, 1993, Hosteller et al); 5,256,641 (Oct. 26, 1993, Yatvin et al); 5,411,947 (May 2, 1995, Hosteller et al); 5,463,092 (Oct. 31, 1995, Hostetler et al); 5,543,389 (Aug. 6, 1996,
- optically active and racemic forms may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism.
- the present invention encompasses racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein.
- the optically active forms can be prepared by, for example, resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase or by enzymatic resolution.
- the average daily intake (in a Western diet) of vitamin B ⁇ is about 4-5 g. Additional synthesis of cobalamin may be produced in the ileum and the right colon, but in an unknown amount. The total lumenal cobalamin that must be assimilated each day in humans is estimated at 7-14 g, the sum of the dietary and endogenous cobalamin.
- Intestinal epithelial cells possess carriers and transporters that are highly efficient in the uptake of the small products of digestion, such as vitamins, minerals and amino acids. These mechanisms are necessary for the uptake of these molecules, as the epithelial cell layer presents an almost impenetrable barrier to peptides larger than five or six amino acids in size.
- the cobalamins of the present invention are large molecules that are not absorbed directly from the intestine, as they are too big to diffuse across the intestinal wall. Therefore, the absorption of the cobalamins is dependent upon transport proteins.
- the uptake of vitamin B12 from the intestine to the blood is perhaps the most complex uptake mechanism of all the vitamins, involving at least four separate cobalamin binding proteins and receptors.
- IF intrinsic factor
- HC haptocorrin
- TC-I transcobalamin I
- TC-III transcobalamin III
- TC-II transcobalamin II
- IF and TC II deficiencies lead to abnormalities such as megaloblastic anemia and demyelinating disorder of the nervous system.
- IF is a 45 kDa (in humans) to 55 kDa (in hogs) plasma glycoprotein with 15%> carbohydrate content.
- HC's are 58 kDa (in humans) to 60 kDa (in rabbits) plasma glycoproteins of 33-40% carbohydrate content with 16-19 sialic acid residues.
- Human TC-II is a 43 kDa plasma protein (in humans) with 0% carbohydrate content.
- Each binding protein has a separate affinity for cobalamin, as well as separate cell receptors.
- cobalamin is initially bound by HC in the stomach, followed by IF in the small intestine. An IF receptor is then involved in the uptake of the IF-cobalamin complex by the intestinal epithelial cell, leading to the proteolytic release of cobalamm, and subsequent binding to TC-II.
- IF is of particular relevance to the field of oral peptide and protein delivery. Therefore, IF is mainly produced in the gastric body and medium sized ducts and HC is mainly produced in granulocytes, the yolk sac, mammary glands, salivary acini and ducts.
- cobalamin is also bound to HC (derived from white cells) or to TC-II. The former complex is taken up by the liver, delivering free cobalamm to the intestinal lumen as the first limb of an enterohepatic circulation.
- IF is the most specific of the cobalamin-binding proteins. Cyanocobalamin, hydoxy-cobalamin (HOCbl), methylcobalamin (MeCbl) and adenyosylcobalamin
- HC comprises a group of immunologically identical proteins secreted into many body fluids (plasma, milk, amniotic fluid, saliva and gastric juices) from many types of cells (granulocytes, mammary glands, yolk sac or visceral placental membranes, salivary duct and acinar cells, and gastric mucosa of some species).
- proteins were known previously as R proteins (for rapid elecfrophoresis), non-intrinsic factors or transcobalamin I and III. They are characterized by different glycosylation processes and account for much of the total bound cobalamin in the serum (about 80% of bound cobalamin in serum).
- HC is degraded by pancreatic enzymes, freeing cobalamin to combine with other transport proteins, most notably IF.
- the IF-cobalamin complex is resistant to proteolytic digestion.
- the cobalamin-transport protein is internalized via receptor-mediated endocytosis, the cobalamin is cleaved from transport protein via protease(s) and bound to transcobalamin II (TC II). From there, the TC Il-cobalamin complex is used for the transport of absorbed cobalamin to peripheral tissues. Therefore, TC-II is found in most tissues.
- TC II inhibit the transport of cobalamins and block the proliferation of leukemic cells in vitro (McLean, G. R. et al. Blood, 1997 , 89, 235-242).
- the major cobalamin binder is not HC, but rather TC-II (Fedosov, S. N. et al. Biochemistry 1995, 34, 16082-16087 and Fedosov, S. N. et al.Biochim. Biophys. Acta. 1996, 1292, 113- 119).
- Matrices formed in this manner are able to release the transport protein by dissociating the cobalamin from the matrix, thus providing the transport protein saturated with cobalamin, circumventing the denaturant effect of chaotrophic agents.
- ion exchange chromatography or ammonium sulfate fractionation is used prior to the purification of the transport protein via an affinity column to concentrate the sample.
- ion exchange or size exclusion chromatography is used subsequent to the purification of the transport protein via an affinity column.
- Figure 2 and Figure 3 each illustrate the four step synthesis used to prepare three cyanocobalamin-nido-carborane conjugates.
- o-Carborane carboxylic acid (2) was prepared by reacting o-carborane with n-butyllithium and carbon dioxide in ether for approximately one hour at -78°C. Treatment with thionyl chloride gave o-carborane carboxylic acid chloride (3), which was allowed to react with 1,4-butanediamine in pyridine to give the amide linked nido-carboranoyl(4-aminobutyl)amide (4).
- Compound (4) was linked to the b-monocarboxylic acid of cyanocobalamin, the d-monocarboxylic acid of cyanocobalamin or both the b- and d-dicarboxylic acid of cyanocobalamin.
- hydroxybenzotriazole and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide was added to facilitate the formation of the amide bond.
- compounds wherein the residue of a molecule comprising B-10 is linked to the 6-position of a compound of formula I can be prepared by reducing a corresponding Co (III) compound of formula I to form a nucleophilic Co (II) compound and treating this Co (II) compound with a residue of a molecule comprising B-10 (or a derivative thereof) comprising a suitable leaving group, such as a halide (e.g., a chloride).
- a suitable leaving group such as a halide (e.g., a chloride).
- Compounds wherein the linker is linked to the 6-position of a compound of formula I can be prepared by preparing a nucleophilic Co (II) species as described herein above, and reacting it with a linker comprising a suitable leaving group, such as a halide (e.g. a chloride). Peptides and amino acids can be attached to the 6-position by reducing a conesponding Co (III) compound of formula I to form a nucleophilic Co (II) compound, and treating the Co (II) compound with a suitable alkylating agent comprising an amino acid or peptide.
- a suitable leaving group such as a halide (e.g. a chloride).
- Coupling of L-T to the ribose moiety at K or G 1 may be accomplished by activating the natural OH at either K or G 1 with a suitable reagent such as succinic anhydride, to yield a reactive group such as a carboxylate. This technique is described in detail in Toraya, Bioinorg. Chem. 4:245-255, 1975.
- Coupling of L-T to M can be accomplished using techniques described in detail in Jacobsen, Anal. Biochem. 113:164-171, 1981.
- the residue of vitamm B ⁇ or its analog can be prepared by any suitable means known in the art.
- a monocarboxylic acid or dicarboxylic acid of cobalamin can be prepared as disclosed in U.S. patent No. 5,739,313.
- These compounds can be prepared by the mild acid hydrolysis of cyanocobalamin, which has been shown to yield a mixture of mono-, a dicarboxylic acid and one tricarboxylic acid.
- carboxylic acids are derived from the propionamide side chains designated b, d- and e-, as discussed hereinabove, which are more susceptible to hydrolysis than the amide groups on acetamide side chains a-, c-, and g-.
- Non-limiting examples of proliferative disorders other than neoplasms that can be treated with a TC- or IF- binding carrier linked to a neutron capture therapy agent include those in Table 1, as well as any others listed or described in the Background of the invention or otherwise in the specification.
- Nonlimiting examples of neoplastic diseases or malignancies treatable with the TC- or IF- binding carrier linked to a neutron capture agent are listed in Table 2.
- Prefened modes of administration of the TC- or IF-binding carriers and neutron capture agents are parenteral, intravenous, intradermal, intra-articular, intra-synovial, intrathecal, infra-arterial, intracardiac, intramuscular, subcutaneous, intraorbital, intracapsular, infraspinal, intrasternal, topical, transdermal patch, via rectal, vaginal or urethral suppository, peritoneal, percutaneous, nasal spray, surgical implant, internal surgical paint, infusion pump, or via catheter.
- the agent and carrier are administered in a slow release formulation such as an implant, bolus, microparticle, microsphere, nanoparticle or nanosphere.
- the TC- or IF-binding carriers/neutron capture agents can, for example, be administered intravenously or intraperitoneally by infusion or injection. Solutions of the substance can be prepared in water, optionally mixed with a nontoxic surfactant.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the substance which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
- the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, normal saline, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
- the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, benzyl alcohol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the mjectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
- Sterile mjectable solutions are prepared by incorporating the substance in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
- the prefened methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
- Injectable solutions are particularly advantageous for local administration of the therapeutic composition.
- parenchymal injection can be used to deliver the therapeutic composition directly to a tumorous growth.
- Intra-articular injection is a prefened alternative in cases of arthritis where the practitioner wishes to treat one or only a few (such as 2-6) joints.
- the therapeutic compounds are injected directly into lesions (infra-lesion administration) in appropriate cases.
- Intradermal administration is an alternative for dermal lesions.
- TDD Transdermal drag delivery
- a transdermal therapeutic system see, Barry, Dermatological Formulations, (1983) p. 181 and literature cited therein.
- Transdermal drag delivery has several advantages over oral delivery. When compared to oral delivery, TDD avoids gastrointestinal drag metabolism, reduces first pass effects and provides a sustained release of drugs for up to seven days (Elias, et al. Percutaneous Absorption: Mechanisms-Methodology-Drag Delivery; Marcel Dekker, NY: 1, 1989). This method is especially useful with many therapeutic proteins that are susceptible to gastrointestinal degradation and exhibit poor gastrointestinal uptake. When compared to injections, TDD eliminates the associate pain and the possibility of infection.
- Topical delivery systems have been designed largely for transdermal administration of low molecular weight drags, by definition they are capable of percutaneous delivery. They can be readily adapted to administration of the therapeutic compounds of the invention by appropriate selection of the rate-controlling microporous membrane. Topical application can also be achieved by applying the compound of interest, in a cream, lotion, ointment, or oil based carrier, directly to the skin. Typically, the concentration of therapeutic compound in a cream, lotion or oil is 1-2%.
- the therapeutic compound is formulated into a solution, suspension, aerosol or particulate dispersion appropriate for application to the pulmonary system.
- the therapeutic agent may be inhaled via nebulizer, inhalation capsule, inhalation aerosol, nasal solution, intratracheal as a solution via syringe, or endotracheal tube as an aerosol or via as a nebulizer solution.
- Aerosols are prepared using an aqueous aerosol, liposomal preparation or solid particles containing the compound.
- a nonaqueous (e.g. fluorocarbon propellant) suspension could be used.
- Sonic nebulizers are prefened because they minimize exposing the therapeutic compound to shear, which can result in degradation of the compound.
- the prototype formulation for nasal solutions will contain the vitamin B ⁇ 2 conjugate dissolved in a suitable aqueous or non- aqueous solvent such as propylene glycol, an antioxidant and aromatic oils as flavoring agents.
- a suitable aqueous or non- aqueous solvent such as propylene glycol, an antioxidant and aromatic oils as flavoring agents.
- the formulation may also contain suitable propellant(s).
- the therapeutic compound is formulated into solutions, suspensions and ointments appropriate for use in the eye.
- opthalmic formulations see Mitra (ed.), Ophthalmic Drag Delivery Systems, Marcel Dekker, Inc., New York, New York (1993), and also Havener, W. H., Ocular Pharmacology, C.V. Mosby Co., St. Louis (1983).
- Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Patent No. 4,938,949.
- the amount of the substance required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
- a suitable dose for nuclear medicine (using a radioactive imaging agent) will be in the range of from about 0.1 ⁇ g/patient to about 1000 ⁇ g/patient, from about 0.5 to about 500 ⁇ g/patient, or from 1 ⁇ g/patient to about 100 ⁇ g/patient.
- a suitable dose for imaging medicine (using a paramagnetic imaging agent) will be in the range of from about 0.1 mg/patient to about 100 mg/patient, from about 0.5 to about 50 mg/patient, or from 1 mg/patient to about 10 mg/patient.
- a suitable dose will be in the range of from about 0.05 picograms/kilogram to about 100 mg/kg, from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg kg/day.
- the substance is conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
- the substance should be administered to achieve peak plasma concentrations of from about 0.05 to about 100 ⁇ M, preferably, about 1 to 50 ⁇ M, most preferably, about 2 to about 30 ⁇ M. This may be achieved, for example, by the intravenous injection of a 0.005 to 10%> solution of the substance, optionally in saline, or orally administered as a bolus containing about 0.5-250 mg of the substance. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the substance.
- the substance may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
- the cobalamin conjugates may be administered orally in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
- a pharmaceutically acceptable vehicle such as an inert diluent or an edible carrier.
- the substance may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
- Such compositions and preparations should contain at least 0.1% of the substance.
- the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of substance in such therapeutically useful compositions is such that an effective dosage level will be obtained.
- Tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fractose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
- a liquid carrier such as a vegetable oil or a polyethylene glycol.
- any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
- the substance may be incorporated into sustained-release preparations and devices.
- Sublingual tablets are designed to dissolve very rapidly. Examples of such formulations include ergotamine tartrate, isosorbide dinitrate, isoproterenol HCl.
- the formulation of these tablets contain, in addition to the drag, a limited number of soluble excipients, usually lactose and powdered sucrose, but occasionally dextrose and mannitol.
- the process of making sublingual tablets involves moistening the blended powder components with an alcohol-water solvent system containing approximately 60% alcohol and 40% water.
- the prototype formulation for sublingual tablets may contain a binder such as povidone or HPMC, diluents such as lactose, mannitol, starch or cellulose, a disintegrant such as pregelatinized or modified starch, lubricants such as magnesium stearate, stearic acid or hydrogenated vegetable oil, a sweetener such as saccharin or sucrose and suitable flavoring and coloring agents.
- a binder such as povidone or HPMC
- diluents such as lactose, mannitol, starch or cellulose
- a disintegrant such as pregelatinized or modified starch
- lubricants such as magnesium stearate, stearic acid or hydrogenated vegetable oil
- a sweetener such as saccharin or sucrose and suitable flavoring and coloring agents.
- the TC binding carrier and the neutron capture agent be administered parenterally, not orally, to increase bioavailability and delivery to proliferative tissue.
- oral administration of the TC- or IF-binding carrier/neutron capture agent provides insufficient bioavailability to treat proliferative disorders. It is important, and perhaps essential, to administer the neutron capture agent in a manner that does not rely on the ileal intrinsic factor receptor binding absorption pathway of the active agent.
- the TC- or IF-binding carrier and the neutron capture agent can be administered in the course of surgical or medical treatment of the afflicted site.
- the TC- or IF-binding carrier and neutron capture agent can be positioned directly at the site of proliferation during the course of surgery either by painting the formulation onto the surface of the afflicted area (with or without a carrier matrix) or by depositing a bolus of material in a suitable matrix that is released into the afflicted area over time.
- the TC- or IF-binding carrier and the neutron capture agent are administered directly into the proliferative mass via injection or catheter.
- the TC-binding or IF- binding carrier and neutron capture agent can be effectively administered and neutron capture therapy initiated prior to surgical resection to shrink the tumor and thus decrease the possibility of the uncontrollable spread of diseased cells during the resection.
- the agent and carrier are administered in a slow release formulation such as an implant, bolus, microparticle, microsphere, nanoparticle or nanosphere.
- sustained release compositions include semipermeable polymer matrices in the form of shaped articles, e.g., films, microcapsules or microspheres.
- Sustained release matrices include, for example, polylactides (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and ⁇ -ethyl-L-glutamate (Sidman et al, Biopolymers 22:547-556, 1983), or poly-D-(-)-3-hydroxybutyric acid (EP 133,988).
- Sustained release compositions also include one or more liposomally entrapped compounds of formula I.
- Such compositions are prepared by methods known per se, e.g., as taught by Epstein et al. Proc. Nail. Acad. Sci. USA 82:3688-3692, 1985.
- the liposomes are of the small (200-800 A) unilamellar type in which the lipid content is greater than about 30 moi % cholesterol, the selected proportion being adjusted for the optimal therapy.
- implants are "matrix" type, and comprise an active compound dispersed in a matrix of a carrier material.
- the carrier material may be either porous or non-porous, solid or semi-solid, and permeable or impermeable to the active compound.
- Matrix devices are typically biodegradable, i.e., they slowly erode after administration. Alternatively, matrix devices may be nondegradable, and rely on diffusion of the active compound through the walls or pores of the matrix. Matrix devices are preferred for the applications contemplated herein.
- the invention provides a surgical implant for localized delivery of an anti-proliferative agent comprising the cobalamin conjugate of the present invention, and a biodegradable binder.
- the implant preferably is capable of releasing and delivering the cobalamin conjugate to substantially all of an area of clear margin that results from a surgical resection, and is also preferably capable of releasing the cobalamin conjugate at a substantially constant rate.
- the invention provides a method of delivering a neutron capture agent to an area of clear margin following a surgical resection comprising (i) providing an implant comprising a TC- or IF-binding carrier linked to a neutron capture agent and a biodegradable binder; and (ii) placing the implant into a void created by surgical resection.
- the surgical implant can exhibit a variety of forms.
- the implant is a bolus, comprising a viscous and deformable material capable of being shaped and sized before or during implantation to complement a void created by a surgical resection, and sufficiently deformable upon implantation to contact substantially all of an area of clear margin.
- the surgical implant can also comprising a plurality of capsules that can be poured into the void created by a surgical resection. These capsules will contain the cobalamin conjugate and a suitable binder. Because they are flowable, they can be poured into the void created by a surgical lumpectomy, and thereby contact substantially all of the areas of clear margin.
- compositions for the implant are known and can be used in practicing the invention. Such compositions are described in, for example, Chasin et al., Biodegradable Polymers as Drag Delivery Systems, Marcel Dekker Inc., NY, ISBN 0- 8247-8344-1. Preferable compositions are pharmaceutically acceptable, biodegradable, and meet the particular release profile characteristics that are required to achieve the administration regime involved.
- the implant typically comprises a base composition that acts as a matrix to contain and hold the contents of the implant together.
- the base composition can, in rum, comprise one or more constituents.
- Examples of base compositions include polymers and copolymers of anhydrides, orthoester, lactic acid, glycolic acid, dioxonane, trimethylene carbonate, ⁇ -caprolactone, phosphazene and glyceryl monostearate.
- the base composition for the matrix comprises a polyanhydride, which can be synthesized via the dehydration of diacid molecules by melt condensation. Degradation times can be adjusted from days to years according to the hydrophobicity of the monomer selected. The materials degrade primarily by surface erosion and possess excellent in vivo compatibility.
- the polyanhydride is formed from sebasic acid and hexadecandioic acid (poly(SA-HDA anhydride). Wafer- like implants using this base composition have been approved for use in brain cancer, as
- the implant optionally can comprise erosion and biodegradation enhancers that facilitate the erosion of the matrix, the dissolution of the core composition, or the uptake of the core composition via metabolic processes.
- erosion and biodegradation enhancers are biodegradable in biological fluids, and biocompatible.
- Hydrophilic constituents are typical, because they are capable of enhancing the erosion of the implant in the presence of biological fluids.
- K. Juni et al, Chem. Pha ⁇ n. Bull., 33, 1609 (1985) disclose that the release rate of bleomycin from polylactic acid microspheres is greatly enhanced by incorporating fatty acid esters into the microspheres.
- Other exemplary hydrophilic constituents are described, for example, in Wade & Weller,
- Surfactants further enhance the erosion of the matrix and the release of the drug.
- Surfactants are generally capable of increasing the wettability and the solubility of the base composition in biological fluids, and thereby causing the disintegration and erosion of the implant.
- Surfactants can also help to break down the core composition matrix when, for example, the method of forming the dosage form has reduced the solubility of any of the constituents.
- Surfactants can also improve the uptake of the dosage fonns into the bloodstream.
- Suitable surfactants include, for example, glyceryl based surfactants such as glyceryl monooleate and glyceryl monolaurate, poloxamers such as Pluronic F127, and polysorbates such as polyoxyethylene sorbitan monooleate (“Tween 80").
- the implant could also include components that retard the rate at which the implant erodes or biodegrades (erosion and/or biodegradation retardants).
- Hydrophobic constituents are a particularly suitable class of components for retarding the rate at which the outer layer biodegrades. Suitable hydrophobic constituents are described, for example, in the Handbook of Pharmaceutical Excipients, the disclosure from which being hereby incorporated by reference. Exemplary hydrophobic constituents include peanut oil, olive oil and castor oil.
- the most desirable base compositions generally release the drag substantially continuously, and biodegrade completely shortly after substantially all of the drug has been effectively released.
- the amount of drag included in the dosage forms is determined by the total amount of the drag to be administered, and the rate at which the drag is to be delivered. The total amount of the drug to be delivered is determined according to clinical requirements, and in keeping with the considerations that typically inform drag dosage determinations in other contexts.
- the surgical implant also can contain one or more other drags having therapeutic efficacy in the intended applications, such as an antibiotic, an analgesic or an anesthetic.
- the TC- or IF-binding carrier and neutron capture agent is optionally administered in a controlled release formulation, which can be a degradable or nondegradable polymer, hydrogel, organogel, or other physical construct that modifies the bioabsorption, half life or biodegradation of the TC- or IF-binding carrier/neutron capture agent.
- the controlled release formulation can be a material that is painted or otherwise applied onto the afflicted site, either internally or externally.
- the invention provides a biodegradable bolus or implant that is inserted into the pocket created by surgical resection of a tumor, or directly into the tumor itself.
- the controlled release formulation can be applied to a psoriatic lesion, eczema, atopic dermatitis, lichen planus, wart, pemphigus vulgaris, actinic keratosis, basal cell carcinoma or squamous cell carcinoma.
- the controlled release formulation can likewise be applied to a blood vessel to treat or prevent restenosis, retinopathies or atherosclerosis.
- the controlled release formulation with appropriated selected neutron capture agent can be used to coat a transplanted organ or tissue to prevent rejection. It can alternatively be implanted or otherwise applied near the site of rheumatoid arthritis.
- biodegradable polymers have developed rapidly since the synthesis and biodegradability of polylactic acid was first reported in 1966 by Kulkarni et al. "Polylactic acid for surgical implants," Arch. Surg., 93, 839.
- polymers are now known to biodegrade, such as polyanhydrides and polyorthoesters, which take advantage of labile backbone linkages (see: Domb et al. Macromolecules, 22, 3200, 1989; and Heller et al. Biodegradable Polymers as Drag Delivery Systems, Dekker, NY: 1990).
- polymers which degrade into naturally occurring materials have also been described, such as crosslinking gelatin, hyaluronic acid (della Valle et al. U.S.
- Patent No. 4,987,744 and U.S. Patent No. 4,957,744) and polyaminoacids (Miyake et al., 1974), which spurred the usage of polyesters by Holland et al. Controlled Release, 4, 155, 1986 and alph-hydroxy acids (i.e. lactic acid and glycolic acid), which remain the most widely used biodegradable materials for applications ranging from closure devices (sutures and staples) to drug delivery systems (Smith et al. U.S. Patent No. 4,741,337; Spilizeqski et al. J. Control. ReL, 2, 197, 1985).
- These polymers can be tailored to degrade at a desired rate and with a desired kinetics by selecting the appropriate monomers, method of preparation and molecular weight. Differences in crystallinity of the monomer can alter the polymeric degradation rate. Due to the relatively hydrophobic nature of most polymers, actual mass loss can begin with the oligomeric fragments that are small enough to be water soluble; hence, even the initial molecular weight can influence the degradation rate.
- Hydrogels can be used in controlled release formulations.
- Such polymers are formed from macromers with a polymerizable, non-degradable, region that is separated by at least one degradable region.
- the water soluble, non-degradable, region can form the central core of the macromer and have at least two degradable regions which are attached to the core, such that upon degradation, the non-degradable regions (in particular a polymerized gel) are separated.
- the macromers are PEG-oligoglycolyl-acrylates, with the appropriate end caps to permit rapid polymerization and gelation.
- Acrylates can be polymerized readily by several initiating systems such as eosin dye, ultraviolet or visible light.
- the polyethyleneglycol (PEG) is highly hydrophilic and biocompatible.
- the oligoglycolic acid is a poly(a-hydroxy acid) which can be readily degraded by hydrolysis of the ester linkage into glycolic acid, a nontoxic metabolite.
- Other chain extensions include polylactic acid, polycaprolactone, polyorthoesters, polyanhydrides and polypeptides.
- This entire network can be gelled into a biodegradable network that can be used to entrap and homogeneously disperse water-soluble drugs for delivery at a controlled rate. Further, the gel can entrap particulate suspensions of water-insoluble drags.
- U.S. Patent No. 4,352,883 to Lim et al. entitled “Encapsulation of Biological Material” discloses the encapsulation of proteins within a membrane by suspending the protein in an aqueous medium containing a water-soluble gum that can be reversibly gelled to form the suspension into droplets. These droplets can be gelled further into discrete, shape-retaining, water insoluble temporary capsules with the aid of a solution of multivalent cations.
- the temporary capsules then can be further wrapped by an ionically cross-linking surface layer to form a semipermeable membrane around the capsules that is permeable to small molecules but impermeable to larger molecules.
- Microencapsulations of glycoproteins have also been well described.
- U.S. Patent No. 4,324,683 to Lim et al. entitled "Encapsulation of Labile Biological Material” encapsulates a glycoprotein by a two-step interfacial polymerization process to form capsules with well-controlled porosity. The microcapsules serve to protect the active substances from attack by microorganisms and from any immunological response.
- U.S. Patent No. 5,718,921 to Mathiowitz et al. (Microspheres Comprising Polymer and Drag Dispersed There Within) discloses a method to encapsulate relatively temperature-labile drags into a microsphere.
- the permeability of both the liposome and the sunounding matrix is directly proportional to the liposome integrity
- the permeability of the liposome can be engineered by modifying the composition and the method for making the liposome to produce liposome that are sensitive to specific stimuli such as temperature, pH or light.
- the liposome can be destabilized and broken down over a period of time.
- Other systems have been developed, e.g. U.S. Patent No.
- Nanoparticles are especially useful in the delivery of drags parenterally or intravenously such that the delivery device is small with a long circulating half-life.
- a number of injectable drag delivery systems have been investigated, including microcapsules, microparticles, liposomes and emulsions.
- the major obstacle for these delivery systems is the rapid clearance of the materials from the blood stream by the macrophages of the reticuloendothelial system (RES).
- RES reticuloendothelial system
- polystyrene particles as small as sixty nanometers in diameter are cleared from the blood within two to three minutes.
- Liposomal drag delivery systems have also been extensively studied for this application because they were expected to freely circulate in the blood. Coating of the liposomes with poly(ethylene glycol) (PEG) increased the half-life of the carriers due to
- U.S. Patents that describe controlled release formulations are: U.S. Patent No. 5,356,630 to Laurencin et al. (Delivery System for Controlled Release of Bioactive Factors); ; U.S. Patent No. 5,797,898 to Santini, Jr. et al. (Microchip Drug Delivery Devices); U.S. Patent No. 5,874,064 to Edwards et al. (Aerodynamically Light
- Chemotherapeutic Agents for Treating Solid Tumors U.S. Patent No. 5,837,752 Semi- Interpenetrating Polymer Networks; U.S. Patent No. 5,814,599 Transdermal Delivery Of Encapsulated Drags; U.S. Patent No. 5,804,178 Implantation Of Cell-Matrix Structure Adjacent Mesentery, Omentum Or Peritoneum Tissue; U.S. Patent No. 5,797,898 Microchip Drag Delivery Devices; U.S. Patent No. 5,770,417 Three-Dimensional Fibrous Scaffold Containing Attached Cells For Producing Vascularized Tissue hi Vivo; U.S. Patent No.
- Patent No. 5,122,367 Polyanhydride bioerodible controlled release implants for administration of stabilized growth hormone U.S. Patent No. 5,100,668 Controlled release systems containing heparin and growth factors
- U.S. Patent No. 5,019,379 Unsaturated polyanhydrides U.S. Patent No. 5,010,167 Poly(amide-and imide-co-anhydride) for biological application
- U.S. Patent No. 4,948,587 Ultrasound enhancement of transbuccal drag delivery
- U.S. Patent No. 4,946,929 Bioerodible articles useful as implants and prostheses having predictable degradation rates U.S. Patent No. 4,933,431 One step preparation of poly(amide- anhydride);
- the di-carborane required a longer gradient using the same mobile phases; 5% B to 65% B over 25 minutes and held at 65% B for 15 minutes before returning to initial conditions.
- the separations were monitored by UV absorption at 214 NM.
- the flow was 1.0 mL/minute and was split post- column allowing ⁇ 10 ⁇ to flow into the mass spectrometer.
- Mass spectral data was collected using electrospray ionization in positive mode over a mass range of 300 to 2300 AMU at a dwell time of 0.3 ms/0.1 AMU.
- Synthetic samples were prepared at 5 or 10 mg/mL in pump A mobile phase and an aliquot injected onto the HPLC (1-5 ⁇ L). Retention times of the mono- and di-carborane products were determined to be 13.3 minutes and 16.2 minutes respectively.
- Purification of the b and d mono-carborane products was achieved by collecting fractions at the elution times for several injections. The collected fractions were combined and dried to a powder. A portion of the purified product was dissolved in methanol:H2 ⁇ (1:1) and reanalyzed by HPLC-MS to ascertain the purity.
- o-Carborane, butyllithium (1.6 M solution in hexanes) and putrescine were purchased from Aldrich Chemical Company (Milwaukee, WI).
- the water-soluble carbodiimide l-ethyl-3(3'-dimethylaminopropyl) carbodiimide and 1-hydroxybenzo- triazole were from Sigma (St. Louis, MO).
- Thin layer chromatography (TLC) silica gel plates were obtained from Eastman Kodak Company.
- the cyanocobalamin-b, d, and e monocarboxylic acids and the b, d-dicarboxylic acid were prepared as described before (see U.S. Patent Number 5,739,313, and D. L. Anton, et al., J. Am. Chem. Soc, 1980, 102, 2212-2219), and were provided by Professor Kahl of the Department of Medicinal Chemistry at the University of California, San Francisco.
- o-Carborane carboxylic acid (2.0 g, 10.6 mmol), dried over P2O5, was dissolved in 30 mL thionyl chloride and heated under reflux for 3 hours. The solution was cooled to room temperature, evaporated to dryness and dried over P 2 ⁇ 5 (2.05 g, 9.9 mmol, 93%>) to provide (3), which was used without further purification.
- Cyano cobalamin 500 mg was dissolved in 100 mL deoxygenated water containing 10 mg C0CI 2 , and reduced with sodium borohydride to give the corresponding Co (I) compound. After 30 minutes, 3-chloropropyl amine hydrochloride (130 mg) dissolved in 5 mL deoxygenated ethanol was added. After one hour, at room temperature, the mixture was desalted via phenol extraction. The ammopropylcarbolamine was back extracted into water after the addition of 1 volume of acetone and 3 volumes of ether. The aqueous solution was concentrated and the desired 6-(3-aminoprop-l-yl)cobalamin crystallized from aqueous acetone (yield 510 mg).
- 6-(3-aminoprop-l-yl)cobalamin 300 mg
- hydroxybenzotriazole 270 mg
- 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide 382 mg
- o-carborane monocarboxylic acid dissolved in water (50 mL) and acetone (20 mL) and allowed to react at room temperature for 3 hours.
- the reaction mixture was concentrated to remove acetone and desalted via phenol extraction.
- the concentrated aqueous solution was crystallized from aqueous acetone to give the title compound.
- DAPC DTPA-aminopropylcobalamin
- the analogs competitively blocked Co-57-cyanocobalamin from binding to the transcobalamin proteins. Therefore, the cpm of the modified UBBC assay was significantly lower than that of the clinical runs.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2002055530A3 (fr) * | 2000-10-25 | 2003-01-23 | Mayo Foundation For Medical Education And Research | Conjugues de fixation au recepteur de transcobalamine utiles pour le traitement d'une proliferation cellulaire anormale |
WO2004056840A1 (fr) * | 2002-12-20 | 2004-07-08 | Astrazeneca Ab | Nouveaux composes utiles dans la therapie de capture de neutrons par le bore |
EP1435973A1 (fr) * | 2001-09-28 | 2004-07-14 | Mayo Foundation For Medical Education And Research | Administration combinee de proteines de transport et de cobalamine conjuguee pour delivrance d'agents |
US7141233B2 (en) | 1995-11-13 | 2006-11-28 | Mayo Foundation For Medical Education And Research | Radionuclide labeling of vitamin B12 and coenzymes thereof |
US7179445B2 (en) | 1999-10-15 | 2007-02-20 | Mayo Foundation For Medical Education And Research | Cobalamin conjugates useful as imaging and therapeutic agents |
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US5877165A (en) * | 1995-11-02 | 1999-03-02 | Brookhaven Science Associates | Boronated porhyrins and methods for their use |
WO2000045857A2 (fr) * | 1999-02-01 | 2000-08-10 | Schering Aktiengesellschaft | Macrocycles metalliques pour formes de radiotherapie en deux etapes |
WO2000062808A2 (fr) * | 1999-04-16 | 2000-10-26 | Mayo Foundation For Medical Education And Research | Conjugues de cobalamine utilises comme agents antitumoraux |
-
2001
- 2001-10-25 AU AU2002239719A patent/AU2002239719A1/en not_active Abandoned
- 2001-10-25 WO PCT/US2001/050782 patent/WO2002042318A2/fr active Application Filing
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US5877165A (en) * | 1995-11-02 | 1999-03-02 | Brookhaven Science Associates | Boronated porhyrins and methods for their use |
WO2000045857A2 (fr) * | 1999-02-01 | 2000-08-10 | Schering Aktiengesellschaft | Macrocycles metalliques pour formes de radiotherapie en deux etapes |
WO2000062808A2 (fr) * | 1999-04-16 | 2000-10-26 | Mayo Foundation For Medical Education And Research | Conjugues de cobalamine utilises comme agents antitumoraux |
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COLLINS D A ET AL: "TRANSCOBALAMIN II RECEPTOR IMAGING VIA RADIOLABELED DIETHYLENE-TRIAMINEPENTAACETATE COBALAMIN ANALOGS" JOURNAL OF NUCLEAR MEDICINE, SOCIETY OF NUCLEAR MEDICINE. NEW YORK, US, vol. 38, no. 5, May 1997 (1997-05), pages 717-723, XP002940342 ISSN: 0161-5505 * |
HOGENKAMP H P C ET AL: "Synthesis and characterization of nido-carborane-cobalamin conjugates" NUCLEAR MEDICINE AND BIOLOGY, ELSEVIER SCIENCE PUBLISHERS, NEW YORK, NY, US, vol. 27, no. 1, January 2000 (2000-01), pages 89-92, XP004188293 ISSN: 0969-8051 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7141233B2 (en) | 1995-11-13 | 2006-11-28 | Mayo Foundation For Medical Education And Research | Radionuclide labeling of vitamin B12 and coenzymes thereof |
US7179445B2 (en) | 1999-10-15 | 2007-02-20 | Mayo Foundation For Medical Education And Research | Cobalamin conjugates useful as imaging and therapeutic agents |
WO2002055530A3 (fr) * | 2000-10-25 | 2003-01-23 | Mayo Foundation For Medical Education And Research | Conjugues de fixation au recepteur de transcobalamine utiles pour le traitement d'une proliferation cellulaire anormale |
EP1435973A1 (fr) * | 2001-09-28 | 2004-07-14 | Mayo Foundation For Medical Education And Research | Administration combinee de proteines de transport et de cobalamine conjuguee pour delivrance d'agents |
EP1435973A4 (fr) * | 2001-09-28 | 2007-05-02 | Mayo Foundation | Administration combinee de proteines de transport et de cobalamine conjuguee pour delivrance d'agents |
WO2004056840A1 (fr) * | 2002-12-20 | 2004-07-08 | Astrazeneca Ab | Nouveaux composes utiles dans la therapie de capture de neutrons par le bore |
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WO2002042318A3 (fr) | 2002-10-10 |
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