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  Anthracycline derivativesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Radionuclide Or Intended Radionuclide Containing; Adjuvant Or Carrier Compositions; Intermediate Or Preparatory Compositions, Attached To Lymphokine, Cytokine, Or Other Secreted Growth Regulatory Factor, Differentiation Factor, Or Intercellular Mediator Specific For A Hematopoietic Cell (e.g., Interferon, Interleukin, Macrophage Factor, Colony Stimulating Factor, Erythropoietin); Derivative ThereofThe Patent Description & Claims data below is from USPTO Patent Application 20070258890. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention relates to new anthracycline derivatives and their use in cancer therapy and cancer diagnosis. BACKGROUND [0002] Doxorubicin (C.sub.27H.sub.29NO.sub.11; MW: 543.53), abbreviated as DOX, also known among other names as adriamycin, or adriablastine is an antibiotic and antineoplastic agent of the anthracycline family (see structure below). DOX was originally isolated from the aquatic bacterium Streptomyces peucetius var. coesius and since the early 1970s, anthracyclines, in particular doxorubicin and daunorubicin, and alkylating agents (cyclophosphamide, melphalan, etc.) are the most versatile and most frequently used chemotherapeutic agents in the clinic today [1]. Anthracyclines are amphipathic molecules consisting of a hydrophobic aglycone heterocycle with a quinone-hydrochinone functional group and a hydrophilic aminosugar moiety [2,3]. Chemical Structure of Daunorubicin and Doxorubicin [0003] Doxorubicin is used extensively in the treatment of bone and soft tissue sarcomas and carcinomas of the lung, breast, thyroid, bladder, ovary, testis, head, and neck [1,4]. Doxorubicin is also used against leukemias and lymphomas but daunorubicin is the primarily treatment against acute leukemias. The overall response rates for doxorubicin is 45% for thyroid cancer, 41% for lymphomas, 33% for bladder carcinomas, 26% for sarcomas, 25% for ovarian carcinomas, 24% for leukemias [5]. [0004] Doxorubicin has multiple mechanisms of action but the main anti-tumour activity of doxorubicin and other anthracyclines stems from their ability to intercalate with DNA resulting in blockade of DNA-, RNA- and protein-synthesis. Anthracyclines also inhibit topoisomerase II and impair DNA repair [1,5]. Because of their quinone-hydroquinone functional group, anthracyclines are thought to be involved in the generation of free radicals leading to DNA damage [2]. Anthracyclines bind specifically to cardiolipin, a phospholipid found in high concentrations in cardiac mitochondria and membranes of malignant cells, which may explain cardiotoxic side effects of doxorubicin [1]. Anthracyclines have narrow therapeutic indices, i.e. the administered dose has to be within narrow limits, since the drug has no effect if the dosage is too small and severe side effects can result if the dosage is too large. The acute dose-limiting toxicity of doxorubicin is bone-marrow suppression, leukopenia, and stomatitis occurring in 80% of treated patients. Other side effects include alopecia (100%), nausea and vomiting (20-55%), cardiac toxicity, i.e. supraventricular arrhythmias, heart block, ventricular tachycardia and even congestive heart failure in 1-10% of patients. [0005] Previously, anthracycline derivatives have been disclosed by e.g. Pribe (2003) Chemico-Biological Interactions 145:349-358, U.S. Pat. No. 4,948,880, U.S. Pat. No. 6,673,907, and WO00/56267. These derivatives have cytotoxic effect in cancer treatment. [0006] Radionuclide therapy has a relatively small but important role in cancer therapy and is currently gaining increasing attention. Radionuclide therapy implements nuclear radiation to eradicate malignant cells. The radiation can be generated by stable nuclides e.g. .sup.10B and .sup.157Gd following neutron activation or by radioactive nuclides. The most commonly used therapeutic radionuclide especially against thyroid cancer is the intermediate-range (800 .mu.m) .beta.-emitter, .sup.131I, but administration of .sup.131I causes considerable radiation damage in healthy tissue [6]. However, due to these side effects the therapeutic potential of short-range, low-energy Auger electron emitters, such as .sup.125I, is getting progressively wider recognition. In order for it to be effective in anticancer treatment, .sup.125I has to be delivered directly and selectively into tumour cell nuclei since .sup.125I is not toxic unless it is within a few nanometres from the DNA [7]. .sup.125I therapy thus requires a method of specific nuclear delivery, which has previously been achieved using .sup.125I-labelled nucleosides, oligonucleotides, steroid hormones and growth factors but a need for improvement has been recognized [7]. [0007] Murali D. and DeJesus. O, Bioorganic & Medicinal Chemistry letters 8 (1998) 3419-3422, describes a radiolabelled daunorubicin derivative having improved cytotoxic properties compared to doxorubicin. No results are presented in the article, and no continuation of this work has been published. [0008] Targeted drug delivery via liposomes minimizes the dose-limiting side effects of conventional cancer chemotherapy such as bone marrow suppression, mucositis, cardiac-, neuro-, and nephro-toxicity [1] by encapsulating the cytotoxic agent into membrane bound vesicles (liposomes) and coupling tumour-specific antibodies to the liposome membrane (targeted liposomes). Targeted liposomes in the blood are actively and selectively taken up by tumour cells overexpressing the targeted surface marker. However, despite some progress, this strategy has so far not resulted in a major improvement in chemotherapy [8]. [0009] Thus, there is a great need for more potent therapeutic agents and treatment strategies. SUMMARY OF THE INVENTION [0010] The present invention relates to diagnostic and therapeutic agents possessing DNA-intercalating properties and to which nuclides can be coupled. The present invention further relates to drug delivery systems for these diagnostic or therapeutic agents and therapeutic and diagnostic methods using said agents or drug delivery systems. The present invention is intended for cancer diagnostics and therapy. The aim of the present invention is to deliver a nuclide specifically into tumour cell nuclei and thus to combine the benefits of radionuclide therapy, chemotherapy, and targeted liposomal drug delivery in a single two-step targeting approach that minimizes cytotoxic side effects in healthy tissue. Thus, the present invention provides a new therapeutic strategy with novel drugs, which are potentially more potent than previously known chemotherapeutic drugs. [0011] Anthracyclines are potent anticancer drugs by themselves. In the present application, the inventors have synthesized amino-benzyl derivatives of daunorubicin (drug precursors), which have similar cytotoxicity profiles as the commercially successful anthracyclines doxorubicin and daunorubicin. When the present inventors iodinated the drug precursors with .sup.125I, they obtained radiotherapeutic agents being more effective against cultured tumor cells, To protect healthy tissue and to deliver the radionuclide selectively into malignant cancer cells, the .sup.125I-coupled daunorubicin derivatives can be encapsulated into targeted liposomes, which serve as specific drug delivery vehicles for tumor cells. [0012] The results of the experiments described herein confirm that the therapeutic agents according to the present invention can successfully be encapsulated into targeted liposomes, and that the drugs are well retained under the experimental preparation and assay conditions. After incubation with tumour cells, the above-mentioned agents reach and bind to the cell nucleus with a similar affinity as that of doxorubicin. When bound to DNA, the radiotherapeutic agent causes DNA fragmentation, leading to a tumour cell growth inhibition of several orders of magnitudes higher than that caused by doxorubicin and daunorubicin, two of the most successful chemotherapeutic agents in the clinic today. [0013] None of the drugs precursors or radiotherapeutic drugs according to the present invention have previously been described in the prior art. [0014] According to one aspect of the invention, there is provided anthracycline derivatives that serve as precursor molecules for the radiotherapeutic agents, and which will henceforth be referred to as drug precursors. The drug precursors intercalate with DNA and possess cytostatic properties. The drug precursors can thus be used in cell- or tissue-targeted cancer therapy by themselves. The anthracycline derivatives (drug precursors) are defined in claims 1-3. [0015] According to a further aspect of the invention, there is provided radiotherapeutic drugs that can be used in cell- or tissue-targeted radiotherapy. The radiotherapeutic agents are generated from their precursors by linking the drug precursors to a nuclide or a chemical group containing a nuclide. Such a nuclide may be a radioactive nuclide, a stable nuclide, or a nuclide that can be activated by exposure to neutrons or photons, e.g. .sup.10B (as part of a boron-rich cage-compound derivative such as the closo-carboranes o-, m- or p-C.sub.2H.sub.12B.sub.10) and will henceforth be referred to as nuclides. The radiotherapeutic drugs are defined in claims 4-5. [0016] According to a still further aspect of the invention, the radiotherapeutic drug may also be used as an imaging tool for cancer diagnostics. The use as an imaging tool is defined in claim 6. [0017] According to a still further aspect of the invention, the drug precursor or radiotherapy drug may also be used as a DNA targeting agent, i.e. as a DNA-interacting agent as defined in claim 7. [0018] According to a still further aspect of the invention, there is also provided drug delivery systems. Said system preferably comprises a carrier capable of encapsulating the drug precursors or radiotherapeutic drugs (possessing DNA-interacting properties) and guide drugs specifically or preferentially to the targeted cell population. Consequently, cell- and tissue-damaging effects will affect preferentially targeted cells and tissues. Such drug delivery systems may involve single- or multiple-step targeting strategies. The DNA-intercalating properties of the drug precursors are the basis of the DNA-targeting step that directs their cytotoxic effects to the nucleus or, when the nuclide is coupled to the drug precursor, localizes the radioactivity emitted from the nuclide to the cell nucleus. This targeting step, which will henceforth be referred to as the DNA-targeting step, thus dramatically increases the therapeutic effect of the radiotherapeutic drugs and reduces damage to healthy cells and tissues. [0019] To differentiate between malignant and healthy tissue, the radiotherapeutic drugs are directed towards cancer cells or tissues using a drug delivery system that exhibits a tumour-cell specific targeting agent at its surface as a cell-targeting step in a two-step targeting strategy, which will henceforth be referred to as the cell-targeting step. The drug carrier is capable of enclosing or binding the radiotherapy drug and directing its transport after systemic administration to and preferably across membranes of targeted cells. The cytotoxic and/or radiotoxic effect of the radiotherapeutic drugs will consequently be localized to the targeted cell population. The drug delivery system is defined in claims 8-13. [0020] According to a still farther aspect of the invention, there is also provided a method of diagnosing or treating cancer, comprising administering said drug delivery systems including the precursor drug or radiotherapeutic drug to a patient in need thereof. In addition to its use as a treatment against solid tumours, the invention is also envisioned as a treatment against metastasizing tumour cells in systemic circulation after removal of the primary tumour. The treatment could be particularly beneficial against disseminated breast cancer, but also against disseminated ovarian, prostate and colorectal cancers. [0021] Said therapeutic methods may also be used in combination with subsequent tumour radiation when the location of the tumour is known. Local radiotherapy can be achieved by using stable nuclides and activation by external irradiation with neutrons or photons. Continue reading... Full patent description for Anthracycline derivatives Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Anthracycline derivatives patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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