Doxorubicin (C27H29NO11; 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

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].
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.
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.
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. 10B and 157Gd following neutron activation or by radioactive nuclides. The most commonly used therapeutic radionuclide especially against thyroid cancer is the intermediate-range (800 μm) β-emitter, 131I, but administration of 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 125I, is getting progressively wider recognition. In order for it to be effective in anticancer treatment, 125I has to be delivered directly and selectively into tumour cell nuclei since 125I is not toxic unless it is within a few nanometers from the DNA [7]. 125I therapy thus requires a method of specific nuclear delivery, which has previously been achieved using 125I-labelled nucleosides, oligonucleotides, steroid hormones and growth factors but a need for improvement has been recognized [7].
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.
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]. Thus, there is a great need for more potent therapeutic agents and treatment strategies.