Doxorubicin is an anthracycline antibiotic used in cancer chemotherapy, which is also being evaluated as an antiviral agent. Doxorubicin is classified as an "anthracycline antibiotic" drug.
Two different mechanisms have been proposed to explain doxorubicin anticancer activity, in one it intercalates into the DNA and disrupts the topoisomerase-II DNA repair, leading to DNA-strand breaks at certain sites which are specific for doxorubicin; in the other mechanism, the antibiotic generates free radicals that damage cell membranes, DNA and proteins. Yet, the evidence supports the mechanism of poisoning the topoisomerase-II as the main anti-cancer mechanism for this drug. While therapeutically effective in a variety of tumor cells, doxorubicin is cardiotoxic and causes life-threatening hearth damage. Thus, to minimize this drug’s side-effects, it is usually administered as a conjugate, where the drug is covalently linked to another molecule that targets cancer cells. These various molecules include monoclonal antibodies, peptides, oligonucleotides and different natural and synthetic polymers.
Figure 1: Structures of doxorubicin (adriamycin). (Left) Chemical structure. (Right) 3D structure of the drug-DNA complex. Frederick et al. in 1990 solved the 3D structure for the drug-DNA complex between the drug and d(SGATCG).
In the case of mAbs, the drug can be conjugated to either the whole antibody or its Fab fragment that is specific for some tumor associated antigen and that upon binding to that antigen it is internalized in the cell. Once inside the cell, the conjugate’s linker is cleaved, depending on the linker, either enzymatically or by a change in pH in certain cell compartments, usually the endosome/lysosome, releasing the drug inside the cell. The number of drug molecules attached per antibody may be increase by using polymeric linkers or carriers, this way increasing the cytotoxic effects of the conjugate. Doxorubicin can be also conjugated to certain cyclic or linear peptides in order to enhance cellular uptake and cellular retention, lessening the efficient drug efflux pump of certain cancer cells. In this kind of conjugates, the peptide moiety in addition to acting as a targeting agent would also be a factor in the intracellular drug retention, depending on the time to be degraded intracellularly.
Doxorubicin can also be conjugated to another small molecule, like folic acid, to recognize and bind to folate receptor, which are over expressed in certain tumor cells. By using as linkers small polyethylene glycols, these conjugates can form micelles where the folic acid is exposed to the cell surface, whereas the drug is sequestered in the micelles’ interior. This way the delivery of drug per cell is significantly magnified. Doxorubicin can also be conjugated to small DNA or RNA fragments called aptamers; like antibodies, these oligonucleotides can be screen for their affinity with specific receptors and use them as the targeting moiety of the conjugate. Increased delivery of the drug to cells may be achieved by using a polysaccharide, such as dextran or pullulan, as a scaffold to which a ligand for a cell receptor and doxorubicin are linked covalently; a type of construct that increases the therapeutic benefits of the drug, while minimizing its side effects.