Doxorubicin, originally daunorubicin, is the result of a simultaneous discovery event in the 1950's between researchers in France and Italy. The molecule, a well-known anti-cancer drug used for a variety of indications ranging from acute lymphocytic leukemia to breast cancer, was approved for use in the United States in 1974. Doxorubicin inserts itself into the 'rungs' of the cell's ladder-like DNA. This ultimately causes DNA damage that if left unchecked, induces the cell death process called apoptosis. Despite the broad and promising applications of this drug, its use does have two major drawbacks. First, cancers can become resistant to doxorubicin, typically by reducing their uptake of the drug or by increasing its breakdown once it's inside the cell; this means the drug has less time to do its job. Second, doxorubicin can affect healthy tissue as well, as demonstrated by its commonly noted side effect of cardiotoxicity. Designing a formulation that allows a drug to be effective, while minimizing potential side effects, is a constant goal of pharmacologic research and one that nanoparticles have the potential to achieve.
Nanoparticles are typically 10nm-1mm in size, and can be made of natural materials like lipids or artificial polymers like polylactide-co-glycolide (PLGA). These encapsulate a drug to enhance specificity for the target tissue and cellular uptake. Recently, researchers from the KIIT School of Biotechnology in India have used nanoparticles to set the stage for a potentially new kind of doxorubicin treatment. In their March 2017 Scientific Reports article, Siddharth et al., encapsulated the drug in PLGA-PVA nanoparticles that were double-coated with dextran and chitosan. Dextran is a chain of multiple glucose molecules while chitosan is a chain of multiple glucosamine molecules. Both are biocompatible, further supporting their use in drug formulations. The double coating added to the encapsulation was shown to greatly enhance the activity of doxorubicin compared to standard (non-NP) treatment alone. Specifically, in cell viability assay using a breast cancer cell line, MCF-7, the NP encapsulated drug was found to be effective at a dose roughly one-tenth of that for the non-encapsulated drug, and a double coating with dextran and chitosan further halved the necessary effective dose compared to NP encapsulation alone. This means that in theory, one could administer markedly less of the drug and still have the same characteristic cancer inhibitory effect. The reduced dosage of drug in the body could ultimately translate into fewer cardiotoxic side effects as well. In a second experiment, it was shown that NP encapsulated doxorubicin also inhibited migration of MCF-7 cells, and double coating further enhanced this effect. Lastly, double coated NP's enhanced the uptake of the drug by cancer cells, which ultimately led in their death by inducing DNA damage.
The remarkable effects of nanoparticles and biocompatible coatings seen in a petri dish like those seen in Siddharth et al.'s study hold further promise under the controversial theory of enhanced permeability retention (EPR). Here, tumors generally grow with a poorly formed system of vasculature and lymphatics; when nanoparticles begin to aggregate in this tumor tissue via the circulatory system they are unable to be properly drained through the lymphatic system. The phenomenon would lead to a concentrated delivery of the drug, specifically to tumor tissue. Only further clinical research will reveal the potential in vivo efficacy of this revamped treatment, and the prospects it could hold for the nearly 300,00 new cases of breast cancer that occur each year in the United States alone.
Top image: A doxorubicin-DNA complex.
Image source: PDB entry 1D12- Frederick, C.A. et al. (1990). Structural comparison of anticancer drug-DNA complexes: Adriamycin and daunomycin