Doctor of Philosophy
Matthew C. T. Hartman
Cancer constitutes a terrible burden on modern society. In the United States there are an estimated 1,658,370 new cancer diagnoses resulting in 589,430 deaths in 2015 alone. An estimated 41,170 of these cases will be diagnosed right here in Virginia. With new cancer patients comes the expanding demand for new treatments. As we all know, many modern chemotherapeutics cause adverse reactions to patients. This is because the toxic nature of these therapies often affects normal tissue alongside the tumors that are infesting the body. Therefore, researching novel ways to make chemotherapeutics selective for cancer, while leaving healthy tissue unscathed, is of paramount importance. There are a few ways in which we have approached cancer-specific chemotherapeutics. Through the use of light controlled toxicity and drug release and the targeting of tumor phenotypes such as overexpressed proteins and the Warburg effect, we begin to tackle the problem of non-specificity of current chemotherapeutics.
Combretastatin A-4 (CA4) is highly potent anticancer drug that acts as an inhibitor of tubulin polymerization.[2, 3] The core of the CA4 structure contains a cis-stilbene, and it is known that the trans isomer is significantly less potent. We prepared an azobenzene analog of CA4 (Azo-CA4) that shows 13-35 fold enhancement in potency upon external irradiation. GI50 values in the light were in the mid nM range. Due to its ability to thermally revert to the less toxic trans form, Azo-CA4 also has the ability to automatically turn its activity off with time. Therefore, this work establishes a novel strategy for switchable potency for cancer treatment.
Doxorubicin (Adriamycin) is an anthracycline type of chemotherapeutic that intercalates double-stranded DNA. Although this drug has played a huge role in the treatment of cancer, its usefulness declines in cases of cancer recurrence because of the impact this drug has on the cardiovascular system. Therefore, we prepared this drug as a cell impermeable conjugate that gains penetrability through the use of external radiation.
Folate receptor alpha (FRα) is overexpressed in a variety of cancer cells and accepts folic acid as a natural ligand. Therefore, conjugation of drugs to folic acid introduces a promising way to bring these drugs to cancer cells with greater specificity. We took this concept one step further with the introduction of a photo-labile linker, connecting doxorubicin to folic acid, which offers dual-specificity through ligand targeting and light activation.
Finally, many cancer cells produce adenosine triphosphate, the energy currency of a cell, through an abnormal upregulation of glycolysis. This pathway results in a larger-than-normal production of lactic acid and lowers the pH of cancer cells through a phenomenon known as the Warburg Effect. We hypothesized that through the use of L-canavanine, an L-arginine analog, we could construct short peptides that would gain cell permeability in a low pH environment. Attaching a cargo to these peptides, such as doxorubicin will ultimately allow for targeting the low pH extracellular environment of cancer cells. Through the use of these strategies we have furthered the fight against cancer. Targeting cancer by taking advantage of its phenotypes or through the use of light is vital in reducing negative side-effects of current chemotherapeutics. The novel technologies offered above bring us a step closer to side-effect free treatment of cancer patients.
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