UC San Diego

Cancer remains one of the most difficult diseases to treat. In the past half century, cancer treatment has heavily relied on small molecule drugs, which are very potent on killing cancer cells, but lacks the tumor specificity which brings high toxicity against normal cells. For this reason, the improvement and development of new therapeutics that target cancer cells specifically is critical so that toxicity can be minimized for normal cells.

One potential targeting strategy is to exploit the alterations in amino acid synthesis, or salvage pathways displayed by cancer cells. The goal is to target tumors that are sensitive to one of the conditionally essential or the nonessential amino acids. This allows the normal cells to remain unaffected because they have the ability to synthesize sufficient amounts of necessary amino acids to survive. Unfortunately, most enzymes with the potential for amino acid depletion therapy are derived from nonhuman sources, which makes them highly immunogenic. Therefore, for these enzymes to have clinical efficacy, they must be formulated to be delivered in a way that can avoid or delay the immune response. Arginine deiminase (ADI) is a great example of a nonhuman enzyme that depletes a semi-essential amino acid, arginine, in the human body. ADI has shown some potential in treating hepatocellular carcinoma, melanoma, and some mesotheliomas cancer patients.

The scientific significance of this dissertation is to engineer the recombinant native ADI, PEGylated ADI, and nanoparticle platform to encapsulate ADI so that it can be a better drug candidate compared to its native and PEGylated ADI by assessing their pharmacodynamics and pharmacokinetics properties. PEGylating ADI or other enzymes is the current standard formulation that delivers a nonhuman enzyme by creating a shielding layer around the molecule to delay its immune response. If the proposed silica coated liposome encapsulated ADI nanoparticle platform can be synthesized to avoid the immune response completely, it will out-compete the PEGylation strategy. Finally, the comparison between the different formulations will be tested in vitro and in vivo settings to prove this concept.