UC San Diego

Cancer is the second leading cause of death in the United States and remains a complex disease to treat. The conventional chemotherapies taken at the doses necessary to kill cancer cells often have unacceptable toxicities towards normal cells. Therefore, there is a critical need for therapeutics that are better at targeting cancer cells to minimize toxicity to normal cells.

One possible targeting strategy is to exploit the alterations in amino acid synthesis or salvage pathways displayed by cancer cells. Cancer cells that are auxotrophic for a particular amino acid can be targeted with amino acid deprivation with enzymes that convert the targeted amino acid to other harmless biomolecules. Unfortunately, most of the enzymes with potential for amino acid depletion therapy are derived from non-human sources which are highly immunogenic. Therefore, for non-human enzymes to have clinical efficacy, they must be delivered in a non-immunogenic manner.

Another possible targeting strategy is to exploit the enhanced permeability and retention (EPR) effect to target solid tumors. However, for therapeutics to exploit the EPR effects, they must be small enough (<100 nm) to penetrate the tumor vasculature and remain in circulation for sufficient time to accumulate in the tumor.

The scientific significance of the proposed research is the engineering of a novel nanoparticle-assisted delivery vehicle that (1) protects non-human enzymes from the immune systems to eliminate the problem of immunogenicity, (2) enhances the circulation half-life of the enzymes in order to exploit the EPR effect displayed in solid tumors, and (3) increase the accumulation of the enzymes at the targeted site through active targeting with ligands and ultrasound. All three goals are achieved without modifications to the enzymes, which usually reduces the activity of the enzymes.