M. Marquez, L. Frolova, M. Tartis
New Mexico Institute of Mining and Technology,
Keywords: targeted drug delivery, ultrasound, lipid prodrug, enzymatic cleavage, microbubbles, liposomes
Summary:Due to the incidence and varieties of irresectable cancers, there is a need to restrict potent drug exposure to neoplastic cells and limit exposure to healthy cells. New agents that can aid diagnostics, monitor therapy, and carry drugs to a target are an unmet and urgent priority in the quest to find therapies that both prolong life and maintain quality of life. Microbubbles, which are diagnostic ultrasound contrast agents, have potential in this relatively new field of “theranostics” if they can carry an effective amount of drug. These microbubbles could be site-directed under specific ultrasound parameters, but are composed of a lipid monolayer, severely limiting the amount and type of drugs that can be incorporated. Our strategy is a self-assembly technique utilizing a newly synthesized lipid-like prodrug. Benefits of these novel lipid prodrugs include high incorporation efficiency, rapid intracellular enzymatic activation with high potency, and require relatively little purification compared with current microbubble strategies, allowing more rapid translation into the clinic. Our results in cell culture demonstrate that when incorporated into lipid carriers, such as liposomes, the lipid prodrug is rapidly cleaved once taken up intracellularly and maintains the potency of the parent compound in the nanomolar range. Additionally, there appears to be a level of selectivity, where the activity of the prodrug decreased by three orders of magnitude in normal cancer cell lines compared with cancer cell lines of the same type. When the prodrug is incorporated in microbubbles and exposed to therapeutic ultrasound pulses, site-specific delivery is achieved in adherent cell lines, leaving a distinct pattern of toxicity where ultrasound application is focused and the surrounding cells remain viable. When the microbubbles are merely in contact with the cells, no effect is not observed. These prodrugs may also be incorporated into other lipid-based vehicles that can be targeted or triggered by other means. Long-term goals include a broad approach to drug design based on this initial trial, using drugs that are currently developed and underused due to solubility or toxicity issues.