(409b) Effect of Drug Hydrophobicity on X-Ray-Triggered Drug Release from Peg-PLA/CaWO4 Nanoparticles: A Study of Stereoisomers of paclitaxel

For many locally advanced tumors, the chemotherapy-radiotherapy (CT-RT) combination (“chemoradiation”) is currently the standard of care. Intratumoral (IT) CT-based chemoradiation has the potential to overcome the limitations of conventional systemic CT-RT (side effects). For maximizing the benefits of IT CT-RT, our laboratory has developed a radiation-controlled drug release formulation, in which anticancer drug paclitaxel (PTX) and radioluminescent CaWO₄ (CWO) nanoparticles are co-encapsulated with poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) block copolymers (“PEG-PLA/CWO/PTX”). These PEG-PLA/CWO/PTX nanoparticles enable radiation-controlled release of PTX, and are capable of producing sustained therapeutic effects lasting for at least one month following a single IT injection.

This talk will focus on discussing our recent finding about the effect of the stereochemical structure of PTX on the efficacy of this PEG-PLA/CWO/PTX formulation. Stereochemical differences in two different PTX compounds were characterized by 2D heteronuclear NMR and circular dichroism measurements. The difference in PTX stereochemistry was found to significantly influence the efficacy of the formulation, both in vitro and in vivo. The two compounds showed similar performances when used as free drugs. However, the subtle stereochemical difference significantly influenced their X-ray-triggered release kinetics from the PEG-PLA/CWO/PTX nanoparticles. This difference was manifested in the intratumoral pharmacokinetics and eventually in the survival percentages of test animals (mice) in a human tumor xenograft study. This study demonstrates the importance of the stereochemistry of a drug in a therapy based on a controlled release formulation.