Abstract P6-13-02: Overcoming therapy resistance of metastatic breast cancer by enhanced tumor delivery of polymeric doxorubicin

Abstract

Abstract Metastatic breast cancers are treated with chemotherapy drugs in clinic. However, patients usually develop therapy resistance quickly due to intrinsic and acquired mechanisms. Poor drug delivery to tumor cells may also contribute to therapy resistance. To address both biological and mass transport barriers to effective therapy, we developed a new doxorubicin-based formulation, polymeric doxorubicin (pDox), to be delivered using a porous silicon drug carrier, the multistage vector (MSV). We show the novel, rationally designed MSV/pDox drug enriches in tumor tissues and has considerable therapeutic efficacy in two animal models of triple negative breast cancer lung metastasis, conferring a significant survival advantage to animals treated with MSV/pDox over all other control groups (80% survival for the MSV/pDox group at 24 weeks post treatment vs. 0% survival for all others, log-rank test, p < 0.001). Mechanistically, pDox is released from the MSV as nanoparticles by controlled, sustained kinetics, and enters tumor cells by vesicular transport. The active doxorubicin is released in the acidic environment in lysosomes, exits vesicles in the perinuclear region, and enters the nucleus for drug action. This effective mass transport mechanism kills both the bulk and therapy resistant cells, but avoids cardiac damage. As a result, this new nanodrug has a significantly higher therapeutic window over doxorubicin and Doxil. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-13-02.