BACKGROUND: The marked difference in metabolism observed between tumor and normal cells could contribute to the development of invasive and metastatic forms of breast cancer. The problem is that while patients diagnosed with invasive forms of breast cancer may be initially responsive to treatment, a significant number develop relapsing and even metastatic disease. There is a critical unmet need to develop new therapeutic approaches for patients diagnosed with invasive forms of breast cancer that are effective given the unique metabolism of tumor cells. METHODS: We examined the cytotoxic properties of a novel peptide, CT20p, derived from the C-terminus of Bax. For delivery to cells, the amphipathic nature of CT20p allowed it to be encapsulated in polymeric nanoparticles (NPs). NPs were made using aliphatic hyperbranched polyester (HBPE) that incorporated surface carboxylic groups and interior hydrophobic cavities for encapsulation of CT20p. To examine the cytotoxic potential and targeting capacity of CT20p-HBPE-NPs, we treated MDA-MB-231 breast cancer cells and MCF-10A breast epithelial cells with the peptide-nanoparticle combination and measured changes in mitochondrial function, cell metabolism and induction of apoptotic and non-apoptotic cell death. The ability of CT20p-NP-HBPE to cause tumor regression was examined by subcutaneously implanting MDA-MB-231 cells in nude mice. RESULTS: Initial studies showed that CT20p caused the release of calcein from mitochondrial-like lipid vesicles, without disrupting vesicle integrity, and, when expressed as a fusion protein in cells, localized to mitochondria. While the peptide alone had little effect upon intact cells, likely not penetrating the plasma membrane, when encapsulated and delivered by nanoparticles, CT20p-HBPE-NPs proved an effective killer of breast cancer cells. CT20p-HBPE-NPs initiated non-apoptotic cell death within 3 hours of treatment by targeting mitochondria and deregulating cellular metabolism. Nanoparticles alone or nanoparticles encapsulating a control peptide had minimal effects. The cytotoxicity of CT20p-HPBE-NPs was most pronounced in breast cancer cells, sparing normal, epithelial cells. In implanted breast tumors, CT20p-HBPE-NPs accumulated in tumors within 24 hours and reduced tumor burden by 50-80%. CONCLUSION: These results reveal the innovative features of CT20p that allow nanoparticle-mediated delivery to tumors and the potential application in combination therapies that target the unique metabolism of cancer cells. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-04-13.