P1-15-03: Multistage Vectored Nanotherapeutics for Breast Cancer Metastasis.

Significant progresses have been made on overall survival rates in breast cancer. The five-year survival rate of women diagnosed with Stage I-III breast cancer has been steadily improving decades over decades. These improvements in survival have primarily been attributed to availability of modern diagnostic tools that allow for early detection, and the increased use of adjuvant systemic therapies. However, the situation with breast cancer metastasis is discouraging, with only marginal improvement in some reports to no improvement at all in other studies in survival of the relapsed metastatic patients. More breast cancer patients are killed by cancer metastasis than by the primary cancer. Nanotechnology has played an important role in the fight against breast cancer in the last decade. The first nano-liposomal formulation of doxorubicin (Dox), Doxil, was FDA approved in 1994, and is currently used to treat multiple cancer types including recurrent and refractory breast cancers. More nano-formulated drugs have since been approved. These nanotherapeutics work based on the enhanced permeability and retention (EPR) effect, and still cause severe toxicity to the body, however. To overcome these defects of the first generation of nanotherapeutics, we have developed a silicon-based multistage vector (MSV) system with the aim to specifically delivery drugs to cancer tissues with the least toxicity to the normal organs. These are particle-in-particle “Russian Doll” systems with each stage designed to provide transport across a set of sequential biological barriers, and provide associated levels of targeting specificity. We have demonstrated highly reproducible therapeutic efficacy with this system to deliver the conventional chemotherapy drugs and siRNA oligos. We have generated mouse lung metastasis models with the human breast cancer cell line MDA-MB-231 which was engineered with a luciferase gene, and used multiple doxorubicin formulations to treat the tumor mice. These included free doxorubicin (3 mg/kg weekly), Doxil (6 mg/kg biweekly), a new formulation of doxorubicin in micelles (miDox, 6 mg/kg biweekly), and miDox in MSV (MSV/Dox, 6 mg/kg biweekly). Tumor growth in the lung was monitored by bioluminescence with a Xenogen IVIS200 optical in vivo imaging system. As expected, treatment with free Dox caused significant weight loss indicating drug toxicity, most likely to the heart. Tumor growth in the free Dox treatment group halted initially, but resumed two weeks later. The tumor cells in these animals might have developed resistance to Dox during the treatment. Doxil treatment also triggered weight loss initially. This correlates with the cardiac side effect of the drug observed in clinic. Neither miDox or MSV/Dox caused weight loss. Tumor growth was also inhibited in mice treated with both formulations. The result was much more significant with MSV/Dox than with miDox. No tumor cells were observed in the lung after a 6-week treatment with MSV/Dox, while 40% of the miDox-treated mice still had residue, but detectable tumor cells in the lung. These results indicate that we have developed a powerful system for tumor-specific delivery of therapeutic in the treatment of breast cancer metastasis. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-15-03.