The goal of the proposal is to develop a targeted nanoparticle system for the treatment of breast cancer. Chemotherapy remains one of the major treatment options for metastatic breast cancer; however, acquired resistance to chemotherapeutic agents such as doxorubicin is a major reason for cancer treatment failure. Recently, it has been shown that knocking down the expression of MDR1 P-glycoprotein (P-gp) by P-gp specific siRNA could increase the delivery of doxorubicin to doxorubicin resistant breast cancer cells which could improve the metastatic breast cancer treatment. However, it will be more effective if the particles are selectively targeted to the cancer cells. The aptamer surface labeling will be used to selectively deliver both p-gp siRNA encapsulated nanoparticles and doxorubicin encapsulated nanoparticles to metastatic cancer cells. The efficacy of targeted versus non-targeted delivery of siRNA and doxorubicin nanoparticles to breast cancer cells will be examined. Our hypothesis is that conjugating nanoparticles with a cancer cell specific aptamer should allow selective delivery of therapeutic drugs to tumor cells leading to enhanced cellular toxicity and antitumor effect as compared to unconjugated nanoparticles. This hypothesis will be tested by the following two specific aims. Specific Aim 1: Formulation of nanoparticle-aptamer conjugates for targeted delivery of P-gp siRNA to breast cancer cells. Specific Aim II: Formulation of doxorubicin encapsulated nanoparticles with surface aptamer for targeted delivery to breast cancer cells.