The goal of this 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. The overexpression of ATP binding cassette (ABC) transporters, including P-gp (ABCB1 gene), multidrug resistance protein (MRP) (ABCC gene) and breast cancer resistance protein (BCRP) (ABCG2 gene) is one of the most common causes of multidrug resistance. Down regulating nuclear expression of MDR (multi-drug resistant) genes (i.e. P-gp, MRP-1, BCRP etc.) by siRNA-encapsulated nanoparticles could increase the delivery of doxorubicin, however, it will be more effective if the particles are selectively targeted to the cancer cells. So, we plan to overcome this problem by developing a targeted nanocarrier delivery system for siRNAs into breast cancer cells. For targeted delivery, Her-2 specific aptamer will be used that will bind specifically to the overexpressed Her-2 receptors on the breast cancer cells. The efficacy of targeted (aptamer-labeled) versus non-targeted (non-aptamer-labeled) delivery of siRNA (to knock-down multidrug resistant genes) by nanoparticles into the breast cancer cells will be examined. The major goal of this proposal is to examine whether silencing the multidrug resistant genes such as P-gp or MRP-1 alone or both together by aptamer-labeled nanoparticles could synergistically enhance the delivery of doxorubicin into breast cancer cells. Our hypothesis is that conjugating nanoparticles with a cancer cell specific aptamer would enhance the knock-down of multidrug resistant genes which will increase the delivery of doxorubicin into breast cancer 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 I: Formulation of nanoparticle-aptamer conjugates for targeted delivery of siRNAs to enhance the knock-down of multidrug resistant genes in breast cancer cells. Specific Aim II: To determine whether silencing the expression of multidrug resistant genes by aptamer-labeled siRNA nanoparticles could enhance the delivery of doxorubicin into breast cancer cells in culture.