One third of breast cancer patients initially diagnosed with early stage of the disease will end up with cancer recurrence and require further treatment;the median survival rate of patients with metastatic breast cancer patients is 2 years. The response rate of breast cancer to first line chemotherapies is encouraging, but the majority of patients progress in 7-10 months. Response to subsequent chemotherapies with various agents drops to 20-30% resulting from formidable cancer chemoresistance. The best studied mechanism of resistance is mediated through the alteration in the drug efflux proteins responsible for the removal of many commonly used antineoplastic agents. One possible way to overcome this drug efflux pump is to give higher doses of chemotherapy. There have been several clinical trials that have studied the efficacy of administering high dose chemotherapy and stem cell transplant for high risk patient (non-metastatic) as adjuvant treatment for breast cancer. In a meta-analysis that reviewed the multiple trials on this topic, the authors found that patients with high dose chemotherapy had significantly less breast cancer related events;however, the overall survival was not improved because of treatment toxicity. Therefore, a treatment that could deliver a high dose of chemotherapy to patients with less toxicity should be more effective in breast cancer therapy. There is a second method to overcome breast cancer drug resistance: the combination of anthracyclines and taxanes in the adjuvant setting has been shown to improve disease free survival in patients with positive lymph nodes. Consequently, a treatment regimen that could deliver higher doses of a combination of chemotherapy agents to overcome various mechanisms of chemoresistence would be ideal. Hence, the objective of this project is to develop a nanoparticle, using a unique and novel lipid-polymer hybrid nanoparticle platform, which can contain two chemotherapy drugs, doxorubicin and paclitaxel, with sufficiently high drug loading that a single or few nanoparticles can kill a drug resistant cancer cell. By using the nanoparticle to concurrently deliver the two drugs at high dosage to the same breast cancer cells in a targeted manner, we expect to develop a new paradigm in overcoming cancer drug resistance with clinically-approved anticancer drugs. Taken together, these nanoparticles could offer a promising approach for drug delivery by improving the quality, safety, and effectiveness of encapsulated drugs. PUBLIC HEALTH RELEVANCE: The objective of this project is to develop a nanoparticle, using a unique and novel lipid-polymer hybrid nanoparticle platform, which can contain two chemotherapy drugs, doxorubicin and paclitaxel, with sufficiently high drug loading that a single or few nanoparticles can kill a drug resistant cancer cell. By using the nanoparticle to concurrently deliver the two drugs at high dosage to the same breast cancer cells in a targeted manner, we expect to develop a new paradigm in overcoming cell cancer drug resistance with clinically- approved anticancer drugs. Taken together, these nanoparticles could offer a promising approach for drug delivery by improving the quality, safety, and effectiveness of encapsulated drugs.