Estimates from the American Cancer Society indicate that breast cancer will account for an estimated 41000 deaths in 2009. Advances in chemotherapy have reduced disease recurrence and 5 year survival rate. The advances has however been drawn back because of the increased toxicity to other tissues associated with these chemotherapeutic agents. Nanoparticles (NP) because of their ability to accumulate in tumors have been beneficial in overcoming these problems. Poly (lactic-co-glycolic acid)(PLGA) NPs have the advantage of being biocompatible and biodegradable. PLGA NPs also release their drug load slowly and over a period of time ensuring continuously high level of cancer therapeutics. The utility of poly (lactic-co-glycolic acid)(PLGA) nanoparticles (NP) is hampered by their rapid clearance by cells of the reticuloendothelial system (RES). Clearance by the RES is influenced by the physical properties of the NP. The impact of different physical characteristics on the in vivo behavior of PLGA NPs is not clear. In this study, the role that particle size, charge and the presence of targeting ligands on NP play in their biodistribution, pharmacokinetic and tumor uptake will be assessed. It is hypothesized that, modulating physical characteristics of PLGA NP and inclusion of targeting ligands will improve blood residence time and increase their tumor targeting. The specific aims of the project are 1) Prepare and characterize NP of different size, charge and targeting ligands and determine their cellular uptake 2) Determine the biodistribution of nanoparticles of different size, charge and targeting ligands and 3) Determine in vivo efficacy of NP of different size, charge and targeting ligands. Ability of NP to reduce tumor growth when loaded with doxorubicin will be assessed. Results obtained from these work will increase understanding about how NP characteristics affects their in vivo behavior. This will bring us closer to rational designing of NP for drug delivery.