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Abstract (summary): Current breast cancer treatments lack specificity, leading to dose-limiting cardiotoxicity, which is often coupled with multi-drug resistance (MDR), and thus severely impedes efficacious cancer treatment. Current efforts to utilize chemotherapeutics and MDR inhibitors have failed in the clinic due to low efficacy, off-target toxicities, and altered pharmacokinetics. Synergistic nanoparticles (NPs) offer spatiotemporal control of therapeutics from the injection site to the tumor site. Synergistic NPs co-encapsulate two or more drugs, whereby the co-encapsulated drugs exhibit anti-cancer activity greater than the sum of the anti-cancer activity exhibited by the single-drug loaded NPs. This thesis demonstrates that doubly-loaded NPs are more efficacious against multi-drug resistant (MDR) breast cancer cells in vitro, relative to each drug alone or combined, singly-loaded drug NPs. The NPs, comprising poly(D,L-lactide-co-2-methyl-2-carboxytrimethylene carbonate)-graft-poly(ethylene glycol)-azide (P(LA-co-TMCC)-g-PEG-N3), were used to co-encapsulate two therapeutics and evaluate their synergistic cytotoxicity of MDR cancer cells: vitamin E succinate modified with octahistidine-octaarginine (VES-H8R8) and a pH-responsive prodrug of doxorubicin (pDox). The mechanism of the anti-cancer activity of VES-H8R8 comprised MDR efflux inhibition, mitochondria depolarization with inhibited bioenergetics, and induction of reactive oxygen species, apoptosis and G1 cell cycle arrest. When VES-H8R8 was co-encapsulated with pDox in NPs, synergistic anti-cancer activity against MDR breast cancer cells was observed, but only when co-encapsulated NPs were administered. Work towards NP-mediated delivery of siRNA targeted against an essential protein, eukaryotic translation initiation factor 3 subunit B (eIF3B), is also presented; however, limitations associated with endo/lysosomal accumulation terminated the use of NPs comprising P(LA-co-TMCC)-g-PEG-N3. This thesis provides the groundwork to study synergistic anti-cancer activity against MDR breast cancer in vivo.