DESIGN AND DEVELOPMENT OF A POLYMER-BLEND NANOPARTICLE DRUG DELIVERY SYSTEM TO OVERCOME MULTIDRUG RESISTANCE IN CANCERLilian E. van Vlerken1, Steven R. Little2, Zhenfeng Duan3, Michael V. Seiden3, Robert Langer4, and Mansoor M. Amiji11Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115; vanvlerken.l@neu.edu2Department of Hematology and Oncology, Massachusetts General Hospital, Boston, MA 021143Department of Chemical Engineering, University of Pittsburgh, Pittsburgh, PA 152614Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 AbstractIntroductionMaterials and MethodsResultsConclusionThe development of multi-drug resistance (MDR) is a major barrier to anti-cancer therapy, since this phenotype renders the tumor unresponsive to a multitude of chemotherapeutic options. Alterations in apoptotic signaling have emerged as a common strategy for MDR development, whereby glucosylceramide synthase (GCS) causes bioactivation of the pro-apoptotic mediator ceramide to a non-functional moiety. The objective of this work is to overcome MDR through a nanoparticle-based therapy that administers ceramide (CER) in combination with the chemotherapeutic drug paclitaxel (PTX), to restore apoptotic signaling. For optimal therapeutic efficacy, we have engineered long-circulating polymeric nanoparticles composed of pH responsive poly(beta-amino ester) (PBAE) blended into a hydrophobic matrix consisting of poly(epsilon-caprolactone) (PCL) or poly(lactic-co-glycolic acid) (PLGA). By regulating the blending ratio of the two polymers, we could tune release of the combination therapy, specifically tailored to the tumor environment. Efficacy of the formulation was tested on a breast (MCF7) model of MDR cancer. Optimal size and stability of the nanoparticle formulation was found at a blend of 70%:30% and 80%:20% PCL/PLGA:PBAE, and a drug load of 2.5% PTX and 10% CER. Release studies revealed that the blend composition is pH responsive, where a surge in release occurred when spiked to pH 6.5. Moreover, release of PTX vs. CER could be tuned, where, compared to the 70/30 composition, CER release from the 80/20 PCL/PBAE particle was delayed while PTX release was accelerated. Unlike the other three formulations, the 70/30 PLGA/PBAE formulation released PTX rapidly, upon a drop in pH to 6.5, with a slow sustained release of CER. Efficacy studies then revealed the ability of this tuned therapeutic strategy to greatly chemo-sensitize the MDR cancer type, shown by an increase in cell death up to 79% following treatment with 1 mM PTX and 8.6 mM CER, compared to treatment with PTX alone at the same dose (27% cell death, p