The long-term goal of the proposed research proposal is to develop a targeted paclitaxel nanotherapy that can be used for the treatment of pancreatic cancer (PanCa) in combination with Gemcitabine (GEM). Although many conventional and combinational chemotherapies exist to treat PanCa, significant side effects occur without increasing the survival of patients (not even 2 additional months). Desmoplasia (characterized by excessive fibrosis and extracellular matrix deposition) causes suboptimal drug delivery in tumors and thus induces chemo-resistance. Additionally, certain signaling pathways, abnormal tumor cell membrane lipid structure/composition and restricted drug uptake due to overexpression of drug efflux associated proteins also lead to cancer progression/metastasis and drug resistance. A recent FDA- approved (on Sept. 6, 2013) combination treatment regimen [nab-nanoparticles (i.e., paclitaxel nanoparticles, Abraxane) plus GEM] has marginally improved (only 1.8 months) overall survival (8.5 months vs. 6.7 months with GEM alone). Studies have also shown that PTX altered tumor microenvironment (TME) and reduced desmoplasia, thus improved GEM uptake in pancreatic tumors. We believe that this PTX-mediated marginally improved therapeutic outcome can be further enhanced by using an inimitable tumor specific antibody targeted PTX nanoparticle formulation. We hypothesize that antibody-guided, tumor specific targeted delivery of PPNPs will enhance the bioavailability of PTX in pancreatic tumors and macro/ micro metastatic lesions to attenuate tumor growth and sensitize tumor cells to GEM via decreased desmoplasia, altered TME and SHH/CXCL12/CXCR4, miR-21 mediated oncogenic signaling pathways. This proposal examines two levels of targeting PanCa. The first is MUC13 targeted delivery of PTX to pancreatic tumors as our PPNPs selectively/preferentially reach and accumulate in the tumors/metastatic lesions. Our preliminary data demonstrates that MUC13 targeted nanoparticles effectively target pancreatic tumors. The second level of treatment is intravenous administration of GEM. The first level of targeting will considerably alter TME which will thus promote a better response to GEM. This novel combination therapeutic modality will enhance drug loading specifically to the tumor site, inducing greater anti-cancer effects while minimizing side effects. To achieve these goals, three specific aims are proposed: AIM 1: To Evaluate Chemo- sensitization and TME of PPNPs in PanCa Cells. AIM 2: To Investigate Pharmaco-kinetics/dynamics (PK/PD) and Safety of PPNPs/GEM in a stromal component containing PanCa xenograft mouse model. AIM 3: To Evaluate the Therapeutic Efficacy of MUC13 Targeted PPNP Formulation in clinically relevant transgenic mice and patient derived xenograft (PDX) models. This proposal leads to a better treatment modality by altering tumor-stromal (paracrine) cross-talk and chemo-sensitization in PanCa which are considered to be major roadblocks in PanCa therapeutics. The proposed studies are based on recent clinical observations, thus clinical translation of this approach will be easy and quick.