Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer with a 5-year survival rate less than 9%. New treatments for PDA that are both safe and effective are needed. Currently, chemotherapy (e.g. gemcitabine, nab-paclitaxel) is the preferred treatment, as the tumors in majority of patients (80%) are surgically non-resectable at initial diagnosis. However, even these therapeutic choices have limited efficacy because of the highly immunosuppressive tumor microenvironment and poor tumor penetration due to low density of blood vessels and dense stroma. To overcome these treatment obstacles, the applicant recently developed an immunochemotherapy regimen based on co-delivery of gemcitabine (GEM), paclitaxel (PTX) and indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor NLG919 through a PGEM nanocarrier. Preliminary data showed that the PGEM carrier penetrated to the core of experimental tumors, and, importantly, both hydrophilic GEM and multiple hydrophobic agents with distinct properties could be loaded onto PGEM micelles. Indeed, PGEM co-loaded with PTX and NLG919 induced an improved anti-tumor immune response and was highly efficacious in inhibiting tumor growth in PANC02 xenograft model, most likely through a synergistic tumor killing effect of PTX and GEM, as well as the effect of NLG919 in reversing IDO-mediated immunosuppression. In this application, the applicant proposes to further improve the PGEM carrier by optimizing the units of each constructing motif (Aim 1). In addition, the applicant will test the in vivo targeting efficiency of different PGEM nanocarriers using tumor models that closely mimic human PDA. The pharmacokinetics, biodistribution and penetration of the nanoformulations (Aim 2), as well as their therapeutic effect and the underlying mechanism (Aim 3) will be evaluated. The successful completion of the proposed aims will not only provide an effective regimen for improved PDA immunochemotherapy, but also provide a carrier platform that can be extended to targeted co-delivery of multiple distinct hydrophilic and hydrophobic agents for various combination therapies.
? Development of new therapeutic formulations for the treatment of highly lethal pancreatic cancer is urgently needed. Recently, we developed a tumor permeable carrier that could co-deliver different drugs into tumors, and the formulated nanoparticles demonstrated a strong anti-tumor activity in pancreatic cancer tumor animal model. This application aims to further improve the carrier and evaluate the in vivo targeting efficiency of our nanocarriers using tumor models that closely mimic the human pancreatic cancer, which will provide a potent regimen for enhanced pancreatic cancer immuno-chemotherapy.