PROJECT SUMMARY/ABSTRACT Effective targeted treatments are needed to improve survival of patients with late stage ovarian and other solid tumor cancers of epithelial origin. Epithelial cancers are characterized by an overexpression of tumor tight junctions, specifically the cell adhesion protein desmoglein-2 (DSG2). Unlike in normal epithelial cells, epithelial cancer cells are characterized by abnormal expression of DSG2, displaying the protein three-dimensionally and outside intercellular junctions; as a result, DSG2 is an attractive tumor-specific protein for targeted therapies. We have developed a DSG2-targeting protein called the “junction opener conjugatable to x”, or JOC-x. A key feature of JOC-x, as its name implies, is the ability to conjugate any moiety with functional groups to the engineered free sulfhydryl group on JOC-x. In this phase I SBIR, we will covalently link JOC-x to HDT Bio Corp’s patent-pending Lipid Iron Oxide Nanoparticle (LIONTM) formulation. The LION formulation is a multifunctional nanoparticle platform. At its core, LION consists of the widely used immune potentiating molecule squalene and superparamagnetic iron oxide (SPIO) nanoparticles that give LION the ability to affect tissue contrast in magnetic resonance imaging (MRI). By covalently combining JOC-x with LION, we propose to (specific aim 1) synthesize and thoroughly characterize JOC-LION particles that demonstrate colloidal stability in plasma and effective binding with DSG2. Moreover, (specific aim 2.1) using a 3T clinical MRI scanner at the University of Washington, we will evaluate the ability of five candidate JOC-LION particles to target human DSG2 overexpressing ovarian cancer cells in a transgenic human DSG2 expressing murine model. Finally, since squalene delivered in nanoparticles is an effective activator of the innate immune system, we will (specific aim 2.2) evaluate the potential for induction of anti-tumor activity of candidate JOC-LION particles make the tumor more accessible, both physically, by opening tight junctions, and immunologically, by recruiting immune cells in the tumor microenvironment. The ultimate goal of this phase I proposal is to develop a lead JOC-LION candidate that demonstrates a high degree of selective accumulation in DSG2 overexpressing epithelial tumors and potentially also provides anti-tumor activity. In phase II, we will combine our lead JOC-LION candidate with both traditional and novel cancer therapies to justify clinical product development of our novel tumor junction opening and imaging nanoparticle technology.