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 Corps 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.
Public Health Relevance Statement: PROJECT NARRATIVE More than 90% of solid tumors are of epithelial origin, characterized by overexpression of tumor tight junctions that prevent otherwise effective cancer therapies from entering the tumor and killing the cancer cells. We propose to develop a nanoparticle conjugated protein that will selectively target and open tumor tight junctions. Moreover, the nanoparticles will contain a combination of built-in imaging component that will enable tumor visualization using clinical MRI scanners, and immune stimulants that will message the bodys own immune system to target and kill the cancer cells.
Project Terms: Affect ; Antineoplastic Agents ; Anti-Cancer Agents ; Antineoplastic Drugs ; Antineoplastics ; Cancer Drug ; Neoplastic Disease Chemotherapeutic Agents ; Tumor-Specific Treatment Agents ; anti-cancer drug ; anticancer agent ; anticancer drug ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Carcinoma ; Epithelial cancer ; Malignant Epithelial Neoplasms ; Malignant Epithelial Tumors ; epithelial carcinoma ; Cell Adhesion Molecules ; Adhesion Molecule ; Cell Adhesion Molecule Gene ; cell adhesion protein ; Cells ; Cell Body ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Engineering ; Epithelial Cells ; Goals ; Human ; Modern Man ; Immune system ; allergic/immunologic body system ; allergic/immunologic organ system ; Intercellular Junctions ; Cell Junctions ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Lipids ; Magnetic Resonance Imaging ; MR Imaging ; MR Tomography ; MRI ; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance ; NMR Imaging ; NMR Tomography ; Nuclear Magnetic Resonance Imaging ; Zeugmatography ; Membrane Proteins ; Membrane Protein Gene ; Membrane-Associated Proteins ; Surface Proteins ; Mus ; Mice ; Mice Mammals ; Murine ; Names ; Opsonin ; Particle Size ; Legal patent ; Patents ; Patients ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Proteins ; Squalene ; Sulfhydryl Compounds ; Mercaptans ; Mercapto Compounds ; Thiols ; sulfhydryl group ; Survival Rate ; Technology ; Tissues ; Body Tissues ; Universities ; Washington ; desmoglein 2 ; desmoglein II ; desmosomal glycoprotein 2 ; base ; improved ; Ovarian ; Apical ; Surface ; Clinical ; Penetration ; Phase ; Link ; Epithelial ; Tight Junctions ; Occluding Junctions ; Zonula Occludens ; Selection Criteria ; Solid Neoplasm ; Solid Tumor ; Therapeutic ; Malignant Cell ; cancer cell ; Immunes ; Immune ; 3-D ; 3D ; three dimensional ; 3-Dimensional ; Viral ; Basal Cell ; particle ; polarized cell ; functional group ; Hydrophobicity ; transgenic ; Transgenic Organisms ; Structure ; novel ; monolayer ; Cancer Treatment ; Malignant Neoplasm Therapy ; Malignant Neoplasm Treatment ; anti-cancer therapy ; anticancer therapy ; cancer-directed therapy ; cancer therapy ; Drops ; Malignant Ovarian Neoplasm ; Malignant Ovarian Tumor ; Malignant Tumor of the Ovary ; Ovary Cancer ; ovarian cancer ; Malignant neoplasm of ovary ; Molecular Interaction ; Binding ; preventing ; prevent ; immune competent ; Immunocompetent ; Cancer Model ; CancerModel ; Cancer Prognosis ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Immunologics ; Immunochemical Immunologic ; Immunologic ; Immunological ; Immunologically ; Image ; imaging ; tumor microenvironment ; cancer microenvironment ; design ; designing ; nanoparticle ; nano particle ; nano-sized particle ; nanosized particle ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; innovation ; innovate ; innovative ; mouse model ; murine model ; commercialization ; tumor ; antitumor drug ; anti-tumor drugs ; overexpression ; overexpress ; multimodality ; multi-modality ; product development ; targeted treatment ; targeted drug therapy ; targeted drug treatments ; targeted therapeutic ; targeted therapeutic agents ; targeted therapy ; targeted imaging ; Formulation ; Innate Immune System ; recruit ; lead candidate ; superparamagnetism ; superparamagnetic ; iron oxide nanoparticle ; iron oxide nano particle ; Visualization ;
