Project Grant F31HL178361

ELUCIDATING NANOPARTICLE SHAPE REQUIREMENTS TO MAXIMIZE LYMPHATIC AND LYMPH NODE TARGETED DRUG DELIVERY - LYMPHATIC VESSELS ARE THE CRITICAL CONNECTION BETWEEN PERIPHERAL TISSUE AND THE LYMPH NODES, WHERE ADAPTIVE IMMUNE RESPONSES ARE SHAPED. RECENT ADVANCEMENTS HAVE SHOWN THAT NANOPARTICLE-MEDIATED DELIVERY OF THERAPEUTICS TO THE LYMPH NODES CAN ENHANCE EFFECTIVENESS OF IMMUNOTHERAPIES, INCLUDING INCREASING LENGTH OF VACCINE DURATION AND RESPONSE TO CANCER IMMUNOTHERAPY. THE LYMPH NODES CAN BE TARGETED BY TAKING ADVANTAGE OF THE FACT THAT SMALL PARTICULATES ARE PREFERENTIALLY TRANSPORTED INTO LYMPHATIC VESSELS AND THUS ACCUMULATE IN THE DOWN-STREAM LYMPH NODES. WHILE THE EFFECT OF MATERIAL PROPERTIES LIKE SURFACE CHEMISTRY ON NANOPARTICLE TRANSPORT HAS BEEN STUDIED BY MY THESIS LAB AND OTHERS, THE IMPACT OF SHAPE REMAINS POORLY UNDERSTOOD. MY PRELIMINARY DATA SUGGESTS THAT ROD-SHAPED NANOPARTICLES EXHIBIT INCREASED TRANSPORT ACROSS THE LYMPHATIC BARRIER COMPARED TO SPHERICAL NANOPARTICLES, AS EVIDENCED BY INCREASED TRANSPORT ACROSS LYMPHATIC ENDOTHELIAL CELLS IN VITRO AS WELL AS GREATER ACCUMULATION IN THE LYMPH NODES. IN THE PROPOSED PROJECT, I AIM TO INVESTIGATE HOW VARIOUS NANOPARTICLE SHAPES, INCLUDING ELLIPSES, RODS, DISCS, AND WORMS, INFLUENCE TRANSPORT INTO LYMPHATICS VESSELS AND ACCUMULATION IN LYMPH NODES. LEVERAGING A MODEL POLYSTYRENE NANOPARTICLE SYSTEM, I WILL EMPLOY MECHANICAL STRETCHING TO MODIFY NANOPARTICLE SHAPE, ALLOWING CONTROLLED EXPLORATION OF SHAPE-DEPENDENT TRANSPORT MECHANISMS. THROUGH COMPREHENSIVE IN VITRO STUDIES, I WILL ELUCIDATE SHAPE EFFECTS ON NANOPARTICLE UPTAKE BY LYMPHATIC ENDOTHELIAL CELLS (LECS) AND DISSECT UNDERLYING TRANSCELLULAR AND PARACELLULAR TRANSPORT MECHANISMS USING TRANSPORT INHIBITORS AND IMMUNOSTAINING. WE ALSO HAVE EXCITING PRELIMINARY DATA SUGGESTING THAT ROD SHAPED NANOPARTICLES PENETRATE INTO THE LYMPH NODE PARENCHYMA. THUS, HERE I WILL EXAMINE THE ACCUMULATION OF DIFFERENTLY SHAPED NANOPARTICLES IN THE LYMPH NODES AND THE DISTRIBUTION OF THESE NANOPARTICLES WITHIN THE LYMPH NODE PARENCHYMA AND ITS CELLS. I WILL EVALUATE NANOPARTICLE LYMPH NODE ACCUMULATION AND BIODISTRIBUTION BY INTRADERMALLY INJECTING DIFFERENTLY SHAPED NANOPARTICLES IN MICE AND USING IN VIVO IMAGING, FLUORESCENCE MICROSCOPY, AND FLOW CYTOMETRY. BY UNRAVELING THE INTRICACIES OF NANOPARTICLE UPTAKE AND DISTRIBUTION WITHIN THE LYMPHATIC SYSTEM, THIS RESEARCH AIMS TO INFORM THE DESIGN OF MORE EFFECTIVE LYMPHATIC-TARGETED DRUG DELIVERY SYSTEMS, POTENTIALLY REVOLUTIONIZING IMMUNOTHERAPEUTIC APPROACHES FOR VARIOUS DISEASES. RECENT ADVANCEMENTS HAVE UNDERSCORED THE VITAL ROLE OF LYMPHATIC VESSELS IN IMPROVING IMMUNOTHERAPY EFFECTIVENESS BY DELIVERING IMMUNOTHERAPIES TO THE LYMPH NODES. WHILE IMPACT OF MATERIAL PROPERTIES LIKE SURFACE CHEMISTRY ON NANOPARTICLE TRANSPORT TO THE LYMPH NODES VIA LYMPHATIC VESSELS HAS BEEN ESTABLISHED, THE INFLUENCE OF SHAPE REMAINS POORLY UNDERSTOOD. THIS PROPOSAL SEEKS TO INVESTIGATE HOW NANOPARTICLE SHAPE AFFECTS TRANSPORT INTO LYMPHATIC VESSELS AND ACCUMULATION IN LYMPH NODES, WHICH HAS THE POTENTIAL TO PROVIDE IMPROVED DESIGN CRITERIA FOR NANOPARTICLE-BASED DRUG DELIVERY TO LYMPHATIC VESSELS AND THE LYMPH NODES, YIELDING MORE EFFECTIVE DRUG DELIVERY SYSTEMS FOR IMMUNOTHERAPY.