Optimization of Therapeutic Lipid-Coated Mesoporous Silica Nanoparticle Vaccines

Monophosphoryl lipid A (MPL) is the biologically active portion of lipopolysaccharide (LPS), a major constituent of the outer membrane of gram negative bacteria. MPL, which is used clinically as an adjuvant in vaccines, stimulates antigen-presenting cells (APC) by targeting Toll-like receptor 4 (TLR-4). While MPL has similar adjuvant activity to LPS, it is 1000 times less toxic. Activated APC secrete cytokines and have elevated surface expression of co-stimulatory molecules. Our research seeks to create a nanoparticle-based vaccine that utilizes the well-characterized adjuvant properties of MPL in combination with the model antigen ovalbumin to stimulate APC and to deliver antigen that can be processed and presented by APC in association with major histocompatibility complex to ovalbumin transformed cancer cells. We propose to use lipid-coated mesoporous silica nanoparticles (LC-MSN), a platform that we have successfully used for delivery of diverse cargo, including proteins and nucleic acids.

Our LC-MSN technology builds on the success of liposomal delivery systems by increasing nanoparticle stability and loading capacity through addition of a mesostructured silica core. MPL integrates into the lipid bilayer and is presented on the surface of the LC-MSN for easy binding to surface TLR-4 on APC. Here we present studies aimed at optimizing multivalent surface presentation of MPL to maximize the immunogenic response to LC-MSN. We have created LC-MSN using MSN with different surface chemistries, diverse liposomal preparation procedures, and variable loading ratios of ovalbumin to MSN cores.