Viral Mimicking Iron-Oxide Nanoplatforms for Highly Efficient Lymph Node Delivery and Lymphocyte Activation

Abstract

Iron-oxide nanoparticles have been widely investigated as both diagnostic and therapeutic agents. Yet, as therapeutic agents, very limited research has been conducted to explore the potential of iron-oxide nanoparticles in vaccinology. Notably, there are no iron-oxide nanoparticle-based vaccines for cancer immunotherapy or infectious disease currently on the market. This reality is confounding because of the seemingly dynamic potential of iron-oxide nanoparticles in these applications. More specifically, iron-oxide nanoparticles possess numerous material characteristics that would make them highly attractive as carriers of vaccine components to immunologically relevant sites, such as the lymph nodes. These material characteristics include biodegradability, magnetic susceptibility, particle size control and surface composition diversity, among others. Accordingly, here we proposed to investigate the ability to leverage iron-oxide nanoparticles for lymph node targeting and lymphocyte activation toward design of efficacious vaccines.

In part one of this thesis, we explored how iron-oxide nanoparticles could be leveraged for the activation of humoral immunity. Activation of humoral immunity can be exploited to stimulate the production of antigen-specific antibodies with variable effector functionality that could be employed in both diagnostic and therapeutic applications (e.g. vaccines). Specifically, for engagement with the humoral immunity system, we developed an inorganic Au@Fe hybrid nanoparticle platform, coined inorganic virus-like nanoparticle (IVLN). As compared to traditional nanoparticle technologies, the IVLN mimics viral structure through the incorporation spherical geometry, topographical spiky antigenic clusters, optimal spatial distribution of antigenic clusters and extremely high local density of antigen with those clusters. We demonstrate that IVLNs dramatically improve B-cell activation, germinal center formation and production of antigen-specific antibodies with functional efficacy against HER2+ breast cancer in mice. Notably, as compared to traditional nanoparticle technologies, IVLNs increase the population of antigen-specific B-cells by 6-fold resulting in a 4 to 18-fold improvement in antigen-specific IgG production in-vivo.

In part two of this thesis, we investigated how iron-oxide nanoparticles could be leveraged for the activation of cellular immunity. Activation of cellular immunity facilitates the production of cytotoxic T lymphocytes with potential efficacy in the treatment of infectious diseases, as well as cancer. Specifically, for engagement with the cellular immunity branch, we developed a novel method to engineer lipid-coated iron-oxide nanoparticles (IONP-ML) using the phenomenon of lipid-stitching. This method allowed fabrication of IONP-ML with precise control of particle size, ultra high-density of biomolecule loading, and high MRI visibility. These characteristics translated to unprecedented in-vivo performance. Remarkably, the IONP-ML facilitated up to 200-fold increase in biomolecular loading and 9 to 40-fold increase in lymph node targeting efficiency as compared to previously reported technologies. As such, these materials could be broadly applicable in the efficient and tailored presentation of biomolecules in the lymph nodes toward induction of cellular immunity.

Overall, the work presented herein reaffirms the robust potential of iron-oxide based nanoplatforms as drug delivery vehicles, imaging modalities and immunomodulatory agents for both humoral and cellular immunity, thereby providing justification for the continued research, development and clinical translation of iron-oxide based nanoplatforms.