Gold Nanoparticle Platforms for Antigen and Adjuvant Delivery in Cancer Immunotherapy
Mattos Almeida, Joao Paulo
Doctor of Philosophy
Cancer immunotherapy is a growing treatment modality with the promise to yield systemic and targeted treatments for cancer. Major modalities such as radiation, chemotherapy, and surgery are limited in that they are either too localized--as is the case with radiation and surgery—and cannot be effective in metastatic disease, or they are not targeted-- as with chemotherapy--thus leading to severe toxicities. Immunotherapy aims to stimulate the body’s immune system against disease, allowing one to circumvent such challenges because the immune system can act systemically and can have specific activity against cancer cells expressing antigens of interest. The development of an effective cancer vaccine and subsequent immune response requires the delivery of an antigen for immune recognition and of an adjuvant for an inflammatory response. Gold nanoparticles (AuNPs) are promising vaccine carriers because they are generally non-toxic, can be synthesized in the optimal sizes for lymphatic drainage and cell uptake, and can be readily conjugated with antigens and adjuvants for delivery. This thesis project characterizes AuNP distribution in the immune system and details the development of AuNP mediated delivery of antigens and adjuvants for cancer immunotherapy. In our work, we have detailed AuNP distribution within immune cells of the spleen and the tumor microenvironment, thereby identifying that AuNPs associate with a range of immune populations, including B cells, dendritic cells, and macrophages, all of which can be potentially targeted for immune modulation. Next we developed AuNP complexes capable of delivering the CpG oligonucleotide adjuvant, demonstrating that AuNP delivery promotes the therapeutic effect of CpG in vitro and in vivo. In addition, we studied AuNP mediated delivery of the ovalbumin (OVA) peptide antigen and showed that AuNP delivery enhances vaccination with the antigen in vivo, subsequently causing tumor inhibition and prolonged survival in both prophylactic and established tumor models. The thesis thus elucidates AuNP interactions with the immune system and demonstrates that the technology is an effective platform for delivery of immune modulatory agents.