dc.creator | Shae, Daniel | |
dc.date.accessioned | 2020-08-21T21:05:37Z | |
dc.date.available | 2020-03-11 | |
dc.date.issued | 2019-03-11 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-03042019-120929 | |
dc.identifier.uri | http://hdl.handle.net/1803/10674 | |
dc.description.abstract | I detail the rational design and optimization of STING-NPs: a nanoparticle delivery platform that stimulates innate immunity and T cell activation through targeted activation of the stimulator of interferon genes (STING) protein, a critical cytosolic immune sensor of oncogenesis that has historically been difficult to target due to the poor pharmacokinetic properties of its natural ligand, cGAMP. STING-NPs comprise self-assembling, pH responsive, and endosomolytic polymers and overcome delivery barriers associated with cGAMP delivery by facilitating the cellular uptake and endosomal escape of cGAMP, facilitating a 2-3 order of magnitude enhancement in drug potency.
Administration of STING-NPs in murine tumor models initiates a multifaceted pro-inflammatory program associated with type I interferon expression and recruitment of T cells into the tumor microenvironment, eliciting tumor suppression or complete rejection through both intratumoral and systemic administration routes. Strikingly, STING-NP treatment is capable of mediating rejection of primary tumor growth as well as generating systemic and long-lived antitumor immunity, manifesting in suppression of distal tumor growth and resistance to cancer cell rechallenge. Efficacy is improved with the addition of checkpoint blockade antibodies, demonstrating that STING-NP treatment can sensitize tumors to ICB. Finally, the activity of STING-NPs is validated in an ex vivo model of freshly resected human melanoma. | |
dc.format.mimetype | application/pdf | |
dc.subject | Cancer Immunotherapy | |
dc.title | Design and Optimization of ‘Smart’ Nanoparticles for Targeting of the STING Pathway with Applications in Cancer Immunotherapy | |
dc.type | dissertation | |
dc.contributor.committeeMember | Jeffrey C. Rathell | |
dc.contributor.committeeMember | Scott A. Guelcher | |
dc.contributor.committeeMember | Paul E. Laibinis | |
dc.contributor.committeeMember | Justin M. Balko | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Chemical Engineering | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2020-03-11 | |
local.embargo.lift | 2020-03-11 | |
dc.contributor.committeeChair | John T. Wilson | |