dc.creator | Jackson, Meredith Allyn | |
dc.date.accessioned | 2020-08-24T11:50:32Z | |
dc.date.available | 2021-07-08 | |
dc.date.issued | 2019-07-08 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-07082019-105259 | |
dc.identifier.uri | http://hdl.handle.net/1803/15435 | |
dc.description.abstract | While siRNA nanomedicine holds great potential for unlocking otherwise “undruggable” targets, it also faces significant delivery challenges to non-liver targets such as tumors. In particular, polymeric delivery vehicles are inhibited from clinical translation by their poor circulation half-lives, low degrees of target tissue uptake, and carrier-associated toxicities. In this work, we present strategies to maximize the therapeutic window of intravenously administered siRNA nano-polyplexes and to understand the mechanisms of nanopolyplex-associated toxicities.
Here, we comprehensively compare poly(ethylene glycol) [PEG] to zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) [PMPC] polyplex coronas and demonstrate that high molecular weight polyplex coronas extend polyplex half-lives five-fold compared to lower molecular weight coronas. We show that zwitterionic PMPC coronas achieve superior tumor gene silencing and tumor cell uptake in vivo compared to PEG-based coronas. We further optimize PMPC-based polyplex formulations by varying charge ratios and by improving hydrophobic stabilization using palmitic acid-siRNA conjugates. We demonstrate that a strategy of “dual hydrophobization” reduces the amount of carrier polymer required to achieve optimal pharmacokinetic profiles while also improving polyplex safety. Finally, we have identified a novel mechanism of toxicity associated with high-dose polyplex administration. Knowledge of this mechanism will inform future polyplex designs enable more effective nanomedicines. | |
dc.format.mimetype | application/pdf | |
dc.subject | Pharmacokinetics | |
dc.subject | Kupffer Cells | |
dc.subject | toxicology | |
dc.subject | PAF | |
dc.subject | siRNA | |
dc.subject | Drug Delivery | |
dc.title | Maximizing the Therapeutic Window and Elucidating the Toxicity Mechanisms of Intravenous siRNA Polyplex-Based Cancer Nanomedicines | |
dc.type | dissertation | |
dc.contributor.committeeMember | Todd Giorgio | |
dc.contributor.committeeMember | Rebecca Cook | |
dc.contributor.committeeMember | Dana Brantley-Sieders | |
dc.contributor.committeeMember | John Wilson | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Biomedical Engineering | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2021-07-08 | |
local.embargo.lift | 2021-07-08 | |
dc.contributor.committeeChair | Craig Duvall | |