Show simple item record

Maximizing the Therapeutic Window and Elucidating the Toxicity Mechanisms of Intravenous siRNA Polyplex-Based Cancer Nanomedicines

dc.creatorJackson, Meredith Allyn
dc.date.accessioned2020-08-24T11:50:32Z
dc.date.available2021-07-08
dc.date.issued2019-07-08
dc.identifier.urihttps://etd.library.vanderbilt.edu/etd-07082019-105259
dc.identifier.urihttp://hdl.handle.net/1803/15435
dc.description.abstractWhile 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.mimetypeapplication/pdf
dc.subjectPharmacokinetics
dc.subjectKupffer Cells
dc.subjecttoxicology
dc.subjectPAF
dc.subjectsiRNA
dc.subjectDrug Delivery
dc.titleMaximizing the Therapeutic Window and Elucidating the Toxicity Mechanisms of Intravenous siRNA Polyplex-Based Cancer Nanomedicines
dc.typedissertation
dc.contributor.committeeMemberTodd Giorgio
dc.contributor.committeeMemberRebecca Cook
dc.contributor.committeeMemberDana Brantley-Sieders
dc.contributor.committeeMemberJohn Wilson
dc.type.materialtext
thesis.degree.namePHD
thesis.degree.leveldissertation
thesis.degree.disciplineBiomedical Engineering
thesis.degree.grantorVanderbilt University
local.embargo.terms2021-07-08
local.embargo.lift2021-07-08
dc.contributor.committeeChairCraig Duvall


Files in this item

Icon

This item appears in the following Collection(s)

Show simple item record