Maximizing the Therapeutic Window and Elucidating the Toxicity Mechanisms of Intravenous siRNA Polyplex-Based Cancer Nanomedicines
Jackson, Meredith Allyn
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2019-07-08
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.