Dual carrier-cargo hydrophobization and charge ratio optimization improve the systemic circulation and safety of zwitterionic nano-polyplexes.

Jackson MA, Bedingfield SK, Yu F, Stokan ME, Miles RE, Curvino EJ, Hoogenboezem EN, Bonami RH, Patel SS, Kendall PL, Giorgio TD, Duvall CL
Biomaterials. 2019 192: 245-259

PMID: 30458360 · PMCID: PMC6534819 · DOI:10.1016/j.biomaterials.2018.11.010

While polymeric nano-formulations for RNAi therapeutics hold great promise for molecularly-targeted, personalized medicine, they possess significant systemic delivery challenges including rapid clearance from circulation and the potential for carrier-associated toxicity due to cationic polymer or lipid components. Herein, we evaluated the in vivo pharmacokinetic and safety impact of often-overlooked formulation parameters, including the ratio of carrier polymer to cargo siRNA and hydrophobic siRNA modification in combination with hydrophobic polymer components (dual hydrophobization). For these studies, we used nano-polyplexes (NPs) with well-shielded, zwitterionic coronas, resulting in various NP formulations of equivalent hydrodynamic size and neutral surface charge regardless of charge ratio. Doubling nano-polyplex charge ratio from 10 to 20 increased circulation half-life five-fold and pharmacokinetic area under the curve four-fold, but was also associated with increased liver enzymes, a marker of hepatic damage. Dual hydrophobization achieved by formulating NPs with palmitic acid-modified siRNA (siPA-NPs) both reduced the amount of carrier polymer required to achieve optimal pharmacokinetic profiles and abrogated liver toxicities. We also show that optimized zwitterionic siPA-NPs are well-tolerated upon long-term, repeated administration in mice and exhibit greater than two-fold increased uptake in orthotopic MDA-MB-231 xenografts compared to commercial transfection reagent, in vivo-jetPEI. These data suggest that charge ratio optimization has important in vivo implications and that dual hydrophobization strategies can be used to maximize both NP circulation time and safety.

Copyright © 2018 Elsevier Ltd. All rights reserved.

MeSH Terms (14)

Animals Cations Cell Line, Tumor Female Humans Hydrophobic and Hydrophilic Interactions Mice, Inbred BALB C Mice, Nude Nanostructures Neoplasms Polymers RNA, Small Interfering RNAi Therapeutics Tissue Distribution

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