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Dual carrier-cargo hydrophobization and charge ratio optimization improve the
systemic circulation and safety of zwitterionic nano-polyplexes.
Authors Jackson MA, Bedingfield SK, Yu F, Stokan ME, Miles RE, Curvino EJ, Hoogenboezem
EN, Bonami RH, Patel SS, Kendall PL, Giorgio TD, Duvall CL
Submitted By Submitted Externally on 6/24/2019
Status Published
Journal Biomaterials
Year 2019
Date Published 2/1/2019
Volume : Pages 192 : 245 - 259
PubMed Reference 30458360
Abstract 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


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