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Kupffer cell release of platelet activating factor drives dose limiting
toxicities of nucleic acid nanocarriers.
Authors Jackson MA, Patel SS, Yu F, Cottam MA, Glass EB, Hoogenboezem EN, Fletcher RB,
Dollinger BR, Patil P, Liu DD, Kelly IB, Bedingfield SK, King AR, Miles RE,
Hasty AM, Giorgio TD, Duvall CL
Submitted By Submitted Externally on 2/22/2021
Status Published
Journal Biomaterials
Year 2021
Date Published 1/1/2021
Volume : Pages 268 : 120528
PubMed Reference 33285438
Abstract This work establishes that Kupffer cell release of platelet activating factor
(PAF), a lipidic molecule with pro-inflammatory and vasoactive signaling
properties, dictates dose-limiting siRNA nanocarrier-associated toxicities.
High-dose intravenous injection of siRNA-polymer nano-polyplexes (si-NPs)
elicited acute, shock-like symptoms in mice, associated with increased plasma
PAF and consequently reduced PAF acetylhydrolase (PAF-AH) activity. These
symptoms were completely prevented by prophylactic PAF receptor inhibition or
Kupffer cell depletion. Assessment of varied si-NP chemistries confirmed that
toxicity level correlated to relative uptake of the carrier by liver Kupffer
cells and that this toxicity mechanism is dependent on carrier endosome
disruptive function. 4T1 tumor-bearing mice, which exhibit increased circulating
leukocytes, displayed greater sensitivity to these toxicities. PAF-mediated
toxicities were generalizable to commercial delivery reagent in vivo-jetPEI® and
an MC3 lipid formulation matched to an FDA-approved nanomedicine. These
collective results establish Kupffer cell release of PAF as a key mediator of
siRNA nanocarrier toxicity and identify PAFR inhibition as an effective strategy
to increase siRNA nanocarrier tolerated dose.


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