Abstract
Biomaterials 2021, 268,
Kupffer cell release of platelet activating factor drives dose limiting toxicities of nucleic acid nanocarriers
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
This work establishes that Kupffer cell release of platelet activating factor (PAF), a lipidic molecule with proinflammatory 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 vivojetPEI (R) 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.