Kupffer cell release of platelet activating factor drives dose limiting toxicities of nucleic acid nanocarriers
| Autor: | Evan B. Glass, Allyson R. King, Isom B. Kelly, Alyssa M. Hasty, Prarthana Patil, Todd D. Giorgio, Bryan R. Dollinger, Fang Yu, Sean K. Bedingfield, Rachel E. Miles, Shrusti S. Patel, Meredith A. Jackson, Danielle D. Liu, Ella N. Hoogenboezem, Craig L. Duvall, Matthew A. Cottam |
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| Rok vydání: | 2020 |
| Předmět: |
PAF acetylhydrolase
Endosome Kupffer Cells Biophysics Bioengineering 02 engineering and technology Pharmacology Article Biomaterials 03 medical and health sciences chemistry.chemical_compound Mice Therapeutic index Mediator In vivo medicine Animals RNA Messenger Platelet Activating Factor 030304 developmental biology 0303 health sciences Innate immune system Platelet-activating factor Chemistry Kupffer cell Biological Transport Lipid signaling 021001 nanoscience & nanotechnology medicine.anatomical_structure Mechanics of Materials Toxicity Ceramics and Composites Nucleic acid lipids (amino acids peptides and proteins) Nanocarriers 0210 nano-technology Signal Transduction |
| Zdroj: | Biomaterials |
| ISSN: | 1878-5905 |
| Popis: | In vivonanocarrier-associated toxicity is a significant and poorly understood hurdle to clinical translation of siRNA nanomedicines. In this work, we demonstrate that platelet activating factor (PAF), an inflammatory lipid mediator, plays a key role in nanocarrier-associated toxicities, and that prophylactic inhibition of the PAF receptor (PAFR) completely prevents these toxicities. High-dose intravenous injection of siRNA-polymer nano-complexes (si-NPs) elicited acute, shock-like symptoms (vasodilation and vascular leak) in mice and caused a three-fold increase in blood PAF levels. PAFR inhibition completely prevented these toxicities, indicating PAF activity is a primary driver of systemic si-NP toxicity. Pre-treatment with clodronate liposomes fully abrogated si-NP-associated increases in blood PAF and consequent toxicities, suggesting that nanoparticle uptake by Kupffer macrophages is the source of PAF. Assessment of varied si-NP chemistries further confirmed that toxicity level correlated to relative uptake of the carrier by liver Kupffer cells and that this toxicity mechanism is dependent on the endosome disruptive function of the carrier. Finally, the PAF toxicity mechanism was shown to be generalizable to commercial delivery reagentin vivo-jetPEI®and an MC3 lipid nanoparticle formulated to match an FDA-approved siRNA nanomedicine. Greater sensitivity to the PAF mechanism occurs in 4T1 tumor-bearing mice, a mammary tumor model known to exhibit increased circulating leukocytes and potential to respond to inflammatory insult. These results establish Kupffer cell release of PAF as a key mediator ofin vivonucleic acid nanocarrier toxicity and identify PAFR inhibition as an effective prophylactic strategy to increase maximum tolerated dose and reduce nanocarrier-associated adverse events.SignificanceNon-viral nucleic acid nanocarriers can enablein vivogene therapy, but their potential interaction with innate immune cells can cause dose-limiting toxicities. Nanoparticle toxicities are currently poorly understood, making it difficult to identify relevant design criteria for maximizing nanoparticle safety. This work connects nanoparticle-associated toxicities to the release of platelet activating factor (PAF) by liver Kupffer cells. Small molecule inhibition of the PAF receptor (PAFR) completely prevents severe adverse events associated with high doses of multiple polymer-based formulations and a lipid nanoparticle matching the composition of the first clinically-approved siRNA nanomedicine. This study identifies PAF as a toxicity biomarker for future nanomedicine discovery programs. Further, PAFR inhibition should be explored as a strategy to expand the therapeutic index of nanomedicines. |
| Databáze: | OpenAIRE |
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