PMID- 29858051
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240214
IS  - 2162-2531 (Print)
IS  - 2162-2531 (Electronic)
IS  - 2162-2531 (Linking)
VI  - 11
DP  - 2018 Jun 1
TI  - Immunogenicity Testing of Lipidoids In Vitro and In Silico: Modulating 
      Lipidoid-Mediated TLR4 Activation by Nanoparticle Design.
PG  - 159-169
LID - S2162-2531(18)30017-9 [pii]
LID - 10.1016/j.omtn.2018.02.003 [doi]
AB  - Therapeutics based on small interfering RNA (siRNA) have promising potential as 
      antiviral and anti-inflammatory agents. To deliver siRNA across cell membranes to 
      reach the RNAi pathway in the cytosol of target cells, non-viral nanoparticulate 
      delivery approaches are explored. Recently, we showed that encapsulation of siRNA 
      in lipid-polymer hybrid nanoparticles (LPNs), based on poly(DL-lactic-co-glycolic 
      acid) (PLGA) and cationic lipid-like materials (lipidoids), remarkably enhances 
      intracellular delivery of siRNA as compared to siRNA delivery with LPNs modified 
      with dioleoyltrimethylammoniumpropane (DOTAP) as the lipid component. However, 
      the potential immune modulation by these cationic lipids remains unexplored. By 
      testing lipidoids and DOTAP for innate immune-receptor-activating properties 
      in vitro, we found that neither lipidoids nor DOTAP activate human Toll-like 
      receptor (TLR) 2, 3, 7, and 9. However, in contrast to DOTAP, lipidoids are 
      strong agonists for TLR4 and activate murine antigen-presenting cells in vitro. 
      This agonistic effect was further confirmed in silico using a prediction model 
      based on crystal structures. Also, lipidoids formulated as lipoplexes or as 
      stable nucleic acid lipid particles, which was the reference formulation for 
      siRNA delivery, proved to activate TLR4. However, by combining lipidoids with 
      PLGA into LPNs, TLR4 activation was abrogated. Thus, lipidoid-mediated TLR4 
      activation during siRNA delivery may be modulated via optimization of the 
      formulation design.
CI  - Copyright (c) 2018 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - de Groot, Anne Marit
AU  - de Groot AM
AD  - Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, 
      the Netherlands.
FAU - Thanki, Kaushik
AU  - Thanki K
AD  - Department of Pharmacy, Faculty of Health and Medical Sciences, University of 
      Copenhagen, 2100 Copenhagen, Denmark.
FAU - Gangloff, Monique
AU  - Gangloff M
AD  - Department of Biochemistry, University of Cambridge, Cambridge, UK.
FAU - Falkenberg, Emily
AU  - Falkenberg E
AD  - Department of Pharmacy, Faculty of Health and Medical Sciences, University of 
      Copenhagen, 2100 Copenhagen, Denmark.
FAU - Zeng, Xianghui
AU  - Zeng X
AD  - Department of Pharmacy, Faculty of Health and Medical Sciences, University of 
      Copenhagen, 2100 Copenhagen, Denmark.
FAU - van Bijnen, Djai C J
AU  - van Bijnen DCJ
AD  - Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, 
      the Netherlands.
FAU - van Eden, Willem
AU  - van Eden W
AD  - Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, 
      the Netherlands.
FAU - Franzyk, Henrik
AU  - Franzyk H
AD  - Department of Drug Design and Pharmacology, Faculty of Health and Medical 
      Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
FAU - Nielsen, Hanne M
AU  - Nielsen HM
AD  - Department of Pharmacy, Faculty of Health and Medical Sciences, University of 
      Copenhagen, 2100 Copenhagen, Denmark.
FAU - Broere, Femke
AU  - Broere F
AD  - Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, 
      the Netherlands.
FAU - Gay, Nick J
AU  - Gay NJ
AD  - Department of Biochemistry, University of Cambridge, Cambridge, UK.
FAU - Foged, Camilla
AU  - Foged C
AD  - Department of Pharmacy, Faculty of Health and Medical Sciences, University of 
      Copenhagen, 2100 Copenhagen, Denmark. Electronic address: 
      camilla.foged@sund.ku.dk.
FAU - Sijts, Alice J A M
AU  - Sijts AJAM
AD  - Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, 
      the Netherlands. Electronic address: e.j.a.m.sijts@uu.nl.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - MR/P02260X/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
DEP - 20180213
PL  - United States
TA  - Mol Ther Nucleic Acids
JT  - Molecular therapy. Nucleic acids
JID - 101581621
PMC - PMC5992342
OTO - NOTNLM
OT  - SNALPs
OT  - TLR4
OT  - immune modulation
OT  - lipid-polymer hybrid nanoparticles
OT  - lipidoids
OT  - lipoplexes
OT  - molecular modeling
OT  - stable nucleic acid lipid particles
EDAT- 2018/06/03 06:00
MHDA- 2018/06/03 06:01
PMCR- 2018/02/13
CRDT- 2018/06/03 06:00
PHST- 2017/08/14 00:00 [received]
PHST- 2018/02/06 00:00 [revised]
PHST- 2018/02/06 00:00 [accepted]
PHST- 2018/06/03 06:00 [entrez]
PHST- 2018/06/03 06:00 [pubmed]
PHST- 2018/06/03 06:01 [medline]
PHST- 2018/02/13 00:00 [pmc-release]
AID - S2162-2531(18)30017-9 [pii]
AID - 10.1016/j.omtn.2018.02.003 [doi]
PST - ppublish
SO  - Mol Ther Nucleic Acids. 2018 Jun 1;11:159-169. doi: 10.1016/j.omtn.2018.02.003. 
      Epub 2018 Feb 13.