PMID- 31398360
OWN - NLM
STAT- MEDLINE
DCOM- 20201015
LR  - 20201015
IS  - 1873-4995 (Electronic)
IS  - 0168-3659 (Linking)
VI  - 310
DP  - 2019 Sep 28
TI  - Mechanistic profiling of the release kinetics of siRNA from lipidoid-polymer 
      hybrid nanoparticles in vitro and in vivo after pulmonary administration.
PG  - 82-93
LID - S0168-3659(19)30468-7 [pii]
LID - 10.1016/j.jconrel.2019.08.004 [doi]
AB  - Understanding the release kinetics of siRNA from nanocarriers, their cellular 
      uptake, their in vivo biodistribution and pharmacokinetics is a fundamental 
      prerequisite for efficient optimisation of the design of nanocarriers for 
      siRNA-based therapeutics. Thus, we investigated the influence of composition on 
      the siRNA release from lipid-polymer hybrid nanoparticles (LPNs) consisting of 
      cationic lipidoid 5 (L(5)) and poly(DL-lactic-co-glycolic acid) (PLGA) intended 
      for pulmonary administration. An array of siRNA-loaded LPNs was prepared by 
      systematic variation of: (i) the L(5) content (10-20%, w/w), and (ii) the 
      L(5):siRNA ratio (10,1-30:1, w/w). For comparative purposes, L(5)-based 
      lipoplexes, L(5)-based stable nucleic acid lipid nanoparticles (SNALPs). and 
      dioleoyltrimethylammoniumpropane (DOTAP)-modified LPNs loaded with siRNA were 
      also prepared. Release studies in buffer and lung surfactant-containing medium 
      showed that siRNA release is dependent on the presence of both surfactant and 
      heparin (a displacing agent) in the release medium, since these interact with the 
      lipid shell structure thereby facilitating decomplexation of L(5) and siRNA, as 
      evident from the retarded siRNA release when the L(5) content and the L(5):siRNA 
      ratio were increased. This confirms the hypothesis that siRNA loaded in LPNs is 
      predominantly present as complexes with the cationic lipid and primarily is 
      located near the particle surface. Cellular uptake and tolerability studies in 
      the human macrophage cell line THP-1 and the type I-like human alveolar 
      epithelial cell line hAELVi, which together represents a monolayer-based barrier 
      model of lung epithelium, indicated that uptake of LPNs was much higher in THP-1 
      cells in agreement with their primary clearance role. In vivo biodistributions of 
      formulations loaded with Alexa Fluor(R) 750-labelled siRNA after pulmonary 
      administration in mice were compared by using quantitative fluorescence imaging 
      tomography. The L(5)-modified LPNs, SNALPs and DOTAP-modified LPNs displayed 
      significantly increased lung retention of siRNA as compared to L(5)-based 
      lipoplexes, which had a biodistribution profile comparable to that of non-loaded 
      siRNA, for which >50% of the siRNA dose permeated the air-blood barrier within 
      6 h and subsequently was excreted via the kidneys. Hence, the enhanced lung 
      retention upon pulmonary administration of siRNA-loaded LPNs represents a 
      promising characteristic that can be used to control the delivery of the siRNA 
      cargo to lung tissue for local management of disease.
CI  - Copyright (c) 2019 Elsevier B.V. All rights reserved.
FAU - Thanki, Kaushik
AU  - Thanki K
AD  - Department of Pharmacy, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Universitetsparken 2, DK-2100 Copenhagen O, Denmark.
FAU - van Eetvelde, Delphine
AU  - van Eetvelde D
AD  - Department of Pharmacy, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Universitetsparken 2, DK-2100 Copenhagen O, Denmark.
FAU - Geyer, Antonia
AU  - Geyer A
AD  - Laboratory of MacroMolecular Cancer Therapeutics (MMCT), Department of 
      Pharmaceutical Chemistry, University of Vienna, Vienna A-1090, Austria.
FAU - Fraire, Juan
AU  - Fraire J
AD  - Laboratory for General Biochemistry and Physical Pharmacy, Ghent University, 9000 
      Gent, Belgium.
FAU - Hendrix, Remi
AU  - Hendrix R
AD  - Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland 
      University, 66123 Saarbrucken, Germany.
FAU - Van Eygen, Hannelore
AU  - Van Eygen H
AD  - Department of Pharmacy, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Universitetsparken 2, DK-2100 Copenhagen O, Denmark.
FAU - Putteman, Emma
AU  - Putteman E
AD  - Department of Pharmacy, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Universitetsparken 2, DK-2100 Copenhagen O, Denmark.
FAU - Sami, Haider
AU  - Sami H
AD  - Laboratory of MacroMolecular Cancer Therapeutics (MMCT), Department of 
      Pharmaceutical Chemistry, University of Vienna, Vienna A-1090, Austria.
FAU - de Souza Carvalho-Wodarz, Cristiane
AU  - de Souza Carvalho-Wodarz C
AD  - Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland 
      University, 66123 Saarbrucken, Germany.
FAU - Franzyk, Henrik
AU  - Franzyk H
AD  - Department of Drug Design and Pharmacology, Faculty of Health and Medical 
      Sciences, University of Copenhagen, Jagtvej 162, DK-2100 Copenhagen O, Denmark.
FAU - Nielsen, Hanne Morck
AU  - Nielsen HM
AD  - Department of Pharmacy, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Universitetsparken 2, DK-2100 Copenhagen O, Denmark.
FAU - Braeckmans, Kevin
AU  - Braeckmans K
AD  - Laboratory for General Biochemistry and Physical Pharmacy, Ghent University, 9000 
      Gent, Belgium.
FAU - Lehr, Claus-Michael
AU  - Lehr CM
AD  - Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland 
      University, 66123 Saarbrucken, Germany.
FAU - Ogris, Manfred
AU  - Ogris M
AD  - Laboratory of MacroMolecular Cancer Therapeutics (MMCT), Department of 
      Pharmaceutical Chemistry, University of Vienna, Vienna A-1090, Austria.
FAU - Foged, Camilla
AU  - Foged C
AD  - Department of Pharmacy, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Universitetsparken 2, DK-2100 Copenhagen O, Denmark. Electronic 
      address: camilla.foged@sund.ku.dk.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190806
PL  - Netherlands
TA  - J Control Release
JT  - Journal of controlled release : official journal of the Controlled Release 
      Society
JID - 8607908
RN  - 0 (Drug Carriers)
RN  - 0 (Lipids)
RN  - 0 (RNA, Small Interfering)
RN  - 1SIA8062RS (Polylactic Acid-Polyglycolic Acid Copolymer)
SB  - IM
MH  - Administration, Inhalation
MH  - Animals
MH  - Drug Carriers/*chemistry
MH  - Drug Liberation
MH  - Epithelial Cells/drug effects/metabolism
MH  - Gene Silencing
MH  - Humans
MH  - Lipids/*chemistry
MH  - Lung/*drug effects/metabolism
MH  - Macrophages, Alveolar/drug effects/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Models, Theoretical
MH  - Nanoparticles/*chemistry
MH  - Polylactic Acid-Polyglycolic Acid Copolymer/*chemistry
MH  - RNA, Small Interfering/*administration & dosage/pharmacokinetics
MH  - THP-1 Cells
MH  - Tissue Distribution
OTO - NOTNLM
OT  - Drug delivery
OT  - Imaging
OT  - Lipid-polymer hybrid nanoparticles (LPNs)
OT  - Lipidoids
OT  - Nanomedicine
OT  - Pulmonary administration
OT  - Release
OT  - siRNA
EDAT- 2019/08/10 06:00
MHDA- 2020/10/21 06:00
CRDT- 2019/08/10 06:00
PHST- 2019/04/30 00:00 [received]
PHST- 2019/08/04 00:00 [revised]
PHST- 2019/08/05 00:00 [accepted]
PHST- 2019/08/10 06:00 [pubmed]
PHST- 2020/10/21 06:00 [medline]
PHST- 2019/08/10 06:00 [entrez]
AID - S0168-3659(19)30468-7 [pii]
AID - 10.1016/j.jconrel.2019.08.004 [doi]
PST - ppublish
SO  - J Control Release. 2019 Sep 28;310:82-93. doi: 10.1016/j.jconrel.2019.08.004. 
      Epub 2019 Aug 6.