PMID- 31385541
OWN - NLM
STAT- MEDLINE
DCOM- 20200131
LR  - 20200225
IS  - 1521-0464 (Electronic)
IS  - 1071-7544 (Print)
IS  - 1071-7544 (Linking)
VI  - 26
IP  - 1
DP  - 2019 Dec
TI  - Targeting murine alveolar macrophages by the intratracheal administration of 
      locked nucleic acid containing antisense oligonucleotides.
PG  - 803-811
LID - 10.1080/10717544.2019.1648589 [doi]
AB  - The pulmonary delivery of locked nucleic acid containing antisense 
      oligonucleotides (LNA-ASOs) is expected to be a novel therapeutic approach for 
      lung diseases. However, there are two concerns to be considered: immune 
      responses, as the lung has a distinct immune mechanism to protect it from inhaled 
      pathogens; and leakage into blood, since the lung is permeable to small 
      molecules. As phagocytic alveolar macrophages reside in the alveolar space, it is 
      hypothesized that inhaled LNA-ASOs effectively accumulate and exert a knockdown 
      (KD) effect on these cells at low doses. Thus, targeting alveolar macrophages by 
      inhaled LNA-ASOs may reduce these risks. To test this hypothesis, LNA-ASOs 
      targeting Scarb1 or Hprt1 were intratracheally administered to mice. We confirmed 
      the remarkable accumulation of intratracheally administered LNA-ASOs in murine 
      alveolar macrophages and found that they exerted a significant and 
      sequence-dependent KD effect. The dose required for KD in alveolar macrophages 
      was lower than that required to induce KD in the whole lung. Furthermore, when a 
      KD effect was observed in alveolar macrophages, no KD effect was observed in the 
      liver or kidney; however, several inflammatory cytokines were increased in the 
      lung. These results suggest the potential application of LNA-ASOs as an inhaled 
      drug specific to alveolar macrophages. However, further studies on the 
      immuno-stimulatory effects of LNA-ASOs will be necessary for the development of 
      novel inhaled therapeutic agents.
FAU - Uemura, Yasunori
AU  - Uemura Y
AD  - a Immunology & Allergy Research Laboratories, Immunology & Allergy R&D Unit, R&D 
      Division, Kyowa Kirin Co., Ltd , Nagaizumi-cho , Japan.
FAU - Kobayashi, Katsuya
AU  - Kobayashi K
AD  - a Immunology & Allergy Research Laboratories, Immunology & Allergy R&D Unit, R&D 
      Division, Kyowa Kirin Co., Ltd , Nagaizumi-cho , Japan.
LA  - eng
PT  - Journal Article
PL  - England
TA  - Drug Deliv
JT  - Drug delivery
JID - 9417471
RN  - 0 (Oligonucleotides)
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (locked nucleic acid)
SB  - IM
MH  - Animals
MH  - Female
MH  - Injection, Intratympanic/methods
MH  - Kidney/drug effects
MH  - Liver/drug effects
MH  - Lung/drug effects
MH  - Macrophages, Alveolar/*drug effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Oligonucleotides/*administration & dosage
MH  - Oligonucleotides, Antisense/*administration & dosage
PMC - PMC6713109
OTO - NOTNLM
OT  - Pulmonary delivery
OT  - alveolar macrophages
OT  - antisense oligonucleotides
OT  - locked nucleic acid
EDAT- 2019/08/07 06:00
MHDA- 2020/02/01 06:00
PMCR- 2019/08/06
CRDT- 2019/08/07 06:00
PHST- 2019/08/07 06:00 [entrez]
PHST- 2019/08/07 06:00 [pubmed]
PHST- 2020/02/01 06:00 [medline]
PHST- 2019/08/06 00:00 [pmc-release]
AID - 1648589 [pii]
AID - 10.1080/10717544.2019.1648589 [doi]
PST - ppublish
SO  - Drug Deliv. 2019 Dec;26(1):803-811. doi: 10.1080/10717544.2019.1648589.