PMID- 24143095
OWN - NLM
STAT- MEDLINE
DCOM- 20140404
LR  - 20220331
IS  - 1178-2013 (Electronic)
IS  - 1176-9114 (Print)
IS  - 1176-9114 (Linking)
VI  - 8
DP  - 2013
TI  - Targeting miRNA-based medicines to cystic fibrosis airway epithelial cells using 
      nanotechnology.
PG  - 3907-15
LID - 10.2147/IJN.S47551 [doi]
AB  - Cystic fibrosis (CF) is an inherited disorder characterized by chronic airway 
      inflammation. microRNAs (miRNAs) are endogenous small RNAs which act on messenger 
      (m) RNA at a post transcriptional level, and there is a growing understanding 
      that altered expression of miRNA is involved in the CF phenotype. Modulation of 
      miRNA by replacement using miRNA mimics (premiRs) presents a new therapeutic 
      paradigm for CF, but effective and safe methods of delivery to the CF epithelium 
      are limiting clinical translation. Herein, polymeric nanoparticles are 
      investigated for delivery of miRNA mimics into CF airway epithelial cells, using 
      miR-126 as a proof-of-concept premiR cargo to determine efficiency. Two polymers, 
      polyethyleneimine (PEI) and chitosan, were used to prepare miRNA nanomedicines, 
      characterized for their size, surface (zeta) potential, and RNA complexation 
      efficiency, and screened for delivery and cytotoxicity in CFBE41o- (human F508del 
      cystic fibrosis transmembrane conductance regulator bronchial epithelial) cells 
      using a novel high content analysis method. RNA extraction was carried out 24 
      hours post transfection, and miR-126 and TOM1 (target of Myb1) expression (a 
      validated miR-126 target) was assessed. Manufacture was optimized to produce 
      small nanoparticles that effectively complexed miRNA. Using high content 
      analysis, PEI-based nanoparticles were more effective than chitosan-based 
      nanoparticles in facilitating uptake of miRNA into CFBE41o- cells and this was 
      confirmed in miR-126 assays. PEI-premiR-126 nanoparticles at low 
      nitrogen/phosphate (N/P) ratios resulted in significant knockdown of TOM1 in 
      CFBE41o- cells, with the most significant reduction of 66% in TOM1 expression 
      elicited at an N/P ratio of 1:1 while chitosan-based miR-126 nanomedicines failed 
      to facilitate statistically significant knockdown of TOM1 and both nanoparticles 
      appeared relatively nontoxic. miRNA nanomedicine uptake can be qualitatively and 
      quantitatively assessed rapidly by high content analysis and is highly 
      polymer-dependent but, interestingly, there is not a direct correlation between 
      the levels of miRNA uptake and the downstream gene knockdown. Polymeric 
      nanoparticles can deliver premiRs effectively to CFBEs in order to modulate gene 
      expression but must be tailored specifically for miRNA delivery.
FAU - McKiernan, Paul J
AU  - McKiernan PJ
AD  - Respiratory Research Division, Department of Medicine, Royal College of Surgeons 
      in Ireland Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
FAU - Cunningham, Orla
AU  - Cunningham O
FAU - Greene, Catherine M
AU  - Greene CM
FAU - Cryan, Sally-Ann
AU  - Cryan SA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131011
PL  - New Zealand
TA  - Int J Nanomedicine
JT  - International journal of nanomedicine
JID - 101263847
RN  - 0 (MicroRNAs)
RN  - 0 (Nanocapsules)
SB  - IM
MH  - Cell Line
MH  - Cystic Fibrosis/genetics/pathology/*therapy
MH  - Epithelial Cells
MH  - Genetic Therapy/*methods
MH  - Humans
MH  - MicroRNAs/*administration & dosage/chemistry/*genetics
MH  - Nanocapsules/*administration & dosage/*chemistry/ultrastructure
MH  - Particle Size
MH  - Respiratory Mucosa/*physiopathology
PMC - PMC3798151
OTO - NOTNLM
OT  - TOM1
OT  - cystic fibrosis
OT  - high content analysis
OT  - inflammation
OT  - miR-126
OT  - nanotechnology
EDAT- 2013/10/22 06:00
MHDA- 2014/04/05 06:00
PMCR- 2013/10/11
CRDT- 2013/10/22 06:00
PHST- 2013/10/22 06:00 [entrez]
PHST- 2013/10/22 06:00 [pubmed]
PHST- 2014/04/05 06:00 [medline]
PHST- 2013/10/11 00:00 [pmc-release]
AID - ijn-8-3907 [pii]
AID - 10.2147/IJN.S47551 [doi]
PST - ppublish
SO  - Int J Nanomedicine. 2013;8:3907-15. doi: 10.2147/IJN.S47551. Epub 2013 Oct 11.