PMID- 22085632
OWN - NLM
STAT- MEDLINE
DCOM- 20120504
LR  - 20161125
IS  - 1879-0720 (Electronic)
IS  - 0928-0987 (Linking)
VI  - 45
IP  - 1-2
DP  - 2012 Jan 23
TI  - Chitosan-based therapeutic nanoparticles for combination gene therapy and gene 
      silencing of in vitro cell lines relevant to type 2 diabetes.
PG  - 138-49
LID - 10.1016/j.ejps.2011.10.029 [doi]
AB  - Glucagon like peptide 1 (GLP-1), a blood glucose homeostasis modulating incretin, 
      has been proposed for the treatment of type 2 diabetes mellitus (T2DM). However, 
      native GLP-1 pharmacokinetics reveals low bioavailability due to degradation by 
      the ubiquitous dipeptydil peptidase IV (DPP-IV) endoprotease. In this study, the 
      glucosamine-based polymer chitosan was used as a cationic polymer-based in vitro 
      delivery system for GLP-1, DPP-IV resistant GLP-1 analogues and siRNA targeting 
      DPP-IV mRNA. We found chitosans to form spherical nanocomplexes with these 
      nucleic acids, generating two distinct non-overlapping size ranges of 141-283 nm 
      and 68-129 nm for plasmid and siRNA, respectively. The low molecular weight high 
      DDA chitosan 92-10-5 (degree of deacetylation, molecular weight and N:P ratio 
      (DDA-Mn-N:P)) showed the highest plasmid DNA transfection efficiency in HepG2 and 
      Caco-2 cell lines when compared to 80-10-10 and 80-80-5 chitosans. Recombinant 
      native GLP-1 protein levels in media of transfected cells reached 23 ng/L while 
      our DPP-IV resistant analogues resulted in a fivefold increase of GLP-1 protein 
      levels (115 ng/L) relative to native GLP-1, and equivalent to the Lipofectamine 
      positive control. We also found that all chitosan-DPP-IV siRNA nanocomplexes were 
      capable of DPP-IV silencing, with 92-10-5 being significantly more effective in 
      abrogating enzymatic activity of DPP-IV in media of silenced cells, and with no 
      apparent cytotoxicity. These results indicate that specific chitosan formulations 
      may be effectively used for the delivery of plasmid DNA and siRNA in a 
      combination therapy of type 2 diabetes.
CI  - Copyright (c) 2011 Elsevier B.V. All rights reserved.
FAU - Jean, Myriam
AU  - Jean M
AD  - Institute of Biomedical Engineering, Department of Chemical Engineering, Ecole 
      Polytechnique, P.O. Box 6079, Station Centre-ville, Montreal, Quebec, Canada.
FAU - Alameh, Mohamad
AU  - Alameh M
FAU - De Jesus, Diogo
AU  - De Jesus D
FAU - Thibault, Marc
AU  - Thibault M
FAU - Lavertu, Marc
AU  - Lavertu M
FAU - Darras, Vincent
AU  - Darras V
FAU - Nelea, Monica
AU  - Nelea M
FAU - Buschmann, Michael D
AU  - Buschmann MD
FAU - Merzouki, Abderrazzak
AU  - Merzouki A
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111109
PL  - Netherlands
TA  - Eur J Pharm Sci
JT  - European journal of pharmaceutical sciences : official journal of the European 
      Federation for Pharmaceutical Sciences
JID - 9317982
RN  - 0 (Dipeptidyl-Peptidase IV Inhibitors)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 89750-14-1 (Glucagon-Like Peptide 1)
RN  - 9012-76-4 (Chitosan)
RN  - EC 3.4.14.5 (DPP4 protein, human)
RN  - EC 3.4.14.5 (Dipeptidyl Peptidase 4)
SB  - IM
MH  - Acetylation
MH  - Caco-2 Cells
MH  - Chemical Phenomena
MH  - Chitosan/adverse effects/*chemistry
MH  - Diabetes Mellitus, Type 2/genetics/therapy
MH  - Dipeptidyl Peptidase 4/chemistry/genetics/metabolism
MH  - Dipeptidyl-Peptidase IV Inhibitors/administration & dosage/chemistry/*metabolism
MH  - *Gene Silencing
MH  - *Gene Transfer Techniques
MH  - Genetic Therapy/methods
MH  - Glucagon-Like Peptide 1/*analogs & derivatives/genetics/metabolism/therapeutic 
      use
MH  - HT29 Cells
MH  - Hep G2 Cells
MH  - Humans
MH  - Molecular Weight
MH  - Nanoparticles/adverse effects/*chemistry/ultrastructure
MH  - Particle Size
MH  - RNA, Small Interfering/administration & dosage/chemistry/*metabolism
MH  - Recombinant Fusion Proteins/genetics/metabolism/therapeutic use
MH  - Recombinant Proteins/genetics/metabolism/therapeutic use
EDAT- 2011/11/17 06:00
MHDA- 2012/05/05 06:00
CRDT- 2011/11/17 06:00
PHST- 2011/06/13 00:00 [received]
PHST- 2011/09/20 00:00 [revised]
PHST- 2011/10/31 00:00 [accepted]
PHST- 2011/11/17 06:00 [entrez]
PHST- 2011/11/17 06:00 [pubmed]
PHST- 2012/05/05 06:00 [medline]
AID - S0928-0987(11)00389-7 [pii]
AID - 10.1016/j.ejps.2011.10.029 [doi]
PST - ppublish
SO  - Eur J Pharm Sci. 2012 Jan 23;45(1-2):138-49. doi: 10.1016/j.ejps.2011.10.029. 
      Epub 2011 Nov 9.