PMID- 32441510
OWN - NLM
STAT- MEDLINE
DCOM- 20210514
LR  - 20210624
IS  - 1936-086X (Electronic)
IS  - 1936-0851 (Print)
IS  - 1936-0851 (Linking)
VI  - 14
IP  - 6
DP  - 2020 Jun 23
TI  - Targeted Delivery of Notch Inhibitor Attenuates Obesity-Induced Glucose 
      Intolerance and Liver Fibrosis.
PG  - 6878-6886
LID - 10.1021/acsnano.0c01007 [doi]
AB  - As the prevalence of obesity-induced type 2 diabetes mellitus (T2DM) and 
      nonalcoholic steatohepatitis (NASH) continue to increase, the need for 
      pharmacologic therapies becomes urgent. However, endeavors to identify and 
      develop novel therapeutic strategies for these chronic conditions are balanced by 
      the need for safety, impeding clinical translation. One shared pathology of these 
      two diseases is a maladaptive reactivation of the Notch signaling pathway in 
      liver. Notch antagonism with gamma-secretase inhibitors effectively suppresses 
      hepatic glucose production and reduces liver fibrosis in NASH, but its 
      extrahepatic side effects, particularly goblet cell metaplasia, limit therapeutic 
      utility. To overcome this barrier, we developed a nanoparticle-mediated delivery 
      system to target gamma-secretase inhibitor to liver (GSI NPs). GSI NP application 
      reduced hepatic glucose production in diet-induced obese mice and reduced hepatic 
      fibrosis and inflammation in mice fed a NASH-provoking diet, without apparent 
      gastrointestinal toxicity. By changing the delivery method, these results provide 
      proof-of-concept for the repurposing of a previously intolerable medication to 
      address unmet needs in the clinical landscape for obesity-induced T2DM and NASH.
FAU - Richter, Lauren R
AU  - Richter LR
AUID- ORCID: 0000-0001-7319-0480
FAU - Wan, Qianfen
AU  - Wan Q
FAU - Wen, Di
AU  - Wen D
AD  - Department of Bioengineering, University of California, Los Angeles, California 
      90095, United States.
AD  - California NanoSystems Institute, Jonsson Comprehensive Cancer Center and Center 
      for Minimally Invasive Therapeutics, University of California, Los Angeles, 
      California 90095, United States.
AD  - Joint Department of Biomedical Engineering, University of North Carolina at 
      Chapel Hill and North Carolina State University, Raleigh, North Carolina 27695, 
      United States.
FAU - Zhang, Yuqi
AU  - Zhang Y
AD  - Department of Bioengineering, University of California, Los Angeles, California 
      90095, United States.
AD  - Joint Department of Biomedical Engineering, University of North Carolina at 
      Chapel Hill and North Carolina State University, Raleigh, North Carolina 27695, 
      United States.
FAU - Yu, Junjie
AU  - Yu J
FAU - Kang, Jin Ku
AU  - Kang JK
FAU - Zhu, Changyu
AU  - Zhu C
AD  - Department of Medicine, Columbia University, New York, New York 10032, United 
      States.
AD  - Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial 
      Sloan Kettering Cancer Center, New York, New York 10065, United States.
FAU - McKinnon, Elizabeth L
AU  - McKinnon EL
AD  - Department of Pathology and Laboratory Medicine, University of British Columbia, 
      Vancouver, British Columbia V6T 2B5, Canada.
FAU - Gu, Zhen
AU  - Gu Z
AD  - Department of Bioengineering, University of California, Los Angeles, California 
      90095, United States.
AD  - California NanoSystems Institute, Jonsson Comprehensive Cancer Center and Center 
      for Minimally Invasive Therapeutics, University of California, Los Angeles, 
      California 90095, United States.
AD  - Joint Department of Biomedical Engineering, University of North Carolina at 
      Chapel Hill and North Carolina State University, Raleigh, North Carolina 27695, 
      United States.
FAU - Qiang, Li
AU  - Qiang L
FAU - Pajvani, Utpal B
AU  - Pajvani UB
AUID- ORCID: 0000-0001-5991-2723
LA  - eng
GR  - R01 DK112943/DK/NIDDK NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - T32 DK065522/DK/NIDDK NIH HHS/United States
GR  - R01 DK103818/DK/NIDDK NIH HHS/United States
GR  - R01 DK119767/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200522
PL  - United States
TA  - ACS Nano
JT  - ACS nano
JID - 101313589
SB  - IM
MH  - Animals
MH  - *Diabetes Mellitus, Type 2/pathology
MH  - Disease Models, Animal
MH  - *Glucose Intolerance/drug therapy/pathology
MH  - Liver/pathology
MH  - Liver Cirrhosis/drug therapy/pathology
MH  - Mice
MH  - Obesity/drug therapy
PMC - PMC7444843
MID - NIHMS1612808
OTO - NOTNLM
OT  - Notch inhibitor
OT  - drug delivery
OT  - liver fibrosis
OT  - nanomedicine
OT  - nonalcoholic steatohepatitis
OT  - obesity
COIS- The authors declare the following competing financial interest(s): The authors 
      have applied for a patent for GSI NPs. ASSOCIATED CONTENT Supporting Information 
      The Supporting Information is available free of charge at 
      https://pubs.acs.org/doi/10.1021/acsnano.0c01007. Serum lipids, liver lipids, 
      transaminases, and comparison of hair graying between unencapsulated GSI and GSI 
      NPs (Figures S1-S3) (PDF) Complete contact information is available at: 
      https://pubs.acs.org/10.1021/acsnano.0c01007
EDAT- 2020/05/23 06:00
MHDA- 2021/05/15 06:00
PMCR- 2021/06/23
CRDT- 2020/05/23 06:00
PHST- 2020/05/23 06:00 [pubmed]
PHST- 2021/05/15 06:00 [medline]
PHST- 2020/05/23 06:00 [entrez]
PHST- 2021/06/23 00:00 [pmc-release]
AID - 10.1021/acsnano.0c01007 [doi]
PST - ppublish
SO  - ACS Nano. 2020 Jun 23;14(6):6878-6886. doi: 10.1021/acsnano.0c01007. Epub 2020 
      May 22.