PMID- 31306426
OWN - NLM
STAT- MEDLINE
DCOM- 20200217
LR  - 20200309
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 14
IP  - 7
DP  - 2019
TI  - A Warburg effect targeting vector designed to increase the uptake of compounds by 
      cancer cells demonstrates glucose and hypoxia dependent uptake.
PG  - e0217712
LID - 10.1371/journal.pone.0217712 [doi]
LID - e0217712
AB  - Glycoconjugation to target the Warburg effect provides the potential to enhance 
      selective uptake of anticancer or imaging agents by cancer cells. A Warburg 
      effect targeting group, rationally designed to facilitate uptake by glucose 
      transporters and promote cellular accumulation due to phosphorylation by 
      hexokinase (HK), has been synthesised. This targeting group, the C2 modified 
      glucose analogue 2-(2-[2-(2-aminoethoxy)ethoxy]ethoxy)-D-glucose, has been 
      conjugated to the fluorophore nitrobenzoxadiazole to evaluate its effect on 
      uptake and accumulation in cancer cells. The targeting vector has demonstrated 
      inhibition of glucose phosphorylation by HK, indicating its interaction with the 
      enzyme and thereby confirming the potential to facilitate an intracellular 
      trapping mechanism for compounds it is conjugated with. The cellular uptake of 
      the fluorescent analogue is dependent on the glucose concentration and is so to a 
      greater extent than is that of the widely used fluorescent glucose analogue, 
      2-NBDG. It also demonstrates selective uptake in the hypoxic regions of 3D 
      spheroid tumour models whereas 2-NBDG is distributed primarily through the 
      normoxic regions of the spheroid. The increased selectivity is consistent with 
      the blocking of alternative uptake pathways.
FAU - Glenister, Alexandra
AU  - Glenister A
AD  - School of Chemistry, University of Sydney, Camperdown, New South Wales, 
      Australia.
FAU - Simone, Michela I
AU  - Simone MI
AUID- ORCID: 0000-0002-1339-8236
AD  - Discipline of Chemistry, Priority Research Centre for Chemical Biology & Clinical 
      Pharmacology, University of Newcastle, Callaghan, New South Wales, Australia.
FAU - Hambley, Trevor W
AU  - Hambley TW
AUID- ORCID: 0000-0003-1194-1896
AD  - School of Chemistry, University of Sydney, Camperdown, New South Wales, 
      Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190715
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Glucose Transport Proteins, Facilitative)
RN  - 0 (Neoplasm Proteins)
RN  - 9G2MP84A8W (Deoxyglucose)
RN  - EC 2.7.1.1 (Hexokinase)
RN  - EQF2794IRE (4-Chloro-7-nitrobenzofurazan)
RN  - IY9XDZ35W2 (Glucose)
RN  - JE4F4P486R (2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose)
SB  - IM
MH  - 4-Chloro-7-nitrobenzofurazan/*analogs & derivatives/pharmacokinetics/pharmacology
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Deoxyglucose/*analogs & derivatives/pharmacokinetics/pharmacology
MH  - *Drug Delivery Systems
MH  - *Glucose/pharmacokinetics/pharmacology
MH  - Glucose Transport Proteins, Facilitative/*metabolism
MH  - Hexokinase/*metabolism
MH  - Humans
MH  - *Models, Biological
MH  - Neoplasm Proteins/*metabolism
MH  - *Neoplasms/drug therapy/metabolism/pathology
PMC - PMC6629077
COIS- The authors have declared that no competing interests exist.
EDAT- 2019/07/16 06:00
MHDA- 2020/02/18 06:00
PMCR- 2019/07/15
CRDT- 2019/07/16 06:00
PHST- 2019/02/06 00:00 [received]
PHST- 2019/05/16 00:00 [accepted]
PHST- 2019/07/16 06:00 [entrez]
PHST- 2019/07/16 06:00 [pubmed]
PHST- 2020/02/18 06:00 [medline]
PHST- 2019/07/15 00:00 [pmc-release]
AID - PONE-D-19-03652 [pii]
AID - 10.1371/journal.pone.0217712 [doi]
PST - epublish
SO  - PLoS One. 2019 Jul 15;14(7):e0217712. doi: 10.1371/journal.pone.0217712. 
      eCollection 2019.