Can intracellular drug delivery using hyaluronic acid functionalised pH-sensitive liposomes overcome gemcitabine resistance in pancreatic cancer?

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dc.contributor.author Tang, Mingtan en
dc.contributor.author Svirskis, Darren en
dc.contributor.author Leung, Yee Fun en
dc.contributor.author Kanamala, Manju en
dc.contributor.author Wang, Hongbo en
dc.contributor.author Wu, Zimei en
dc.date.accessioned 2019-10-01T20:01:17Z en
dc.date.issued 2019-05-13 en
dc.identifier.issn 0168-3659 en
dc.identifier.uri http://hdl.handle.net/2292/48228 en
dc.description.abstract Chemoresistance poses a major challenge in cancer treatment. This study aims to investigate whether intracellular drug delivery using hyaluronic acid (HA) functionalised pH-sensitive liposomes (HA-pSL) can circumvent gemcitabine resistance in pancreatic cancer (PC). HA-pSL were obtained by covalently conjugating HA with preformed pSL. A resistant PC cell line Gr2000 was developed by exposing MIA PaCa-2 cells to gemcitabine, and characterised for their expression of CD44, a receptor for HA, and drug transporters. Cellular uptake and intracellular trafficking of liposomes were determined by confocal microscopy and HPLC analysis of intracellular drug content. Following a pharmacokinetic study in rats, anti-tumour efficacy was compared between MIA PaCa-2 and Gr2000 xenograft mouse models. HA-pSL with an HA density of 179 μg/μmol had a larger size (152.3 vs 136.3 nm), and higher zeta potential (-46.8 vs -10.5 mV) than pSL. The sensitivity of Gr2000 to gemcitabine reduced 444 times compared to its parental cell line, despite no change to the total drug influx, as drug influx- and efflux-transporters in Gr2000 cells were simultaneously up-regulated. Both cell lines had high expression of CD44. HA facilitated cell uptake without compromising the endosome-escape ability of pSL as evidenced by confocal images and co-localization analysis of the dual-fluorescence labelled liposomes and Lysotracker. HA-pSL significantly outperformed pSL, and increased cellular drug influx by 3.6 times in MIA PaCa-2 cells, and 4.6 times in Gr2000 cells. Both liposomes improved the pharmacokinetic profile of free drug. HA-pSL treatment was superior to pSL, and resulted in 6.4 times smaller tumours (weight) in the MIA PaCa-2 xenograft models, and 3.1 smaller in the Gr2000 models compared with the free drug. Taken together, this study highlighted the use of intracellular delivery strategies (HA-CD44 interaction and endosome escape) to overcome gemcitabine resistance, however, the overall improvement was marginal and tumours still existed. Further improvement in delivery efficiency of HA-pSL to target tumours and additional manipulation of the cellular metabolism of gemcitabine are needed to tackle chemoresistance. en
dc.format.medium Print-Electronic en
dc.language eng en
dc.relation.ispartofseries Journal of controlled release : official journal of the Controlled Release Society en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.title Can intracellular drug delivery using hyaluronic acid functionalised pH-sensitive liposomes overcome gemcitabine resistance in pancreatic cancer? en
dc.type Journal Article en
dc.identifier.doi 10.1016/j.jconrel.2019.05.018 en
pubs.begin-page 89 en
pubs.volume 305 en
dc.rights.holder Copyright: The author en
pubs.end-page 100 en
pubs.publication-status Published en
dc.rights.accessrights http://purl.org/eprint/accessRights/RestrictedAccess en
pubs.subtype Journal Article en
pubs.elements-id 773741 en
pubs.org-id Medical and Health Sciences en
pubs.org-id Medical Sciences en
pubs.org-id Auckland Cancer Research en
pubs.org-id Pharmacy en
dc.identifier.eissn 1873-4995 en
pubs.record-created-at-source-date 2019-05-17 en
pubs.dimensions-id 31096017 en


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