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Development of a gemcitabine-polymer conjugate with prolonged cytotoxicity against a pancreatic cancer cell line

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Joubert, Fanny, Martin, Liam T., Perrier, Sébastien and Pasparakis, George (2017) Development of a gemcitabine-polymer conjugate with prolonged cytotoxicity against a pancreatic cancer cell line. ACS Macro Letters, 6 (5). pp. 535-540. doi:10.1021/acsmacrolett.7b00160

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Official URL: http://dx.doi.org/10.1021/acsmacrolett.7b00160

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Abstract

Gemcitabine (GEM) is a nucleoside analogue of deoxycytidine with limited therapeutic efficacy due to enzymatic hydrolysis by cytidine deaminase (CDA) resulting in compromised half-life in the bloodstream and poor pharmacokinetics. To overcome these limitations, we have developed a methacrylate-based GEM-monomer conjugate, which was polymerized by reversible addition–fragmentation chain transfer (RAFT) polymerization with high monomer conversion (∼90%) and low dispersity (<1.4). The resulting GEM-polymer conjugates were found to form well-defined sub-90 nm nanoparticles (NPs) in aqueous suspension. Subsequently, the GEM release was studied at different pH (∼7 and ∼5) with and without the presence of an enzyme, Cathepsin B. The GEM release profiles followed a pseudo zero-order rate and the GEM-polymer conjugate NPs were prone to acidic and enzymatic degradation, following a two-step hydrolysis mechanism. Furthermore, the NPs exhibited significant cytotoxicity in vitro against a model pancreatic cell line. Although, the half-maximal inhibitory concentration (IC50) of the GEM-monomer and -polymer conjugate NPs was higher than free GEM, the conjugates showed superiorly prolonged activity compared to the parent drug.

Item Type: Journal Article
Subjects: Q Science > QD Chemistry
Q Science > QR Microbiology > QR180 Immunology
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculty of Science, Engineering and Medicine > Science > Chemistry
Library of Congress Subject Headings (LCSH): Conjugated polymers, Cell-mediated cytotoxicity, Pancreas -- Cancer, Nanoparticles
Journal or Publication Title: ACS Macro Letters
Publisher: American Chemical Society
ISSN: 2161-1653
Official Date: 26 April 2017
Dates:
DateEvent
26 April 2017Published
26 April 2017Accepted
Volume: 6
Number: 5
Page Range: pp. 535-540
DOI: 10.1021/acsmacrolett.7b00160
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
Funder: Engineering and Physical Sciences Research Council (EPSRC), University College, London. Excellence Fellowship Award, Royal Society (Great Britain). Wolfson Research Merit Award (RSWRMA), Monash-Warwick Alliance
Grant number: EP/M014649/1 (EPSRC), WM130055 (RSWRMA)

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