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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 ISSN 2161-1653.
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WRAP-development-gemcitabine-polymer-conjugate-prolonged-cytotoxicity-Perrier-2017.pdf - Accepted Version - Requires a PDF viewer. Download (1374Kb) | Preview |
Official URL: http://dx.doi.org/10.1021/acsmacrolett.7b00160
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 | ||||||
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| Subjects: | Q Science > QD Chemistry Q Science > QR Microbiology > QR180 Immunology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
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| 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: |
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| 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 | ||||||
| Date of first compliant deposit: | 30 May 2017 | ||||||
| Date of first compliant Open Access: | 26 April 2018 | ||||||
| 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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