Joubert, F;
Martin, L;
Perrier, S;
Pasparakis, G;
(2017)
Development of a Gemcitabine-Polymer Conjugate with Prolonged Cytotoxicity against a Pancreatic Cancer Cell Line.
ACS Macro Letters
, 6
(5)
pp. 535-540.
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.
| Type: | Article |
|---|---|
| Title: | Development of a Gemcitabine-Polymer Conjugate with Prolonged Cytotoxicity against a Pancreatic Cancer Cell Line |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1021/acsmacrolett.7b00160 |
| Publisher version: | http://dx.doi.org/10.1021/acsmacrolett.7b00160 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1556638 |
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