%0 Journal Article
%@ 2161-1653
%A Joubert, F
%A Martin, L
%A Perrier, S
%A Pasparakis, G
%D 2017
%F discovery:1556638
%J ACS Macro Letters
%N 5
%P 535-540
%T Development of a Gemcitabine-Polymer Conjugate with Prolonged Cytotoxicity against a Pancreatic Cancer Cell Line
%U https://discovery.ucl.ac.uk/id/eprint/1556638/
%V 6
%X 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.
%Z This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.