eprintid: 1556638
rev_number: 33
eprint_status: archive
userid: 608
dir: disk0/01/55/66/38
datestamp: 2017-05-20 21:41:10
lastmod: 2021-12-13 02:52:15
status_changed: 2017-06-14 10:00:49
type: article
metadata_visibility: show
creators_name: Joubert, F
creators_name: Martin, L
creators_name: Perrier, S
creators_name: Pasparakis, G
title: Development of a Gemcitabine-Polymer Conjugate with Prolonged Cytotoxicity against a Pancreatic Cancer Cell Line
ispublished: pub
divisions: UCL
divisions: B02
divisions: C08
note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
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.
date: 2017-05-16
date_type: published
official_url: http://dx.doi.org/10.1021/acsmacrolett.7b00160
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
article_type_text: Journal Article
verified: verified_manual
elements_id: 1294428
doi: 10.1021/acsmacrolett.7b00160
lyricists_name: Joubert, Fanny
lyricists_name: Pasparakis, Georgios
lyricists_id: FJOUB06
lyricists_id: GPASP77
actors_name: Flynn, Bernadette
actors_id: BFFLY94
actors_role: owner
full_text_status: public
publication: ACS Macro Letters
volume: 6
number: 5
pagerange: 535-540
issn: 2161-1653
citation:        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 <https://doi.org/10.1021/acsmacrolett.7b00160>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/1556638/1/Joubert_Development_Gemcitabine-Polymer_Conjugate.pdf