Journal
ACS MACRO LETTERS
Volume 6, Issue 5, Pages 535-540Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmacrolett.7b00160
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Funding
- Engineering and Physical Sciences Research Council (EPSRC) [EP/M014649/1]
- UCL Excellence Fellowship award
- Royal Society Wolfson Merit Award [WM130055]
- Engineering and Physical Sciences Research Council [EP/M014649/1] Funding Source: researchfish
- EPSRC [EP/M014649/1] Funding Source: UKRI
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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 methacrylatebased GEM-monomer conjugate, which was polymerized by reversible addition fragmentation chain transfer (RAFT) polymerization with high monomer conversion (similar to 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 similar to 7and,similar to 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.
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