Enzyme-triggered PEGylated siRNA-nanoparticles for controlled release of siRNA



Research Article

J RNAi Gene Silencing (2014), 10, 490-499

doi: jrgsxx

Published online: 28 January 2014

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Enzyme-triggered PEGylated siRNA-nanoparticles for controlled release of siRNA

Peerada Yingyuad α, Mathieu Mével α, Carla Prata α, Christos Kontogiorgis α,β, Maya Thanou α,β and Andrew D Miller α,β,*

α Imperial College Genetic Therapies Centre, Department of Chemistry, Imperial College London, London, SW7 2AZ, UK

β Institute of Pharmaceutical Science, Franklin-Wilkins Building, 150 Stamford Street, King’s College London, London, SE1 9NH, UK

*Correspondence toAndrew Miller, Email: a.miller07@btinternet.com, Tel: +44 787 963 5513

Received: 11 December 2013, Accepted: 28 January 2014



A key goal of our recent research efforts has been to develop novel ‘triggerable nanoparticle’ systems with real potential utility in vivo. These are designed to be stable from the point of administration until a target site of interest is reached, then triggered for the controlled release of therapeutic agent payload(s) at the target site by changes in local endogenous conditions or through the application of some exogenous stimulus. Here we describe investigations into the use of enzymes to trigger RNAi-mediated therapy through a process of enzyme-assisted nanoparticle triggerability. Our approach is to use PEG2000-peptidyl lipids with peptidyl moieties sensitive to tumour-localized elastase or matrix metalloproteinase-2 digestion, and from these prepare putative enzyme-triggered PEGylated siRNA-nanoparticles. Our results provide initial proof of concept in vitro. From these data, we propose that this concept should be applicable for functional delivery of therapeutic nucleic acids to tumour cells in vivo, although the mechanism for enzyme-assisted nanoparticle triggerability remains to be fully characterized.

KEYWORDS: Liposomes, elastase, enzyme, triggerable nanoparticles, triggered release, peptide