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Post-coupling strategy enables true receptor-targeted nanoparticles


Research Report

J RNAi Gene Silencing (2011), 7, 449-455

doi: jrgsxx

Published online: 18 September 2011

Full Text: (pdf ~380kb)

Post-coupling strategy enables true receptor-targeted nanoparticles

Jianmeizi Chen †, Michael R Jorgensen †, Maya Thanou ‡ and Andrew D Miller †‡*

† Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Armstrong Road, Imperial College London, London SW7 2AZ, UK

‡ Institute of Pharmaceutical Science, Kings College London, Franklin-Wilkins Building, Waterloo Campus, 150 Stamford Street, London SE1 9NH, UK

*Current address: Institute of Pharmaceutical Science, Kings College London, Franklin-Wilkins Building, Waterloo Campus, 150 Stamford Street, London SE1 9NH, UK

*Correspondence toAndrew Miller, Email: a.miller07@btinternet.com, and, andrew.d.miller@kcl.ac.uk, Tel : +44 787 963 5513

Received: 05 July 2011, Accepted: 24 August 2011

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ABSTRACT

A key goal of our research is the targeted delivery of functional biopharmaceutical agents of interest, such as small interfering RNA (siRNA), to selected cells by means of receptor-mediated nanoparticle technologies. Recently, we described how pH-triggered, PEGylated siRNA-nanoparticles (pH triggered siRNA-ABC nanoparticles) were able to mediate the passive targeting of siRNA to liver cellsin vivo. In addition, PEGylated siRNA nanoparticles enabled for long-term circulation (LTC siRNA-ABCnanoparticles, LEsiRNA nanoparticles) were shown to do the same to tumour cells in vivo. Further gains in the efficiency of siRNA delivery are expected to require active targeting with nanoparticles targeted for delivery and cellular uptake by means of attached biological ligands. Here we report on the development of a new synthetic chemistry and a bioconjugation methodology that allows for the controlled formulation of PEGylated nanoparticles which surface-present integrin-targeting peptides unambiguously and so enable integrin receptor-mediated cellular uptake. Furthermore, we present delivery data that provide a clear preliminary demonstration of physical principles that we propose should underpin successful, bonefide receptor-mediated targeted delivery of therapeutic and/or imaging agents to cells.

KEYWORDS: Integrin ligand, integrin receptor, nanoparticles, delivery, cellular uptake, siRNA, RNAi

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