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Nucleic Acids Research 2006 34(2):e16; doi:10.1093/nar/gnj014
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Published online 30 January 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Methods Online

Therapeutic protein transduction of mammalian cells and mice by nucleic acid-free lentiviral nanoparticles

Nils Link, Corinne Aubel1, Jens M. Kelm, René R. Marty, David Greber, Valentin Djonov2, Jean Bourhis1, Wilfried Weber and Martin Fussenegger*

Institute for Chemical and Bio-Engineering (ICB), Swiss Federal Institute of Technology ETH Hoenggerberg HCI F115, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland 1Radiosensibilité des Tumeurs et Tissus Sains, Institut Gustave-Roussy 39 Rue Camille Desmoulins, 94805 Villejuif Cedex, France 2Institute of Anatomy, University of Bern Baltzerstrasse 2, CH-3009 Bern, Switzerland

*To whom correspondence should be addressed. Tel: +41 44 6333448; Fax: +41 44 633 1234; Email: fussenegger{at}chem.ethz.ch

Received November 18, 2005. Revised January 11, 2006. Accepted January 11, 2006.

The straightforward production and dose-controlled administration of protein therapeutics remain major challenges for the biopharmaceutical manufacturing and gene therapy communities. Transgenes linked to HIV-1-derived vpr and pol-based protease cleavage (PC) sequences were co-produced as chimeric fusion proteins in a lentivirus production setting, encapsidated and processed to fusion peptide-free native protein in pseudotyped lentivirions for intracellular delivery and therapeutic action in target cells. Devoid of viral genome sequences, protein-transducing nanoparticles (PTNs) enabled transient and dose-dependent delivery of therapeutic proteins at functional quantities into a variety of mammalian cells in the absence of host chromosome modifications. PTNs delivering Manihot esculenta linamarase into rodent or human, tumor cell lines and spheroids mediated hydrolysis of the innocuous natural prodrug linamarin to cyanide and resulted in efficient cell killing. Following linamarin injection into nude mice, linamarase-transducing nanoparticles impacted solid tumor development through the bystander effect of cyanide.

Present addresses: Jens M. Kelm, Institute for Tissue Engineering and Cell Transplantation, Zurich University Hospital, Raemistrasse 100, CH-8091 Zurich, Switzerland

René R. Marty, Research Department, Basel University Hospital, Hebelstrasse 20, CH-4031 Basel, Switzerland


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