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Delivery of Immunostimulatory RNA Oligonucleotides by Gelatin Nanoparticles Triggers an Efficient Antitumoral Response

Bourquin, Carole*; Wurzenberger, Cornelia*; Heidegger, Simon*; Fuchs, Sebastian; Anz, David; Weigel, Sarah*; Sandholzer, Nadja*; Winter, Gerhard; Coester, Conrad; Endres, Stefan*

doi: 10.1097/CJI.0b013e3181f5dfa7
Basic Studies

RNA oligonucleotides have emerged as a new class of biologicals that can silence gene expression but also stimulate immune responses through specific pattern-recognition receptors. The development of effective delivery systems remains a major challenge for the therapeutic application of the RNA oligonucleotides. In this study, we have established a novel biodegradable carrier system that is highly effective for the delivery of immunostimulatory RNA oligonucleotides. Formulation of RNA oligonucleotides with cationized gelatin nanoparticles potentiates immune activation through the Toll-like receptor 7 (TLR7) in both myeloid and plasmacytoid dendritic cells. Further, nanoparticle-delivered RNA oligonucleotides trigger production of the antitumoral cytokines IL-12 and IFN-α. Binding to gelatin nanoparticles protects RNA oligonucleotides from degradation by nucleases, facilitates their uptake by dendritic cells, and targets these nucleic acids to the endosomal compartment in which they are recognized by TLR7. In these effects, the nanoparticles are superior to the conventional transfection reagents lipofectamine, polyethylenimine, and DOTAP. In vivo, the delivery of TLR7-activating RNA oligonucleotides by gelatin nanoparticles triggers antigen-specific CD8+ T-cell and antibody responses. Indeed, immunization with RNA-loaded nanoparticles leads to an efficient antitumoral immune response in two different mouse tumor models. Thus, gelatin-based nanoparticles represent a novel delivery system for immunostimulatory RNA oligonucleotides that is both effective and nontoxic.

*Center for Integrated Protein Science Munich and Division of Clinical Pharmacology

Departments of Internal Medicine, Innenstadt

Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig-Maximilian University of Munich, Munich, Germany

The authors declared no conflict of interests.

Carole Bourquin and Cornelia Wurzenberger have contributed equally to this work.

Supported by grants from the German Research Foundation (DFG En 169/7-2 and Graduiertenkolleg 1202 to C.B. and S.E., the excellence cluster CIPSM 114 to S.E.), from LMUexcellent (research professorship to S.E.), from the Else-Kröner Fresenius Foundation, and from BayImmuNet to C.B. and S.E. This work is part of the doctoral thesis of SF and SW at the Ludwig-Maximilian University of Munich.

Reprints: Carole Bourquin, Division of Clinical Pharmacology, Ziemssenstr. 1, 80336 München, Germany (e-mail: carole.bourquin@med.lmu.de).

Received for publication February 3, 2010; accepted August 1, 2010

© 2010 Lippincott Williams & Wilkins, Inc.