RNA with chemotherapeutic base analogues as a dual-functional anti-cancer drug

Natalia Teresa Jarzebska; Marina Tusup; Julia Frei; Tobias Weiss; Tim Holzinger; Mark Mellett; Mustafa Diken; Simon Bredl; Michael Weller; Roberto F Speck; Thomas M Kündig; Ugur Sahin; Steve Pascolo

doi:10.1080/2162402X.2022.2147665

RNA with chemotherapeutic base analogues as a dual-functional anti-cancer drug

Oncoimmunology. 2022 Nov 18;11(1):2147665. doi: 10.1080/2162402X.2022.2147665. eCollection 2022.

Authors

Natalia Teresa Jarzebska^{1

2}, Marina Tusup^{1

3}, Julia Frei^{1

3}, Tobias Weiss⁴, Tim Holzinger^{1

3}, Mark Mellett^{1

3}, Mustafa Diken⁵, Simon Bredl⁶, Michael Weller⁴, Roberto F Speck⁶, Thomas M Kündig^{1

3}, Ugur Sahin⁵, Steve Pascolo^{1

3}

Affiliations

¹ Department of Dermatology, University Hospital Zürich (USZ), University of Zürich (UZH), Raemistrasse 100, 8091, Zürich, Switzerland.
² Faculty of Science, University of Zürich, Zürich, Switzerland.
³ Faculty of Medicine, University of Zürich, Zürich, Switzerland.
⁴ Department of Neurology and Clinical Neuroscience Center, University Hospital Zürich (USZ), University of Zürich (UZH), 8091, Zürich, Switzerland.
⁵ BioNTech SE, Mainz, Germany.
⁶ Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich (USZ), University of Zürich (UZH), 8091, Zürich, Switzerland.

Abstract

Nanoparticles of different sizes formulated with unmodified RNA and Protamine differentially engage Toll-like Receptors (TLRs) and activate innate immune responses in vitro. Here, we report that similar differential immunostimulation that depends on the nanoparticle sizes is induced in vivo in wild type as well as in humanized mice. In addition, we found that the schedule of injections strongly affects the magnitude of the immune response. Immunostimulating 130 nm nanoparticles composed of RNA and Protamine can promote lung metastasis clearance but provides no control of subcutaneous tumors in a CT26 tumor model. We further enhanced the therapeutic capacity of Protamine-RNA nanoparticles by incorporating chemotherapeutic base analogues in the RNA; we coined these immunochemotherapeutic RNAs (icRNAs). Protamine-icRNA nanoparticles were successful at controlling established subcutaneous CT26 and B16 tumors as well as orthotopic glioblastoma. These data indicate that icRNAs are promising cancer therapies, which warrants their further validation for use in the clinic.

Keywords: 5FU; Chemotherapy; RNA; immunotherapy; toll like receptor; type I interferon.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Glioblastoma*
Mice
Nanoparticles* / therapeutic use
Protamines
RNA

Substances

RNA
Antineoplastic Agents
Protamines

Grants and funding

This research was funded by the Monique Dornonville de la Cour Stiftung, the Swiss Cancer Research (KFS-5271-02-2021 “Enhancing therapy of cancer using immuno-chemotherapeutic RNA nanoparticles and immune check-point inhibition), The Kelm Stiftung, the University of Zurich (URPP “Translational Cancer Research”), the department of Dermatology at the University Hospital of Zurich, the “Stiftung für wissenschaftliche Forschung an der Universität Zürich”, the Swiss National Science Found NRP 78 program, grant number 4078PO_198321 and the EU grant NEWmRNA (Horizon 2020 research and innovation programme No. 965135).