Targeted siRNA nanocarrier: a platform technology for cancer treatment.

Abstract

The small arginine-rich protein protamine condenses complete genomic DNA into the sperm head. Here, we applied its high RNA binding capacity for spontaneous electrostatic assembly of therapeutic nanoparticles decorated with tumour-cell-specific antibodies for efficiently targeting siRNA. Fluorescence microscopy and DLS measurements of these nanocarriers revealed the formation of a vesicular architecture that requires presence of antibody-protamine, defined excess of free SMCC-protamine, and anionic siRNA to form. Only these complex nanoparticles were efficient in the treatment of non-small-cell lung cancer (NSCLC) xenograft models, when the oncogene KRAS was targeted via EGFR-mediated delivery. To show general applicability, we used the modular platform for IGF1R-positive Ewing sarcomas. Anti-IGR1R-antibodies were integrated into an antibody-protamine nanoparticle with an siRNA specifically against the oncogenic translocation product EWS/FLI1. Using these nanoparticles, EWS/FLI1 knockdown blocked in vitro and in vivo growth of Ewing sarcoma cells. We conclude that these antibody-protamine-siRNA nanocarriers provide a novel platform technology to specifically target different cell types and yet undruggable targets in cancer therapy by RNAi.

• Authors: Nicole Bäumer, Jessica Tiemann, Annika Scheller, Theresa Meyer, Lisa Wittmann, Matias Ezequiel Gutierrez Suburu, Lilo Greune, Matthias Peipp, Neele Kellmann, Annika Gumnior, Caroline Brand, Wolfgang Hartmann, Claudia Rossig, Carsten Müller-Tidow, Dario Neri, Cristian A Strassert, Christian Rüter, Petra Dersch, Georg Lenz, H Phillip Koeffler, Wolfgang E Berdel, Sebastian Bäumer
• Journal: Oncogene (Oncogene) Vol. 41 Issue 15 Pg. 2210-2224 (04 2022) ISSN: 1476-5594 [Electronic] England
• PMID: 35220407 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Oncogene Proteins, Fusion
• Protamines
• Proto-Oncogene Protein c-fli-1
• RNA, Small Interfering
• RNA-Binding Protein EWS

Topics

• Carcinoma, Non-Small-Cell Lung (genetics)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (genetics)
• Male
• Oncogene Proteins, Fusion (genetics)
• Protamines (genetics, metabolism)
• Proto-Oncogene Protein c-fli-1 (genetics)
• RNA, Small Interfering (genetics)
• RNA-Binding Protein EWS (genetics)
• Technology
• Xenograft Model Antitumor Assays