Targeted siRNA lipid nanoparticles for the treatment of KRAS-mutant tumors
- J Control Release. 2023 May:357:67-83. doi: 10.1016/j.jconrel.2023.03.016.
- 1. Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain.
- 2. Research and Application Center for Animal Experiments, Hacettepe University Cancer Institute, Ankara, Turkey.
- 3. Department of Basic Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
- 4. R&D Department of ILKO Pharmaceuticals, Ankara, Turkey.
- 5. Alnylam Pharmaceuticals, 675 West Kendall, Cambridge, MA 02142, United States.
- 6. BioFarma Research Group, CIMUS, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
- 7. Health Research Institute of Navarra (IDISNA), Pamplona, Spain; Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.
- 8. Department of Biotechnology and Nanomedicine, SINTEF Industry, Trondheim, Norway.
- 9. Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain; Department of Pharmacology Pharmacy and Pharmaceutical Technology, School of Pharmacy, Universidade de Santiago de Compostela, Santiago de Compostela 15782, Spain. Electronic address: [email protected].
K-Ras is a highly relevant oncogene that is mutated in approximately 90% of pancreatic cancers and 20-25% of lung adenocarcinomas. The aim of this work was to develop a new anti-KRAS siRNA therapeutic strategy through the engineering of functionalized Lipid Nanoparticles (LNPs). To do this, first, a potent pan anti-KRAS siRNA sequence was chosen from the literature and different chemical modifications of siRNA were tested for their transfection efficacy (KRAS knockdown) and anti-proliferative effects on various Cancer cell lines. Second, a selected siRNA candidate was loaded into tLyp-1 targeted and non-targeted Lipid Nanoparticles (LNPs). The biodistribution and antitumoral efficacy of selected siRNA-loaded LNP-prototypes were evaluated in vivo using a Pancreatic Cancer murine model (subcutaneous xenograft CFPAC-1 Tumors). Our results show that tLyp-1-tagged targeted LNPs have an enhanced accumulation in the tumor compared to non-targeted LNPs. Moreover, a significant reduction in the pancreatic tumor growth was observed when the anti-KRAS siRNA treatment was combined with a classical chemotherapeutic agent, gemcitabine. In conclusion, our work demonstrates the benefits of using a targeting approach to improve tumor accumulation of siRNA-LNPs and its positive impact on tumor reduction.