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Published January 1, 2023 | Version v1
Journal article Open

Targeted siRNA lipid nanoparticles for the treatment of KRAS-mutant tumors

Creators

  • 1. Univ Santiago de Compostela, Ctr Res Mol Med & Chron Dis CIMUS, Santiago De Compostela 15782, Spain
  • 2. Hacettepe Univ, Res & Applicat Ctr Anim Expt, Canc Inst, Ankara, Turkiye
  • 3. Hacettepe Univ, Dept Basic Oncol, Canc Inst, Ankara, Turkiye
  • 4. ILKO Pharmaceut, R&D Dept, Ankara, Turkiye
  • 5. Alnylam Pharmaceut, 675 West Kendall, Cambridge, MA 02142 USA
  • 6. Univ Santiago de Compostela, BioFarma Res Grp, CIMUS, Santiago De Compostela, Spain
  • 7. SINTEF Ind, Dept Biotechnol & Nanomed, Trondheim, Norway

Description

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 sig-nificant 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.

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