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

Anthiya S., ÖZTÜRK S. C., Yanik H., Tavukcuoglu E., ŞAHİN A., Datta D., ...More

Journal of Controlled Release, vol.357, pp.67-83, 2023 (SCI-Expanded, Scopus) identifier identifier

  • Publication Type: Article / Article
  • Volume: 357
  • Publication Date: 2023
  • Doi Number: 10.1016/j.jconrel.2023.03.016
  • Journal Name: Journal of Controlled Release
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Chimica, Compendex, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.67-83
  • Keywords: Combination therapy, KRAS, LNPs, Pancreatic cancer, RNA therapeutics, siRNA, Targeted delivery
  • Bilecik Şeyh Edebali University Affiliated: Yes

Abstract

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.