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

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.
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Category

Academic article

Language

English

Author(s)

  • Shubaash Anthiya
  • Süleyman Can Oztürk
  • Hamdullah Yanik
  • Ece Tavukcuoglu
  • Adem Sahin
  • Dhrubajyoti Datta
  • Klaus Charisse
  • David Moreira Álvarez
  • María Isabel Loza
  • Alfonso Calvo
  • Einar Sulheim
  • Simon Loevenich
  • Geir Klinkenberg
  • Ruth Baumberger Schmid
  • Muthiah Manoharan
  • Güneş Esendağlı
  • Maria Jose Alonso

Affiliation

  • SINTEF Industry / Biotechnology and Nanomedicine
  • University of Navarra
  • University of Santiago de Compostela
  • Hacettepe University Cancer Institute
  • ILKO Pharmaceuticals
  • Alnylam Pharmaceuticals Inc

Year

2023

Published in

Journal of Controlled Release

ISSN

0168-3659

Volume

357

Page(s)

67 - 83

View this publication at Norwegian Research Information Repository