Targeted siRNA lipid nanoparticles for the treatment of KRAS-mutant tumors
Anthiya, Shubaash; Oztürk, Süleyman Can; Yanik, Hamdullah; Tavukcuoglu, Ece; Sahin, Adem; Datta, Dhrubajyoti; Charisse, Klaus; Álvarez, David Moreira; Loza, María Isabel; Calvo, Alfonso; Sulheim, Einar; Loevenich, Simon; Klinkenberg, Geir; Schmid, Ruth Baumberger; Manoharan, Muthiah; Esendağlı, Güneş; Jose Alonso, Maria
Peer reviewed, Journal article
Published version
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https://hdl.handle.net/11250/3125776Utgivelsesdato
2023Metadata
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Sammendrag
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.