RT Journal Article
T1 Targeted siRNA lipid nanoparticles for the treatment of KRAS-mutant tumors
A1 Anthiya, Shubaash
A1 Öztürk, Süleyman Can
A1 Yanik, Hamdullah
A1 Tavukcuoglu, Ece
A1 Şahin, Adem
A1 Datta, Dhrubajyoti
A1 Charisse, Klaus
A1 Moreira Álvarez, David
A1 Loza García, María Isabel
A1 Calvo González, Alfonso
A1 Sulheim, Einar
A1 Loevenich, Simon
A1 Klinkenberg, Geir
A1 Schmid, Ruth
A1 Manoharan, Muthiah
A1 Esendağlı, Güneş
A1 Alonso Fernández, María José
K1 RNA therapeutics
K1 siRNA
K1 Targeted delivery
K1 LNPs
K1 KRAS
K1 Combination therapy
K1 Pancreatic cancer
AB 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
PB Elsevier
YR 2023
FD 2023
LK http://hdl.handle.net/10347/30619
UL http://hdl.handle.net/10347/30619
LA eng
NO Journal of Controlled Release 357 (2023) 67-83
NO This work was supported by the 2-INTRATARGET project (PCIN-2017-129/AEI) funded by MINECO-PCIN-2017-129/AEI, under the frame of EuroNanoMed III; by Consellería de Educación e Ordenación Universitaria, Xunta de Galicia's Grupos de referencia competitiva (grant number ED431C 2017/09). The authors thank TÜBİTAK (The Scientific and Technical Research Council of Turkey) for supporting this project (Project number : 217S068). S.A acknowledges the financial support for his postdoctoral research by the 2-INTRATARGET  project  (PCIN-2017-129/AEI)  funded  by  MINECO-PCIN-2017-129/AEI,  under  the  frame  of  EuroNanoMed  III
DS Minerva
RD 28 abr 2026