TY - JOUR
T1 - A pH-sensitive cationic lipid facilitates the delivery of liposomal siRNA and gene silencing activity in vitro and in vivo
AU - Sato, Yusuke
AU - Hatakeyama, Hiroto
AU - Sakurai, Yu
AU - Hyodo, Mamoru
AU - Akita, Hidetaka
AU - Harashima, Hideyoshi
N1 - Funding Information:
This study was supported in part by a Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science (JSPS) , and a Grant-in-Aid for Scientific Research on Innovative Areas ‘‘Nanomedicine Molecular Science’’ (No. 2306) from Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan , and the Special Education and Research Expenses of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan , and by a Grant for Industrial Technology Research from New Energy and Industrial Technology Development Organization (NEDO) . The authors also wish to thank Dr. Milton S. Feather for his helpful advice in writing the English manuscript.
PY - 2012/11/10
Y1 - 2012/11/10
N2 - Modification of liposomal siRNA carriers with polyethylene glycol, i.e., PEGylation, is a generally accepted strategy for achieving in vivo stability and delivery to tumor tissue. However, PEGylation significantly inhibits both cellular uptake and the endosomal escape process of the carriers. In a previous study, we reported on the development of a multifunctional envelope-type nano device (MEND) for siRNA delivery and peptide-based functional devices for overcoming the limitations and succeeded in the efficient delivery of siRNA to tumors. In this study, we synthesized a pH-sensitive cationic lipid, YSK05, to overcome the limitations. The YSK05-MEND had a higher ability for endosomal escape than other MENDs containing conventional cationic lipids. The PEGylated YSK05-MEND induced efficient gene silencing and overcame the limitations followed by optimization of the lipid composition. Furthermore, the intratumoral administration of the YSK05-MEND resulted in a more efficient gene silencing compared with MENDs containing conventional cationic lipids. Collectively, these data confirm that YSK05 facilitates the endosomal escape of the MEND and thereby enhances the efficacy of siRNA delivery into cytosol and gene silencing.
AB - Modification of liposomal siRNA carriers with polyethylene glycol, i.e., PEGylation, is a generally accepted strategy for achieving in vivo stability and delivery to tumor tissue. However, PEGylation significantly inhibits both cellular uptake and the endosomal escape process of the carriers. In a previous study, we reported on the development of a multifunctional envelope-type nano device (MEND) for siRNA delivery and peptide-based functional devices for overcoming the limitations and succeeded in the efficient delivery of siRNA to tumors. In this study, we synthesized a pH-sensitive cationic lipid, YSK05, to overcome the limitations. The YSK05-MEND had a higher ability for endosomal escape than other MENDs containing conventional cationic lipids. The PEGylated YSK05-MEND induced efficient gene silencing and overcame the limitations followed by optimization of the lipid composition. Furthermore, the intratumoral administration of the YSK05-MEND resulted in a more efficient gene silencing compared with MENDs containing conventional cationic lipids. Collectively, these data confirm that YSK05 facilitates the endosomal escape of the MEND and thereby enhances the efficacy of siRNA delivery into cytosol and gene silencing.
KW - Endosomal escape
KW - Intracellular trafficking
KW - Multifunctional envelope-type nano device (MEND)
KW - pH-sensitive cationic lipid
KW - siRNA delivery
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U2 - 10.1016/j.jconrel.2012.09.009
DO - 10.1016/j.jconrel.2012.09.009
M3 - Article
C2 - 23000694
AN - SCOPUS:84867394662
SN - 0168-3659
VL - 163
SP - 267
EP - 276
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 3
ER -