title: Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid.
abstract: Previously, we developed a multifunctional envelope-type nano device (MEND) for efficient delivery of nucleic acids. For tumor delivery of a MEND, PEGylation is a useful method, which confers a longer systemic circulation and tumor accumulation via the enhanced permeability and retention (EPR) effect. However, PEGylation inhibits cellular uptake and subsequent endosomal escape. To overcome this, we developed a PEG-peptide-DOPE (PPD) that is cleaved in a matrix metalloproteinase (MMP)-rich environment. In this study, we report on the systemic delivery of siRNA to tumors by employing a MEND that is modified with PPD (PPD-MEND). An in vitro study revealed that PPD modification accelerated both cellular uptake and endosomal escape, compared to a conventional PEG modified MEND. To balance both systemic stability and efficient activity, PPD-MEND was further co-modified with PEG-DSPE. As a result, the systemic administration of the optimized PPD-MEND resulted in an approximately 70% silencing activity in tumors, compared to non-treatment. Finally, a safety evaluation showed that the PPD-MEND showed no hepatotoxicity and innate immune stimulation. Furthermore, in a DNA microarray analysis in liver and spleen tissue, less gene alternation was found for the PPD-MEND compared to that for the PEG-unmodified MEND due to less accumulation in liver and spleen.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hatakeyama
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Akita
authors.forename: Erika
authors.initials: E
authors.lastname: Ito
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Motoi
authors.initials: M
authors.lastname: Oishi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nagasaki
authors.forename: Radostin
authors.initials: R
authors.lastname: Danev
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Nagayama
authors.forename: Noritada
authors.initials: N
authors.lastname: Kaji
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Baba
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D000818:Animals; D002460:Cell Line; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046228:Microarray Analysis; D053758:Nanoparticles / Q000737:chemistry*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*
chemical_list: D008055:Lipids; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols