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Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid

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Title: Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid
Authors: Hatakeyama, Hiroto Browse this author
Akita, Hidetaka Browse this author
Ito, Erika Browse this author
Hayashi, Yasuhiro Browse this author
Oishi, Motoi Browse this author
Nagasaki, Yukio Browse this author
Danev, Radostin Browse this author
Nagayama, Kuniaki Browse this author
Kaji, Noritada Browse this author
Kikuchi, Hiroshi Browse this author
Baba, Yoshinobu Browse this author
Harashima, Hideyoshi Browse this author
Keywords: Multifunctional envelope-type nano device (MEND)
Systemic siRNA delivery
Cleavable PEG
Matrix metalloproteinase
PEG dilemma
EPR effect
Issue Date: Jun-2011
Publisher: Elsevier
Journal Title: Biomaterials
Volume: 32
Issue: 18
Start Page: 4306
End Page: 4316
Publisher DOI: 10.1016/j.biomaterials.2011.02.045
PMID: 21429576
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.
Type: article (author version)
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 畠山 浩人

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