| 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) |
| URI: | http://hdl.handle.net/2115/46196 |
| Appears in Collections: | 薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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