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

被引：230

作者：

Hatakeyama, Hiroto ^{[1
,7
]}

Akita, Hidetaka ^{[1
,7
]}

Ito, Erika ^{[1
,7
]}

Hayashi, Yasuhiro ^{[1
,7
]}

Oishi, Motoi ^{[2
,7
]}

Nagasaki, Yukio ^{[3
,4
,5
,6
,7
]}

Danev, Radostin ^{[8
]}

Nagayama, Kuniaki ^{[8
]}

Kaji, Noritada ^{[9
]}

Kikuchi, Hiroshi ^{[10
]}

Baba, Yoshinobu ^{[9
]}

Harashima, Hideyoshi ^{[1
,7
]}

机构：

[1] Hokkaido Univ, Fac Pharmaceut Sci, Kita Ku, Sapporo, Hokkaido 0600812, Japan

[2] Univ Tsukuba, Tsukuba Res Ctr Interdisciplinary Mat Sci TIMS, Tsukuba, Ibaraki 3058573, Japan

[3] Univ Tsukuba, Grad Sch Pure & Appl Sci, Tsukuba, Ibaraki 3058573, Japan

[4] Univ Tsukuba, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki 3058573, Japan

[5] Univ Tsukuba, Satellite Lab, Int Ctr Mat Nanoarchitecton MANA, Tsukuba, Ibaraki 3058573, Japan

[6] Univ Tsukuba, Natl Inst Mat Sci, Tsukuba, Ibaraki 3058573, Japan

[7] Japan Sci & Technol Agcy JST, CREST, Tokyo, Japan

[8] Natl Inst Nat Sci, Okazaki Inst Integrat Biosci, Okazaki, Aichi 4448787, Japan

[9] Nagoya Univ, Grad Sch Engn, Chikusa Ku, Aichi 4648603, Japan

[10] Eisai & Co Ltd, Formulat Res Labs, Ibaraki 3002635, Japan

来源：

BIOMATERIALS | 2011年 / 32卷 / 18期

关键词：

Multifunctional envelope-type nano device (MEND); Systemic siRNA delivery; Cleavable PEG; Matrix metalloproteinase; PEG dilemma; EPR effect; NONVIRAL GENE DELIVERY; INNATE IMMUNE-RESPONSE; INTRACELLULAR TRAFFICKING; EXPRESSION CHANGES; NANO DEVICE; LIPOSOMES; CELLS; PEGYLATION; RNA; DNA;

D O I：

10.1016/j.biomaterials.2011.02.045

中图分类号：

R318 [生物医学工程];

学科分类号：

100103 [病原生物学];

摘要：

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 PEGunmodified MEND due to less accumulation in liver and spleen. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：4306 / 4316

页数：11

共 54 条

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Quantitative three-dimensional analysis of the intracellular trafficking of plasmid DNA transfected by a nonviral gene delivery system using confocal laser scanning microscopy [J].