Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid

被引:324
作者
Hatakeyama, H.
Akita, H.
Kogure, K.
Oishi, M.
Nagasaki, Y.
Kihira, Y.
Ueno, M.
Kobayashi, H.
Kikuchi, H.
Harashima, H.
机构
[1] Hokkaido Univ, Grad Sch Pharmaceut Sci, Lab Mol Design Pharmaceut, Sapporo, Hokkaido 0600812, Japan
[2] Univ Tsukuba, Tsukuaba Res Ctr Interdisciplinary Mat Sci, Tsukuba, Ibaraki 305, Japan
[3] Toyama Med & Pharmaceut Univ, Fac Pharmaceut Sci, Toyama, Japan
[4] Daiichi Pharmaceut Co Ltd, Res Inst, Edogawa Ku, Tokyo 134, Japan
关键词
systemic gene targeting; Multifunctional Envelope-type Nano Device (MEND); cleavable PEG-lipid; matrix metalloproteinase; cancer gene therapy;
D O I
10.1038/sj.gt.3302843
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
For successful cancer gene therapy via intravenous (i.v.) administration, it is essential to optimize the stability of carriers in the systemic circulation and the cellular association after the accumulation of the carrier in tumor tissue. However, a dilemma exists regarding the use of poly(ethylene glycol) (PEG), which is useful for conferring stability in the systemic circulation, but is undesirable for the cellular uptake and the following processes. We report the development of a PEG-peptide-lipid ternary conjugate (PEG-Peptide-DOPE conjugate (PPD)). In this strategy, the PEG is removed from the carriers via cleavage by a matrix metalloproteinase (MMP), which is specifically expressed in tumor tissues. An in vitro study revealed that the PPD-modified gene carrier (Multifunctional Envelope-type Nano Device: MEND) exhibited pDNA expression activity that was dependent on the MMP expression level in the host cells. In vivo studies further revealed that the PPD was potent in stabilizing MEND in the systemic circulation and facilitating tumor accumulation. Moreover, the i.v. administration of PPD or PEG/PPD dually-modified MEND resulted in the stimulation of pDNA expression in tumor tissue, as compared with a conventional PEG-modified MEND. Thus, MEND modified with PPD is a promising device, which has the potential to make in vivo cancer gene therapy achievable.
引用
收藏
页码:68 / 77
页数:10
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