Systemic administration of a PEGylated adenovirus vector with a cancer-specific promoter is effective in a mouse model of metastasis

被引：41

作者：

Yao, X. ^{[2
]}

Yoshioka, Y. ^{[1
,2
]}

Morishige, T. ^{[2
]}

Eto, Y. ^{[2
]}

Watanabe, H. ^{[2
]}

Okada, Y. ^{[3
]}

Mizuguchi, H. ^{[4
,5
]}

Mukai, Y. ^{[2
]}

Okada, N. ^{[2
]}

Nakagawa, S. ^{[1
,2
]}

机构：

[1] Osaka Univ, Ctr Adv Med Engn & Informat, Suita, Osaka 5650871, Japan

[2] Osaka Univ, Grad Sch Pharmaceut Sci, Dept Biotechnol & Therapeut, Suita, Osaka 5650871, Japan

[3] Osaka Univ, Microbial Dis Res Inst, Dept Expt Genome Res, Suita, Osaka 5650871, Japan

[4] Osaka Univ, Grad Sch Pharmaceut Sci, Dept Biochem & Mol Biol, Suita, Osaka 5650871, Japan

[5] Natl Inst Biomed Innovat, Dept Gene Transfer & Regulat, Osaka, Japan

来源：

GENE THERAPY | 2009年 / 16卷 / 12期

关键词：

bioconjugation; metastasis; polymer; TERT promoter; INNATE IMMUNE-RESPONSES; SUICIDE GENE-THERAPY; EXPRESSION; TUMOR; DELIVERY; VIRUS; LIVER; RECEPTOR; TROPISM; CELLS;

D O I：

10.1038/gt.2009.95

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：

Cancer gene therapy by adenovirus vectors (Advs) for metastatic cancer is limited because systemic administration of Adv produces low therapeutic effect and severe side effects. In this study, we generated a dual cancer-specific targeting vector system by using PEGylation and the telomere reverse transcriptase (TERT) promoter and attempted to treat experimental metastases through systemic administration of the vectors. We first optimized the molecular size of PEG and modification ratios used to create PEG-Ads. Systemic administration of PEG-Ad with 20-kDa PEG at a 45% modification ratio (PEG[20K/45%]-Ad) resulted in higher tumor-selective transgene expression than unmodified Adv. Next, we examined the effectiveness against metastases and side effects of a TERT promoter-driven PEG[20K/45%]-Ad containing the herpes simplex virus thymidine kinase (HSVtk) gene (PEG-Ad-TERT/HSVtk). Systemic administration of PEG-Ad-TERT/HSVtk showed superior antitumor effects against metastases with negligible side effects. A cytomegalovirus (CMV) promoter-driven PEG[20K/45%]-Ad also produced anti-metastatic effects, but these were accompanied by side effects. Combining PEG-Ad-TERT/HSVtk with etoposide or 5-fluorouracil enhanced the therapeutic effects with negligible side effects. These results suggest that modification with 20-kDa PEG at a 45% modification ratio is the optimal condition for PEGylation of Adv, and PEG-Ad-TERT/HSVtk is a prototype Adv for systemic cancer gene therapy against metastases. Gene Therapy (2009) 16, 1395-1404; doi: 10.1038/gt.2009.95; published online 30 July 2009

引用

页码：1395 / 1404

页数：10