title: Tumor vascular targeted delivery of polymer-conjugated adenovirus vector for cancer gene therapy.
abstract: Previously, we generated a cancer-specific gene therapy system using adenovirus vectors (Adv) conjugated to polyethylene glycol (Adv-PEG). Here, we developed a novel Adv that targets both tumor tissues and tumor vasculatures after systemic administration by conjugating CGKRK tumor vasculature homing peptide to the end of a 20-kDa PEG chain (Adv-PEG(CGKRK)). In a primary tumor model, systemic administration of Adv-PEG(CGKRK) resulted in ~500- and 100-fold higher transgene expression in tumor than that of unmodified Adv and Adv-PEG, respectively. In contrast, the transgene expression of Adv-PEG(CGKRK) in liver was about 400-fold lower than that of unmodified Adv, and was almost the same as that of Adv-PEG. We also demonstrated that transgene expression with Adv-PEG(CGKRK) was enhanced in tumor vessels. Systemic administration of Adv-PEG(CGKRK) expressing the herpes simplex virus thymidine kinase (HSVtk) gene (Adv-PEG(CGKRK)-HSVtk) showed superior antitumor effects against primary tumors and metastases with negligible side effects by both direct cytotoxic effects and inhibition of tumor angiogenesis. These results indicate that Adv-PEG(CGKRK) has potential as a prototype Adv with suitable efficacy and safety for systemic cancer gene therapy against both primary tumors and metastases.
authors.affiliation: Department of Biotechnology and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: Xinglei
authors.initials: X
authors.lastname: Yao
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morishige
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Eto
authors.forename: Shogo
authors.initials: S
authors.lastname: Narimatsu
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Kawai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizuguchi
authors.forename: Jian-Qing
authors.initials: JQ
authors.lastname: Gao
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mukai
authors.forename: Naoki
authors.initials: N
authors.lastname: Okada
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Nakagawa
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005814:Genes, Viral; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000737:chemistry / Q000627:therapeutic use; D018139:Simplexvirus / Q000235:genetics / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes; D019043:Vascular Neoplasms / Q000628:therapy*
chemical_list: D011092:Polyethylene Glycols; D013937:Thymidine Kinase