RRC ID 38437
Author Yao X, Yoshioka Y, Morishige T, Eto Y, Narimatsu S, Kawai Y, Mizuguchi H, Gao JQ, Mukai Y, Okada N, Nakagawa S.
Title Tumor vascular targeted delivery of polymer-conjugated adenovirus vector for cancer gene therapy.
Journal Mol Ther
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.
Volume 19(9)
Pages 1619-25
Published 2011-9
DOI 10.1038/mt.2011.112
PII S1525-0016(16)32747-2
PMID 21673661
PMC PMC3182347
MeSH Adenoviridae / genetics* Animals Cell Line, Tumor Gene Expression Regulation Gene Transfer Techniques Genes, Viral Genetic Therapy / methods* Genetic Vectors* Mice Mice, Inbred BALB C Mice, Inbred C57BL Polyethylene Glycols / chemistry Polyethylene Glycols / therapeutic use Simplexvirus / genetics Simplexvirus / metabolism Thymidine Kinase / genetics Thymidine Kinase / metabolism Transduction, Genetic Transgenes Vascular Neoplasms / therapy*
IF 8.402
Times Cited 25
Human and Animal Cells