Dual tumor targeting with pH-sensitive and bioreducible polymer-complexed oncolytic adenovirus

Title
Dual tumor targeting with pH-sensitive and bioreducible polymer-complexed oncolytic adenovirus
Author
윤채옥
Keywords
Cancer gene therapy; Oncolytic adenovirus; pH-sensitive; Bioreducible polymer; Systemic administration; Tumor microenvironment
Issue Date
2015-02
Publisher
ELSEVIER SCI LTD
Citation
BIOMATERIALS, v. 41, Page. 53-68
Abstract
Oncolytic adenoviruses (Ads) have shown great promise in cancer gene therapy but their efficacy has been compromised by potent immunological, biochemical, and specific tumor-targeting limitations. To take full advantage of the innate cancer-specific killing potency of oncolytic Ads but also exploit the subtleties of the tumor microenvironment, we have generated a pH-sensitive and bio-reducible polymer (PPCBA)-coated oncolytic Ad. Ad-PPCBA complexes showed higher cellular uptake at pH 6.0 than pH 7.4 in both high and low coxsackie and adenovirus receptor-(CAR)-expressing cells, thereby demonstrating Ad-PPCBA's ability to target the low pH hypoxic tumor microenvironment and overcome CAR dependence for target cell uptake. Endocytic mechanism studies indicated that Ad-PPCBA internalization is mediated by macropinocytosis instead of the CAR-dependent endocytic pathway that internalizes naked Ad. VEGF-specific shRNA-expressing oncolytic Ad complexed with PPCBA (RdB/shVEGF-PPCBA# elicited much more potent suppression of U87 human brain cancer cell VEGF gene expression in vitro, and human breast cancer MCF7 cell/Matrigel plug vascularization in a mouse model, when cancer cells had been previously infected at pH 6.0 versus pH 7.4. Moreover, intratumorally and intravenously injected RdB/shVEGF-PPCBA nanocomplexes elicited significantly higher therapeutic efficacy than naked virus in U87-tumor mouse xenograft models, reducing IL-6, ALT, and AST serum levels. These data demonstrated PPCBA's biocompatibility and capability to shield the Ad surface to prevent innate immune response against Ad after both intratumoral and systemic administration. Taken together, these results demonstrate that smart, tumor-specific, oncolytic Ad-PPCBA complexes can be exploited to treat both primary and metastatic tumors. #C) 2014 Elsevier Ltd. All rights reserved.
URI
http://www.sciencedirect.com/science/article/pii/S0142961214011818http://hdl.handle.net/20.500.11754/22497
ISSN
0142-9612; 1878-5905
DOI
10.1016/j.biomaterials.2014.11.021
Appears in Collections:
COLLEGE OF ENGINEERING[S](공과대학) > BIOENGINEERING(생명공학과) > Articles
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