Enhanced therapeutic efficacy of an adenovirus-PEI-bile-acid complex in tumors with low coxsackie and adenovirus receptor expression
- Authors
- Lee, Cho-Hee; Kasala, Dayananda; Na, Youjin; Lee, Min Sang; Kim, Sung Wan; Jeong, Ji Hoon; Yun, Chae-Ok
- Issue Date
- Jul-2014
- Publisher
- ELSEVIER SCI LTD
- Keywords
- Oncolytic adenovirus; Cancer gene therapy; Deoxycholic acid; Poly(ethyleneimine); Coxsackie and adenovirus receptor
- Citation
- BIOMATERIALS, v.35, no.21, pp.5505 - 5516
- Indexed
- SCIE
SCOPUS
- Journal Title
- BIOMATERIALS
- Volume
- 35
- Number
- 21
- Start Page
- 5505
- End Page
- 5516
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/25830
- DOI
- 10.1016/j.biomaterials.2014.03.060
- ISSN
- 0142-9612
- Abstract
- Adenovirus (Ad) is a potential vehicle for cancer gene therapy. However, cells that express low levels of the coxsackie and adenovirus receptor (CAR) demonstrate poor Ad infection efficiency. We developed a bile acid-conjugated poly(ethyleneimine) (DA3)-coated Ad complex (Ad/DA3) to enhance Ad transduction efficiency. The size distribution and zeta potential of Ad/DA3 increased to 324 +/- 3.08 nm and 10.13 +/- 0.21 my, respectively, compared with those of naked Ad (108 +/- 2.26 nm and -17.7 +/- 1.5 mV). The transduction efficiency of Ad/DA3 increased in a DA3 polymer concentration-dependent manner. Enhanced gene transfer by Ad/DA3 was more evident in CAR-moderate and CAR-negative cancer cells. Competition assays with a CAR-specific antibody revealed that internalization of Ad/DA3 was not mediated primarily by CAR but involved clathrin-, caveolae-, and macropinocytosis-mediated endocytosis. Cancer cell death was significantly increased when oncolytic Ad and DA3 were complexed (RdB-KOX/DA3) compared to that of naked oncolytic Ad and was inversely proportional to CAR levels. Importantly, RdB-KOX/DA3 significantly enhanced apoptosis, reduced angiogenesis, reduced proliferation, and increased active viral replication in human tumor xenografts compared to that of naked Ad. These results demonstrate that a hybrid vector system can increase the efficacy of oncolytic Ad viro-therapy, particularly in CAR-limited tumors. (C) 2014 Elsevier Ltd. All rights reserved.
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