Safety Profiles and Antitumor Efficacy of Oncolytic Adenovirus Coated with Bioreducible Polymer in the Treatment of a CAR Negative Tumor Modelopen access
- Authors
- Jung, Soo-Jung; Kasala, Dayananda; Choi, Joung-Woo; Lee, Soo-Hwan; Hwang, June Kyu; Kim, Sung Wan; Yun, Chae-Ok
- Issue Date
- Jan-2015
- Publisher
- AMER CHEMICAL SOC
- Citation
- BIOMACROMOLECULES, v.16, no.1, pp.87 - 96
- Indexed
- SCIE
SCOPUS
- Journal Title
- BIOMACROMOLECULES
- Volume
- 16
- Number
- 1
- Start Page
- 87
- End Page
- 96
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/25671
- DOI
- 10.1021/bm501116x
- ISSN
- 1525-7797
- Abstract
- Adenovirus (Ad) vectors show promise as cancer gene therapy delivery vehicles, but immunogenic safety concerns and coxsackie and adenovirus receptor (CAR)-dependency have limited their use. Alternately, biocompatible and bioreducible nonviral vectors, including arginine-grafted cationic polymers, have been shown to deliver nucleic acids through a cell penetration peptide (CPP) and protein transduction domain (PTD) effect. We utilized the advantages of both viral and nonviral vectors to develop a hybrid gene delivery vehicle by coating Ad with mPEG-PEI-g-Arg-S-S-Arg-g-PEI-mPEG (Ad/PPSA). Characterization of Ad/PPSA particle size and zeta potential showed an overall size and cationic charge increase in a polymer concentration-dependent manner. Ad/PPSA also showed a marked transduction efficiency increase in both CAR-negative and -positive cells compared to naked Ad. Competition assays demonstrated that Ad/PPSA produced higher transgene expression levels than naked Ad and achieved CAR-independent transduction. Oncolytic Ad (DWP418)/PPSA was able to overcome the nonspecificity of polymer-only therapies by demonstrating cancer-specific killing effects. Furthermore, the DWP418/PPSA nanocomplex elicited a 2.24-fold greater antitumor efficacy than naked Ad in vivo. This was supported by immunohistochemical confirmation of Ad E1As accumulation in MCF7 xenografted tumors. Lastly, intravenous injection of DWP418/PPSA elicited less innate immune response compared to naked Ad, evaluated by interleukin-6 cytokine release into the serum. The increased antitumor effect and improved vector targeting to both CAR-negative and -positive cells make DWP418/PPSA a promising tool for cancer gene therapy.
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