Enhanced therapeutic efficacy of an adenovirus-PEI-bile-acid complex in tumors with low coxsackie and adenovirus receptor expression.

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 mV, 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 virotherapy, particularly in CAR-limited tumors.

• Authors: Cho-Hee Lee, Dayananda Kasala, Youjin Na, Min Sang Lee, Sung Wan Kim, Ji Hoon Jeong, Chae-Ok Yun
• Journal: Biomaterials (Biomaterials) Vol. 35 Issue 21 Pg. 5505-16 (Jul 2014) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 24731708 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Bile Acids and Salts
• Coxsackie and Adenovirus Receptor-Like Membrane Protein
• Polyethyleneimine

Topics

• Adenoviridae (genetics)
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Bile Acids and Salts (chemistry, pharmacology)
• Cell Line, Tumor
• Chemical Phenomena
• Coxsackie and Adenovirus Receptor-Like Membrane Protein (genetics, metabolism)
• Female
• Genetic Vectors (genetics)
• HEK293 Cells
• Humans
• In Situ Nick-End Labeling
• MCF-7 Cells
• Mice
• Mice, Nude
• Microscopy, Electron, Transmission
• Oncolytic Virotherapy (methods)
• Polyethyleneimine (analogs & derivatives, chemistry, pharmacology)
• Transduction, Genetic
• Xenograft Model Antitumor Assays