title: 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.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, Republic of Korea.
authors.forename: Cho-Hee
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, Republic of Korea.
authors.forename: Dayananda
authors.initials: D
authors.lastname: Kasala
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, Republic of Korea.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Na
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Min Sang
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, Republic of Korea; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, Republic of Korea. Electronic address: chaeok@hanyang.ac.kr.
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D050130:Oncolytic Virotherapy / Q000379:methods*; D011094:Polyethyleneimine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001647:Bile Acids and Salts; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011094:Polyethyleneimine
keywords: Cancer gene therapy; Coxsackie and adenovirus receptor; Deoxycholic acid; Oncolytic adenovirus; Poly(ethyleneimine)