title: pH-sensitive oncolytic adenovirus hybrid targeting acidic tumor microenvironment and angiogenesis.
abstract: Although oncolytic adenoviruses (Ads) are an attractive option for cancer gene therapy, the intravenous administration of naked Ad still encounters unfavorable host responses, non-specific interactions, and heterogeneity in targeted cancer cells. To overcome these obstacles and achieve specific targeting of the tumor microenvironment, Ad was coated with the pH-sensitive block copolymer, methoxy poly(ethylene glycol)-b-poly(l-histidine-co-l-phenylalanine) (PEGbPHF). The physicochemical properties of the generated nanocomplex, Ad/PEGbPHF, were assessed. At pH6.4, GFP-expressing Ad/PEGbPHF induced significantly higher GFP expression than naked Ad in both coxsackie and adenovirus receptor (CAR)-positive and -negative cells. To assess the therapeutic efficacy of the Ad/PEGbPHF complex platform, an oncolytic Ad expressing VEGF promoter-targeting transcriptional repressor (KOX) was used to form complexes. At pH6.4, KOX/PEGbPHF significantly suppressed VEGF gene expression, cancer cell migration, vessel sprouting, and cancer cell killing effect compared to naked KOX or KOX/PEGbPHF at pH7.4, demonstrating that KOX/PEGbPHF can overcome the lack of CAR that is frequently observed in tumor tissues. The antitumor activity of KOX/PEGbPHF systemically administered to a tumor xenograft model was significantly higher than that of naked KOX. Furthermore, KOX/PEGbPHF showed lower hepatic toxicity and did not induce an innate immune response against Ad. Altogether, these results demonstrate that pH-sensitive polymer-coated Ad complex significantly increases net positive charge upon exposure to hypoxic tumor microenvironment, allowing passive targeting to the tumor tissue. It may offer superior potential for systemic therapy, due to its improved tumor selectivity, increased therapeutic efficacy, and lower toxicity compared to naked KOX.
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsinmi-ro, Seongdong-gu, Seoul, Republic of Korea.
authors.forename: Joung-Woo
authors.initials: JW
authors.lastname: Choi
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsinmi-ro, Seongdong-gu, Seoul, Republic of Korea.
authors.forename: Soo-Jung
authors.initials: SJ
authors.lastname: Jung
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsinmi-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 Wangsinmi-ro, Seongdong-gu, Seoul, Republic of Korea.
authors.forename: June Kyu
authors.initials: JK
authors.lastname: Hwang
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, The University of Utah, 30S 2000 E, Room 2972, Salt Lake City, UT 84112, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, The University of Utah, 30S 2000 E, Room 2972, Salt Lake City, UT 84112, USA; Utah-Inha Drug Delivery Systems (DDS) and Advanced Therapeutics Research Center, 7-50 Songdo-dong, Yeonsu-gu, Incheon 406-840, Republic of Korea. Electronic address: you.bae@utah.edu.
authors.forename: You Han
authors.initials: YH
authors.lastname: Bae
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsinmi-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 / Q000276:immunology / Q000472:pathogenicity*; D017500:Adenovirus E1A Proteins / Q000235:genetics; D017501:Adenovirus E1B Proteins / Q000235:genetics; D000818:Animals; D015687:Cell Hypoxia; D002465:Cell Movement; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007113:Immunity, Innate; D061986:MCF-7 Cells; D008819:Mice, Nude; D009154:Mutation; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy* / Q000821:virology; D018919:Neovascularization, Physiologic; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D010455:Peptides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D046509:Tissue Culture Techniques; D014161:Transduction, Genetic; D047368:Tumor Burden; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D010455:Peptides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C033223:polyhistidine; C012001:polyphenylalanine; D011092:Polyethylene Glycols; D006639:Histidine; C028210:monomethoxypolyethylene glycol
keywords: Cancer gene therapy; Hypoxia; Oncolytic adenovirus; Systemic administration; Tumor microenvironment; pH-sensitive polymers