title: Bioreducible polymer-conjugated oncolytic adenovirus for hepatoma-specific therapy via systemic administration.
abstract: Systemic administration of adenovirus (Ad) vectors is complicated by host immune responses and viral accumulation in the liver, resulting in a short circulatory virus half-life, low efficacy, and host side effects. Ad surface modification is thus required to enhance safety and therapeutic efficacy. An arginine-grafted bioreducible polymer (ABP) was chemically conjugated to the Ad surface, generating Ad-ΔE1/GFP-ABP. A hepatocellular carcinoma [HCC]-selective oncolytic Ad complex, YKL-1001-ABP, was also generated. Transduction efficiency of Ad-ΔE1/GFP-ABP was enhanced compared to naked Ad-ΔE1/GFP. YKL-1001-ABP elicited an enhanced and specific killing effect in liver cancer cells (Huh7 and HepG2) expressing α-fetoprotein (AFP). Compared with naked Ad, systemic administration of ABP-conjugated Ad resulted in reduced liver toxicity and interleukin (IL)-6 production in vitro and in vivo. Ad-ΔE1/GFP-ABP was more resistant to the neutralizing effects of human serum compared to naked Ad-ΔE1/GFP. ABP conjugation extended blood circulation time 45-fold and reduced anti-Ad Ab neutralization. Moreover, systemic administration of YKL-1001-ABP markedly suppressed growth of Huh7 hepatocellular carcinoma. These results demonstrate that chemical conjugation of ABP to the Ad surface improves safety and efficacy, indicating that ABP-conjugated Ad is a potentially useful cancer therapeutic agent to target cancer via systemic administration.
authors.affiliation: Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Pyung-Hwan
authors.initials: PH
authors.lastname: Kim
authors.forename: Jaesung
authors.initials: J
authors.lastname: Kim
authors.forename: Tae-il
authors.initials: TI
authors.lastname: Kim
authors.forename: Hye Yeong
authors.initials: HY
authors.lastname: Nam
authors.forename: James W
authors.initials: JW
authors.lastname: Yockman
authors.forename: Minjung
authors.initials: M
authors.lastname: Kim
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000256:Adenoviridae / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001672:Biocompatible Materials / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004229:Dithiothreitol / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D057131:Immune Evasion / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D050504:Oncolytic Viruses / Q000187:drug effects*; D010316:Particle Size; D011108:Polymers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D055672:Static Electricity; D014161:Transduction, Genetic; D016896:Treatment Outcome
chemical_list: D001672:Biocompatible Materials; D011108:Polymers; D049452:Green Fluorescent Proteins; D001120:Arginine; D004229:Dithiothreitol