title: Viral genome DNA/lipoplexes elicit in situ oncolytic viral replication and potent antitumor efficacy via systemic delivery.
abstract: Modifying the viral genome to express potent and cancer-selective therapeutic genes has enhanced the role of adenoviruses (Ads) in cancer molecular therapeutics. However, the efficacy of Ad systemic delivery in vivo is limited by neutralizing antibodies, short blood circulation time, and high levels of nonspecific liver uptake resulting in hepatotoxicity. We therefore investigated the systemic delivery of tumor necrosis factor-related apoptosis-inducing ligand-expressing oncolytic Ad genome DNA (pmT-d19/stTR) via lipid envelopment as an alternative approach for cancer virotherapy in an orthotopic lung cancer model. Cationic liposomes (DOTAP/DOPE) were complexed with pmT-d19/stTR to generate pmT-d19/stTR+DOTAP/DOPE with the average diameter of which was 143.3 ± 5.7 nm at the optimal DNA:lipid ratio (1:6). Systemic administration of pmT-d19/stTR+DOTAP/DOPE elicited highly effective antitumor responses in vivo, with tumor volumes decreasing 94.5%, 90.5%, and 92.4% compared to phosphate buffered saline-, naked Ad (mT-d19/stTR)-, or pmT-d19/stTR-treated groups, respectively. Additionally, innate immune responses and Ad-specific neutralizing antibodies were significantly decreased in pmT-d19/stTR+DOTAP/DOPE-treated mice compared to those in the mT-d19/stTR-treated group. The biodistribution profile analyzed by quantitative-PCR and immunohistochemical analysis demonstrated that viral replication occurred preferentially in tumor tissues. Moreover, the viral genome tumor-to-liver ratio was significantly elevated in pmT-d19/stTR+DOTAP/DOPE-treated mice, which was 934- and 27-fold greater than the mT-d19/stTR- and pmT-d19/stTR-treated mice, respectively. These results demonstrate that systemic delivery of oncolytic viral genome DNA with liposomes is a powerful alternative to naked Ad, overcoming the limited clinical applicability of conventional Ads and enabling effective treatment of disseminated metastatic tumors.
authors.affiliation: Nanomedical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Oh-Joon
authors.initials: OJ
authors.lastname: Kwon
authors.forename: Eunah
authors.initials: E
authors.lastname: Kang
authors.forename: Sungwan
authors.initials: S
authors.lastname: Kim
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival; D016207:Cytokines / Q000097:blood; D003588:Cytopathogenic Effect, Viral; D004337:Drug Carriers / Q000737:chemistry*; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage; D016679:Genome, Viral; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D010714:Phosphatidylethanolamines / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D060888:Real-Time Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D017500:Adenovirus E1A Proteins; D016207:Cytokines; D004337:Drug Carriers; D005229:Fatty Acids, Monounsaturated; D010714:Phosphatidylethanolamines; D000644:Quaternary Ammonium Compounds; D053221:TNF-Related Apoptosis-Inducing Ligand; C094877:dioleoyl phosphatidylethanolamine; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane