title: Formulation and in vitro and in vivo evaluation of a cationic emulsion as a vehicle for improving adenoviral gene transfer.
abstract: Advancements in the use of adenoviral vectors in gene therapy have been limited by the need for specific receptors on targeted cell types, immunogenicity and hepatotoxicity following systemic administration. In an effort to overcome the current limitations of adenovirus-mediated gene transfer, cationic emulsions were explored as a vehicle to improve adenoviral vector-mediated gene transfer. Complexation of adenovirus with emulsions containing the cationic lipid 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) enhanced the potency of adenoviral gene transfer as compared to DOTAP liposomes. Among the various emulsion formulations examined, those containing the iodized oil, Lipiodol, as an inner core and stabilized by DOTAP/cholesterol/1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(poly-ethylene glycol)-5000 most efficiently enhanced adenovirus-mediated gene transfer. Optimized Lipiodol-containing emulsions appear to be more strongly associated with adenoviral particles, exhibiting higher complex stability compared to other formulations. They provide the adenovirus with an additional cellular entry mechanism through caveolae-dependent endocytosis, thereby increasing adenovirus entry into cells. Furthermore, adenovirus-emulsion complexation significantly reduced transgene expression in the liver following systemic administration. These findings indicate that emulsion complexation may be a promising strategy for overcoming many of the challenges associated with the use of adenoviruses in gene therapy. Additionally, the observation of increased transgene expression in lung together with reduced expression in liver demonstrates that the adenovirus-emulsion complex may act as a lung-targeting adenoviral gene delivery system.
authors.affiliation: Department of Bioscience and Bioengineering, Sejong University, 98 Kunja-dong, Kwangjin-gu, Seoul 143-747, Republic of Korea.
authors.forename: Soo-Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Genitourinary Cancer Branch, Research Institute, National Cancer Center, Goyang 410-769, Republic of Korea. Electronic address: leesj@ncc.re.kr.
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Bioscience and Bioengineering, Sejong University, 98 Kunja-dong, Kwangjin-gu, Seoul 143-747, Republic of Korea. Electronic address: sjlim@sejong.ac.kr.
authors.forename: Soo-Jeong
authors.initials: SJ
authors.lastname: Lim
mesh_terms: D000256:Adenoviridae / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004274:DNA, Recombinant / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D004655:Emulsions; D004705:Endocytosis; D018014:Gene Transfer Techniques / Q000009:adverse effects; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008081:Liposomes; D008168:Lung / Q000378:metabolism* / Q000821:virology; D008297:Male; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D011897:Random Allocation; D011994:Recombinant Proteins / Q000378:metabolism*; D014771:Virion / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053585:Virus Attachment; D053586:Virus Internalization
chemical_list: D004274:DNA, Recombinant; D004655:Emulsions; D008081:Liposomes; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins
keywords: Adenovirus; Cationic emulsion; Caveolin; Endocytosis; Gene therapy