title: Virus-like particle-mediated intracellular delivery of mRNA cap analog with in vivo activity against hepatocellular carcinoma.
abstract: Adenovirus dodecahedron (Dd), a nanoparticulate proteinaceous biodegradable virus-like particle (VLP), was used as a vector for delivery of an oncogene inhibitor to hepatocellular carcinoma (HCC) rat orthotopic model. Initiation factor eIF4E is an oncogene with elevated expression in human cancers. Cell-impermeant eIF4E inhibitor, cap structure analog (cap) and anti-cancer antibiotic doxorubicin (Dox) were delivered as Dd conjugates. Dd-cap and Dd-dox inhibited cancer cell culture proliferation up to 50 and 84%, respectively, while with free Dox similar results could be obtained only at a 5 times higher concentration. In animal HCC model the combination treatment of Dd-cap/Dd-dox caused 40% inhibition of tumor growth. Importantly, the level of two pro-oncogenes, eIF4E and c-myc, was significantly diminished in tumor sections of treated rats. Attachment to Dd, a virus-like particle, permitted the first demonstration of cap analog intracellular delivery and resulted in improved doxorubicin delivery leading to statistically significant inhibition of HCC tumor growth.
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Zochowska
authors.affiliation: Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland.
authors.forename: Anne-Christine
authors.initials: AC
authors.lastname: Piguet
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland; Centre of New Technologies, University of Warsaw, Warsaw, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Jemielity
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kowalska
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Szolajska
authors.affiliation: University Clinics of Visceral Surgery and Medicine, Inselspital Berne, Berne, Switzerland.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dufour
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland; Therex, TIMC-IMAG, CNRS, Université Joseph Fourier, La Tronche, France. Electronic address: jadwiga.chroboczek@imag.fr.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Chroboczek
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D004317:Doxorubicin / Q000737:chemistry; D004705:Endocytosis; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D008113:Liver Neoplasms / Q000628:therapy*; D050997:Nanomedicine / Q000379:methods; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D058425:Vaccines, Virus-Like Particle / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D039561:Eukaryotic Initiation Factor-4E; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D058425:Vaccines, Virus-Like Particle; D004317:Doxorubicin
keywords: Adenoviral dodecahedron; Cap structure analogs; Doxorubicin; Drug delivery vector; Hepatocellular carcinoma; Oncogene eIF4E; Virus-like particle; eIF4E inhibitor