title: In vivo delivery of antisense MORF oligomer by MORF/carrier streptavidin nanoparticles.
abstract: Tumor targeting by oligomers is largely limited by the pharmacokinetics and cell-membrane transport obstacles. In this article, we describe the use of a delivery nanoparticle, in which streptavidin served as a convenient bridge between a biotinylated oligomer and a biotinylated cell-membrane-penetrating peptide, to improve the delivery of an antisense phosphorodiamidate morpholino (MORF) oligomer in vivo. A biotinylated (99m)Tc-radiolabeled MORF oligomer with a base sequence antisense to the RIalpha mRNA and its sense control were incorporated separately into nanoparticles, along with biotinylated tat or polyarginine carrier. The streptavidin nanoparticles were administrated intravenously to both normal and nude mice bearing SUM149 breast tumor xenografts. The biodistributions showed much higher normal tissue levels for the radiolabeled MORFs, independent of antisense or sense or tat or polyarginine, when administered as the nanoparticles, compared to naked. A statistically significant higher accumulation of both antisense nanoparticles, compared to the respective sense control nanoparticles, was observed, along with much higher tumor accumulations, compared to historical naked controls. This study has provided evidence that the in vivo function of an antisense oligomer within the streptavidin nanoparticle is not impeded, and, as such, the MORF/streptavidin/carrier nanoparticles may be suitable for in vivo tumor delivery of antisense MORF and other oligomers.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Xinrong
authors.initials: X
authors.lastname: Liu
authors.forename: Kayoko
authors.initials: K
authors.lastname: Nakamura
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Mary
authors.initials: M
authors.lastname: Rusckowski
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Hnatowich
mesh_terms: D000818:Animals; D019921:Biotinylation; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000627:therapeutic use*; D060172:Morpholinos; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology / Q000379:methods; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D010455:Peptides / Q000627:therapeutic use; D019809:Streptavidin / Q000627:therapeutic use*; D013667:Technetium / Q000627:therapeutic use
chemical_list: D004337:Drug Carriers; D009025:Morpholines; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D010455:Peptides; C015462:polyarginine; D013667:Technetium; D019809:Streptavidin