title: Auger radiation-induced, antisense-mediated cytotoxicity of tumor cells using a 3-component streptavidin-delivery nanoparticle with 111In.
abstract: When antisense oligomers are intracellular, they migrate to and are retained in the nucleus of tumor cells and therefore may be used to carry Auger electron-emitting radionuclides such as (111)In for effective tumor radiotherapy.
  
  
  METHODS
  Our nanoparticle consists of streptavidin that links 3 biotinylated components: the antiHer2 antibody trastuzumab (to improve pharmacokinetics), the tat peptide (to improve cell membrane transport), and the (111)In-labeled antiRIalpha messenger RNA antisense morpholino (MORF) oligomer.
  
  
  RESULTS
  As evidence of unimpaired function, tumor cell and nuclear accumulations were orders of magnitude higher after incubation with (99m)Tc-MORF/tat/trastuzumab than after incubation with free (99m)Tc-MORF and significantly higher with the antisense than with the sense MORF. In mice, tumor and normal-tissue accumulations of the (99m)Tc-MORF/tat/trastuzumab nanoparticle were comparable to those of free (99m)Tc-trastuzumab, confirming the improved pharmacokinetics due to the trastuzumab component. Although kidneys, liver, and other normal tissues also accumulated the nanoparticle, immunohistochemical evaluation of tissue sections in mice receiving the Cy3-MORF/tat/trastuzumab nanoparticle showed evidence of nuclear accumulation only in tumor tissue. In a dose escalation study, as measured by the surviving fraction, the nanoparticle significantly increased the kill of SK-BR-3 breast cancer Her2+/RIalpha+ cells, compared with all controls.
  
  
  CONCLUSIONS
  Significant radiation-induced antisense-mediated cytotoxicity of tumor cells in vitro was achieved using an Auger electron-emitting antisense MORF oligomer administered as a member of a 3-component streptavidin-delivery nanoparticle.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Xinrong
authors.initials: X
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Kayoko
authors.initials: K
authors.lastname: Nakamura
authors.forename: Sumi
authors.initials: S
authors.lastname: Kawauchi
authors.forename: Ali
authors.initials: A
authors.lastname: Akalin
authors.forename: Dengfeng
authors.initials: D
authors.lastname: Cheng
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; D045744:Cell Line, Tumor; D002470:Cell Survival; D016373:DNA, Antisense / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage*; D005260:Female; D007205:Indium Radioisotopes / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009369:Neoplasms / Q000473:pathology* / Q000532:radiotherapy*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000737:chemistry; D019809:Streptavidin / Q000008:administration & dosage* / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D016373:DNA, Antisense; D004337:Drug Carriers; D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D019809:Streptavidin