title: Systemic image-guided liver cancer radiovirotherapy using dendrimer-coated adenovirus encoding the sodium iodide symporter as theranostic gene.
abstract: Currently, major limitations for the clinical application of adenovirus-mediated gene therapy are high prevalence of neutralizing antibodies, widespread expression of the coxsackie-adenovirus receptor (CAR), and adenovirus sequestration by the liver. In the current study, we used the sodium iodide symporter (NIS) as a theranostic gene to investigate whether coating of adenovirus with synthetic dendrimers could be useful to overcome these hurdles in order to develop adenoviral vectors for combination of systemic oncolytic virotherapy and NIS-mediated radiotherapy.
  
  
  METHODS
  We coated replication-deficient (Ad5-CMV/NIS) (CMV is cytomegalovirus) and replication-selective (Ad5-E1/AFP-E3/NIS) adenovirus serotype 5 carrying the hNIS gene with poly(amidoamine) dendrimers generation 5 (PAMAM-G5) in order to investigate transduction efficacy and altered tropism of these coated virus particles by (123)I scintigraphy and to evaluate their therapeutic potential for systemic radiovirotherapy in a liver cancer xenograft mouse model.
  
  
  RESULTS
  After dendrimer coating, Ad5-CMV/NIS demonstrated partial protection from neutralizing antibodies and enhanced transduction efficacy in CAR-negative cells in vitro. In vivo (123)I scintigraphy of nude mice revealed significantly reduced levels of hepatic transgene expression after intravenous injection of dendrimer-coated Ad5-CMV/NIS (dcAd5-CMV/NIS). Evasion from liver accumulation resulted in significantly reduced liver toxicity and increased transduction efficiency of dcAd5-CMV/NIS in hepatoma xenografts. After PAMAM-G5 coating of the replication-selective Ad5-E1/AFP-E3/NIS, a significantly enhanced oncolytic effect was observed after intravenous application (virotherapy) that was further increased by additional treatment with a therapeutic dose of (131)I (radiovirotherapy) and was associated with markedly improved survival.
  
  
  CONCLUSIONS
  These results demonstrate efficient liver detargeting and tumor retargeting of adenoviral vectors after coating with synthetic dendrimers, thereby representing a promising innovative strategy for systemic NIS gene therapy. Moreover, our study-based on the function of NIS as a theranostic gene allowing the noninvasive imaging of NIS expression by (123)I scintigraphy-provides detailed characterization of in vivo vector biodistribution and localization, level, and duration of transgene expression, essential prerequisites for exact planning and monitoring of clinical gene therapy trials that aim to individualize the NIS gene therapy concept.
authors.affiliation: Department of Internal Medicine II-Campus Grosshadern, University Hospital of Munich, Munich, Germany.
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Grünwald
authors.forename: Alexandra
authors.initials: A
authors.lastname: Vetter
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klutz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Willhauck
authors.forename: Nathalie
authors.initials: N
authors.lastname: Schwenk
authors.forename: Reingard
authors.initials: R
authors.lastname: Senekowitsch-Schmidtke
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.forename: Christian
authors.initials: C
authors.lastname: Zach
authors.forename: Ernst
authors.initials: E
authors.lastname: Wagner
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Per S
authors.initials: PS
authors.lastname: Holm
authors.forename: Manfred
authors.initials: M
authors.lastname: Ogris
authors.forename: Christine
authors.initials: C
authors.lastname: Spitzweg
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000378:metabolism*; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000532:radiotherapy / Q000628:therapy* / Q000821:virology*; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods*; D011877:Radionuclide Imaging; D061089:Radiotherapy, Image-Guided / Q000379:methods*; D027981:Symporters / Q000235:genetics*; D014161:Transduction, Genetic; D000099209:Sodium-Iodide Symporters
chemical_list: D050091:Dendrimers; D007457:Iodine Radioisotopes; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C104700:PAMAM Starburst
keywords: PAMAM dendrimer; adenovirus serotype 5; gene therapy; radiovirotherapy; sodium iodide symporter (NIS)