title: Metallofullerene-based nanoplatform for brain tumor brachytherapy and longitudinal imaging in a murine orthotopic xenograft model.
abstract: OBJECTIVE
  To demonstrate in an orthotopic xenograft brain tumor model that a functionalized metallofullerene (f-Gd₃N@C₈₀) can enable longitudinal tumor imaging and, when radiolabeled with lutetium 177 (¹⁷⁷Lu) and tetraazacyclododecane tetraacetic acid (DOTA) (¹⁷⁷Lu-DOTA-f-Gd₃N@C₈₀), provide an anchor to deliver effective brachytherapy.
  
  
  METHODS
  All experiments involving the use of mice were carried out in accordance with protocols approved by the institutional animal care and use committee. Human glioblastoma U87MG cells were implanted by using stereotactic procedures into the brains of 37 female athymic nude-Foxn1nu mice and allowed to develop into a tumor for 8 days. T1- and T2-weighted magnetic resonance (MR) imaging was performed in five mice. Biodistribution studies were performed in 12 mice at four time points over 7 days to evaluate gadolinium content. Survival studies involved 20 mice that received infusion of a nanoplatform by means of convection-enhanced delivery (CED) 8 days after tumor implantation. Mice in survival studies were divided into two groups: one comprised untreated mice that received f-Gd₃N@CC₈₀ alone and the other comprised mice treated with brachytherapy that received 1.11 MBq of ¹⁷⁷Lu-DOTA-f-Gd₃N@CC₈₀. Survival data were evaluated by using Kaplan-Meier statistical methods.
  
  
  RESULTS
  MR imaging showed extended tumor retention (25.6% ± 1.2 of the infused dose at 52 days, confirmed with biodistribution studies) of the f-Gd₃N@CC₈₀ nanoplatform, which enabled longitudinal imaging. Successful coupling of ¹⁷⁷Lu to the f-Gd₃N@CC₈₀ surface was achieved by using a bifunctional macrocyclic chelator. The extended tumor retention allowed for effective brachytherapy, as indicated by extended survival time (> 2.5 times that of the untreated group) and histologic signs of radiation-induced tumor damage.
  
  
  CONCLUSIONS
  The authors have developed a multimodal nanoplatform and have demonstrated longitudinal tumor imaging, prolonged intratumoral probe retention, biodistribution, and extended survival in an orthotopic xenograft brain tumor model.
authors.affiliation: Department of Radiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0072, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Shultz
authors.forename: John D
authors.initials: JD
authors.lastname: Wilson
authors.forename: Christine E
authors.initials: CE
authors.lastname: Fuller
authors.forename: Jianyuan
authors.initials: J
authors.lastname: Zhang
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dorn
authors.forename: Panos P
authors.initials: PP
authors.lastname: Fatouros
mesh_terms: D000818:Animals; D001918:Brachytherapy / Q000379:methods*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000532:radiotherapy*; D056831:Coordination Complexes; D004195:Disease Models, Animal; D005260:Female; D037741:Fullerenes; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000532:radiotherapy*; D006573:Heterocyclic Compounds, 1-Ring / Q000627:therapeutic use*; D008187:Lutetium / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D036103:Nanotechnology; D009368:Neoplasm Transplantation; D011868:Radioisotopes / Q000627:therapeutic use*; D011877:Radionuclide Imaging
chemical_list: D056831:Coordination Complexes; D037741:Fullerenes; D006573:Heterocyclic Compounds, 1-Ring; D011868:Radioisotopes; D008187:Lutetium