title: Carbon nanotubes enhance CpG uptake and potentiate antiglioma immunity.
abstract: OBJECTIVE
  Stimulation of toll-like receptor-9 (TLR9) by CpG oligodeoxynucleotides (CpG) has been shown to counteract the immunosuppressive microenvironment and to inhibit tumor growth in glioma models. Because TLR9 is located intracellularly, we hypothesized that methods that enhance its internalization may also potentiate its immunostimulatory response. The goal of this study was to evaluate carbon nanotubes (CNT) as a CpG delivery vehicle in brain tumor models.
  
  
  METHODS
  Functionalized single-walled CNTs were conjugated with CpG (CNT-CpG) and evaluated in vitro and in mice bearing intracranial GL261 gliomas. Flow cytometry was used to assess CNT-CpG uptake and antiglioma immune response. Tumor growth was measured by bioluminescent imaging, histology, and animal survival.
  
  
  RESULTS
  CNT-CpG was nontoxic and enhanced CpG uptake both in vitro and intracranial gliomas. CNT-mediated CpG delivery also potentiated proinflammatory cytokine production by primary monocytes. Interestingly, a single intracranial injection of low-dose CNT-CpG (but not free CpG or blank CNT) eradicated intracranial GL261 gliomas in half of tumor-bearing mice. Moreover, surviving animals exhibited durable tumor-free remission (>3 months), and were protected from intracranial tumor rechallenge, demonstrating induction of long-term antitumor immunity.
  
  
  CONCLUSIONS
  These findings suggest that CNTs can potentiate CpG immunopotency by enhancing its delivery into tumor-associated inflammatory cells.
authors.affiliation: Division of Neurosurgery, Department of Surgery, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA.
authors.forename: Dongchang
authors.initials: D
authors.lastname: Zhao
authors.forename: Darya
authors.initials: D
authors.lastname: Alizadeh
authors.forename: Leying
authors.initials: L
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Omar
authors.initials: O
authors.lastname: Farrukh
authors.forename: Edwin
authors.initials: E
authors.lastname: Manuel
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
authors.forename: Behnam
authors.initials: B
authors.lastname: Badie
mesh_terms: D000276:Adjuvants, Immunologic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D018925:Chemokines / Q000378:metabolism; D018899:CpG Islands; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D058726:Nanoconjugates / Q000627:therapeutic use*; D037742:Nanotubes, Carbon; D009368:Neoplasm Transplantation; D011119:Polynucleotides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000276:Adjuvants, Immunologic; D018925:Chemokines; D016207:Cytokines; D058726:Nanoconjugates; D037742:Nanotubes, Carbon; D011119:Polynucleotides; D051217:Toll-Like Receptor 9