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Journal of Neuro-Oncology

, Volume 95, Issue 3, pp 355–365 | Cite as

Convection enhanced delivery of boronated EGF as a molecular targeting agent for neutron capture therapy of brain tumors

  • Weilian Yang
  • Rolf F. BarthEmail author
  • Gong Wu
  • Tianyao Huo
  • Werner Tjarks
  • Michael Ciesielski
  • Robert A. Fenstermaker
  • Brain D. Ross
  • Carol J. Wikstrand
  • Kent J. Riley
  • Peter J. Binns
Laboratory Investigation - Human/Animal Tissue

Abstract

In the present study, we have evaluated a boronated dendrimer-epidermal growth factor (BD-EGF) bioconjugate as a molecular targeting agent for boron neutron capture therapy (BNCT) of the human EGFR gene-transfected F98 rat glioma, designated F98EGFR. EGF was chemically linked to a heavily boronated polyamidoamine dendrimer (BD) by means of the heterobifunctional reagent, mMBS. Biodistribution studies were carried out at 6 h and 24 h following intratumoral (i.t.) injection or intracerebral (i.c.) convection enhanced delivery (CED) of 125I-labeled or unlabeled BD-EGF (40 μg 10B/10 μg EGF) to F98 glioma bearing rats. At 24 h. there was 43% more radioactivity in EGFR(+) tumors following CED compared to i.t. injection, and a doubling of the tumor boron concentration (22.3 μg/g vs. 11.7 μg/g). CED of BD-EGF resulted in a 7.2× increase in the volume of distribution within the infused cerebral hemisphere and a 1.9× increase in tumor uptake of BD-EGF compared with i.t. injection. Based on these favorable biodistribution data, BNCT was carried out at the Massachusetts Institute of Technology nuclear reactor 14 days following i.c. tumor implantation and 24 h. after CED of BD-EGF. These animals had a MST of 54.1 ± 4.7 days compared to 43.0 ± 2.8 days following i.t. injection. Rats that received BD-EGF by CED in combination with i.v. boronophenylalanine (BPA), which has been used in both experimental and clinical studies, had a MST of 86.0 ± 28.1 days compared to 39.8 ± 1.6 days for i.v. BPA alone (P < 0.01), 30.9 ± 1.4 days for irradiated controls and 25.1 ± 1.0 days for untreated controls (overall P < 0.0001). These data have demonstrated that the efficacy of BNCT was significantly increased (P < 0.006), following i.c CED of BD-EGF compared to i.t injection, and that the survival data were equivalent to those previously reported by us using the boronated anti-human-EGF mAb, C225 (cetuximab).

Keywords

Convection enhanced delivery Boronated EGF Boron neutron capture therapy F98 rat glioma 

Notes

Acknowledgements

We thank Ms. Michelle Van Fossen for secretarial assistance in the preparation of this manuscript. The studies described in this report were supported by N.I.H. grants 1R01 CA098945 (R.F. Barth), the Roswell Park Alliance Foundation (R.A. Fenstermaker), and the United States Department of Energy thorugh the program of Innovations in Nuclear Infrastructure and Education, Office of Nuclear Energy, Science and Technology (contract no. DE-FG07-02ID14420DE-FG07-02, K14420), and the Office of Environmental and Biological Research (contract no. DE-FG02-02ER63358).

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Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Weilian Yang
    • 1
  • Rolf F. Barth
    • 1
    Email author
  • Gong Wu
    • 1
  • Tianyao Huo
    • 1
  • Werner Tjarks
    • 2
  • Michael Ciesielski
    • 3
  • Robert A. Fenstermaker
    • 3
  • Brain D. Ross
    • 4
  • Carol J. Wikstrand
    • 5
    • 7
  • Kent J. Riley
    • 6
    • 9
  • Peter J. Binns
    • 6
    • 8
  1. 1.Department of PathologyThe Ohio State UniversityColumbusUSA
  2. 2.Colleges of PharmacyThe Ohio State UniversityColumbusUSA
  3. 3.Department of NeurosurgeryRoswell Park Memorial InstituteBuffaloUSA
  4. 4.Department of RadiologyUniversity of MichiganAnn ArborUSA
  5. 5.Department of MicrobiologySaba University School of MedicineSabaNetherlands Antilles
  6. 6.The Nuclear Reactor LaboratoryMassachusetts Institute of TechnologyCambridgeUSA
  7. 7.Department of PathologyDuke UniversityDurhamUSA
  8. 8.Department of RadiologyMount Auburn HospitalCambridgeUSA
  9. 9.Radiation Monitoring Devices, IncWatertownUSA

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