Authors: Weilian Yang Rolf F Barth Gong Wu Tianyao Huo Werner Tjarks Michael Ciesielski Robert A Fenstermaker Brain D Ross Carol J Wikstrand Kent J Riley Peter J Binns
Publish Date: 2009/07/09
Volume: 95, Issue: 3, Pages: 355-365
Abstract
In the present study we have evaluated a boronated dendrimerepidermal growth factor BDEGF bioconjugate as a molecular targeting agent for boron neutron capture therapy BNCT of the human EGFR genetransfected 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 it injection or intracerebral ic convection enhanced delivery CED of 125Ilabeled or unlabeled BDEGF 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 it injection and a doubling of the tumor boron concentration 223 μg/g vs 117 μg/g CED of BDEGF resulted in a 72× increase in the volume of distribution within the infused cerebral hemisphere and a 19× increase in tumor uptake of BDEGF compared with it injection Based on these favorable biodistribution data BNCT was carried out at the Massachusetts Institute of Technology nuclear reactor 14 days following ic tumor implantation and 24 h after CED of BDEGF These animals had a MST of 541 ± 47 days compared to 430 ± 28 days following it injection Rats that received BDEGF by CED in combination with iv boronophenylalanine BPA which has been used in both experimental and clinical studies had a MST of 860 ± 281 days compared to 398 ± 16 days for iv BPA alone P 001 309 ± 14 days for irradiated controls and 251 ± 10 days for untreated controls overall P 00001 These data have demonstrated that the efficacy of BNCT was significantly increased P 0006 following ic CED of BDEGF compared to it injection and that the survival data were equivalent to those previously reported by us using the boronated antihumanEGF mAb C225 cetuximabWe thank Ms Michelle Van Fossen for secretarial assistance in the preparation of this manuscript The studies described in this report were supported by NIH grants 1R01 CA098945 RF Barth the Roswell Park Alliance Foundation RA 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 DEFG0702ID14420DEFG0702 K14420 and the Office of Environmental and Biological Research contract no DEFG0202ER63358
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