Convection enhanced delivery of boronated EGF as a molecular targeting agent for neutron capture therapy of brain tumors.
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 F98(EGFR). 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 (125)I-labeled or unlabeled BD-EGF (40 microg (10)B/10 microg 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 microg/g vs. 11.7 microg/g). CED of BD-EGF resulted in a 7.2x increase in the volume of distribution within the infused cerebral hemisphere and a 1.9x 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).
Yang
Weilian
W
Department of Pathology, The Ohio State University, 165 Hamilton Hall, 1645 Neil Avenue, Columbus, OH, 43210, USA.
Barth
Rolf F
RF
Department of Pathology, The Ohio State University, 165 Hamilton Hall, 1645 Neil Avenue, Columbus, OH, 43210, USA. rolf.barth@osumc.edu.
Wu
Gong
G
Department of Pathology, The Ohio State University, 165 Hamilton Hall, 1645 Neil Avenue, Columbus, OH, 43210, USA.
Huo
Tianyao
T
Department of Pathology, The Ohio State University, 165 Hamilton Hall, 1645 Neil Avenue, Columbus, OH, 43210, USA.
Tjarks
Werner
W
Colleges of Pharmacy, The Ohio State University, Columbus, OH, USA.
Ciesielski
Michael
M
Department of Neurosurgery, Roswell Park Memorial Institute, Buffalo, NY, USA.
Fenstermaker
Robert A
RA
Department of Neurosurgery, Roswell Park Memorial Institute, Buffalo, NY, USA.
Ross
Brain D
BD
Department of Radiology, University of Michigan, Ann Arbor, MI, USA.
Wikstrand
Carol J
CJ
Department of Microbiology, Saba University School of Medicine, Saba, Netherlands Antilles.|Department of Pathology, Duke University, Durham, NC, USA.
Riley
Kent J
KJ
The Nuclear Reactor Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.|Radiation Monitoring Devices, Inc, Watertown, MA, 02172, USA.
Binns
Peter J
PJ
The Nuclear Reactor Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.|Department of Radiology, Mount Auburn Hospital, Cambridge, MA, USA.
D000818:Animals; D001896:Boron Compounds / Q000493:pharmacokinetics*; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D018481:Convection; D050091:Dendrimers; D016503:Drug Delivery Systems / Q000379:methods; D004815:Epidermal Growth Factor / Q000493:pharmacokinetics*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D007457:Iodine Radioisotopes; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging; D009368:Neoplasm Transplantation; D011073:Polyamines / Q000493:pharmacokinetics; D016016:Proportional Hazards Models; D011874:Radiometry; D051381:Rats; D011916:Rats, Inbred F344; D014162:Transfection
D001896:Boron Compounds; D050091:Dendrimers; D007457:Iodine Radioisotopes; C104700:PAMAM Starburst; D011073:Polyamines; D004815:Epidermal Growth Factor; D066246:ErbB Receptors