Biomedical subjects

Peter J Binns

Publications and source records attributed to Peter J Binns.

7 recordsLinked to original sources

PubMed2006

Molecular targeting and treatment of EGFRvIII-positive gliomas using boronated monoclonal antibody L8A4.

PURPOSE: The purpose of the present study was to evaluate a boronated EGFRvIII-specific monoclonal antibody, L8A4, for boron neutron capture therapy (BNCT) of the receptor-positive rat glioma, F98(npEGFRvIII). EXPERIMENTAL DESIGN: A heavily boronated polyamido amine (PAMAM) dendrimer (BD) was chemically linked to L8A4 by two heterobifunctional reagents, N-succinimidyl 3-(2-pyridyldithio)propionate and N-(k-maleimidoundecanoic acid)hydrazide. For in vivo studies, F98 wild-type receptor-negative or EGFRvIII human gene-transfected receptor-positive F98(npEGFRvIII) glioma cells were implanted i.c. into the brains of Fischer rats. Biodistribution studies were initiated 14 days later. Animals received [(125)I]BD-L8A4 by either convection enhanced delivery (CED) or direct i.t. injection and were euthanized 6, 12, 24, or 48 hours later. RESULTS: At 6 hours, equivalent amounts of the bioconjugate were detected in receptor-positive and receptor-negative tumors, but by 24 hours the amounts retained by receptor-positive gliomas were 60.1% following CED and 43.7% following i.t. injection compared with 14.6% ID/g by receptor-negative tumors. Boron concentrations in normal brain, blood, liver, kidneys, and spleen all were at nondetectable levels (<0.5 microg/g) at the corresponding times. Based on these favorable biodistribution data, BNCT studies were initiated at the Massachusetts Institute of Technology Research Reactor-II. Rats received BD-L8A4 ( approximately 40 microg (10)B/ approximately 750 mug protein) by CED either alone or in combination with i.v. boronophenylalanine (BPA; 500 mg/kg). BNCT was carried out 24 hours after administration of the bioconjugate and 2.5 hours after i.v. injection of BPA for those animals that received both agents. Rats that received BD-L8A4 by CED in combination with i.v. BPA had a mean +/- SE survival time of 85.5 +/- 15.5 days with 20% long-term survivors (>6 months) and those that received BD-L8A4 alone had a mean +/- SE survival time of 70.4 +/- 11.1 days with 10% long-term survivors compared with 40.1 +/- 2.2 days for i.v. BPA and 30.3 +/- 1.6 and 26.3 +/- 1.1 days for irradiated and untreated controls, respectively. CONCLUSIONS: These data convincingly show the therapeutic efficacy of molecular targeting of EGFRvIII using either boronated monoclonal antibody L8A4 alone or in combination with BPA and should provide a platform for the future development of combinations of high and low molecular weight delivery agents for BNCT of brain tumors.

Animals↗

PubMed2006

Selective irradiation of the vascular endothelium has no effect on the survival of murine intestinal crypt stem cells.

The possible role of vascular endothelial cell damage in the loss of intestinal crypt stem cells and the subsequent development of the gastrointestinal (GI) syndrome is addressed. Mice received whole-body epithermal neutron irradiation at a dose rate of 0.57 +/- 0.04 Gy x min(-1). An additional dose was selectively targeted to endothelial cells from the short-ranged (5-9 microm) particles released from neutron capture reactions in 10B confined to the blood by incorporation into liposomes 70-90 nm in diameter. Different liposome formulations produced 45 +/- 7 or 118 +/- 12 microg/g 10B in the blood at the time of neutron irradiation, which resulted in total absorbed dose rates in the endothelial cells of 1.08 +/- 0.09 or 1.90 +/- 0.16 Gy x min(-1), respectively. At 3.5 d after irradiation, the intestinal crypt microcolony assay showed that the 2- to 3-fold increased doses to the microvasculature, relative to the nonspecific whole-body neutron beam doses, caused no additional crypt stem cell loss beyond that produced by the neutron beam alone. The threshold dose for death from the GI syndrome after neutron-beam-only irradiation was 9.0 +/- 0.6 Gy. There were no deaths from the GI syndrome, despite calculated absorbed doses to endothelial cells as high as 27.7 Gy, in the groups that received neutron beam doses of <9.0 Gy with boronated liposomes in the blood. These data indicate that endothelial cell damage is not causative in the loss of intestinal crypt stem cells and the eventual development of the GI syndrome.

Animals↗

PubMed2005

The MIT user center for neutron capture therapy research.

Neutron capture therapy (NCT) research encompasses a wide range of preclinical and clinical studies needed to develop this promising but complex cancer treatment. Many specialized facilities and capabilities including thermal and epithermal neutron irradiation facilities, boron analysis, specialized mixed-field dosimetry, animal care facilities and protocols, cell culture laboratories, and, for human clinical studies, licenses and review board approvals are required for NCT research. Such infrastructure is essential, but much of it is not readily available within the community. This is especially true for neutron irradiation facilities, which often require significant development and capital investment too expensive to duplicate at each site performing NCT research. To meet this need, the NCT group at the Massachusetts Institute of Technology (MIT) has established a User Center for NCT researchers that is already being accessed successfully by various groups. This paper describes the facilities, capabilities and other resources available at MIT and how the NCT research community can access them.

Animals↗

PubMed2004

Neutron capture therapy of epidermal growth factor (+) gliomas using boronated cetuximab (IMC-C225) as a delivery agent.

Cetuximab (IMC-C225) is a monoclonal antibody directed against both the wild-type and mutant vIII isoform of the epidermal growth factor receptor (EGFR). The purpose of the present study was to evaluate the monoclonal antibody (MoAb), cetuximab, as a boron delivery agent for neutron capture therapy (NCT) of brain tumors. Twenty-four hours following intratumoral (i.t.) administration of boronated cetuximab (C225-G5-B(1100)), the mean boron concentration in rats bearing either F98(EGFR) or F98(WT) gliomas were 92.3+/-23.3 microg/g and 36.5+/-18.8 microg/g, respectively. In contrast, the uptake of boronated dendrimer (G5-B(1000)) was 6.7+/-3.6 microg/g. Based on its favorable in vivo uptake, C225-G5-B(1100) was evaluated as a delivery agent for BNCT in F98(EGFR) glioma bearing rats. The mean survival time (MST) of rats that received C225-G5-B(1100), administered by convection enhanced delivery (CED), was 45+/-3d compared to 25+/-3d for untreated control animals. A further enhancement in MST to >59d was obtained by administering C225-G5-B(1100) in combination with i.v. boronophenylalanine (BPA). These data are the first to demonstrate the efficacy of a boronated MoAb for BNCT of an intracerebral (i.c.) glioma and are paradigmatic for future studies using a combination of boronated MoAbs and low molecular weight delivery agents.

Animals↗

PubMed2004

Boronated epidermal growth factor as a delivery agent for neutron capture therapy of EGF receptor positive gliomas.

The purpose of the present study was to further evaluate a boronated dendrimer (BD)-epidermal growth factor bioconjugate (BD-EGF), administered by means of convection enhanced delivery (CED), as a molecular targeting agent for boron neutron capture therapy (BNCT) of the F98(EGFR) glioma. Twenty-four hours following CED of (125)I-labeled BD-EGF 47.4% of the injected dose (ID) was retained in F98(EGFR) gliomas compared to 12.3% in F98(WT) (wildtype) receptor negative tumors. Normal brain values were in the range of 5.9-10.1% ID in the tumor bearing cerebral hemisphere. Boron concentrations in F98(EGFR) gliomas were 22.3 and 11.7 microg/g following CED and i.t. injection, respectively. Based on these results, BNCT studies were initiated at the Massachusetts Institute of Technology nuclear reactor (MITRII). The mean survival time (MST) of rats that received BD-EGF either alone or in combination with boronophenylalanine (BPA), injected i.v., were 53+/-13 d and >61+/-14 d, respectively, compared to 40+/-5 d for BPA alone and 31+/-4 d for irradiated controls. These data show that CED improved the radiobiological effectiveness of BD-EGF and lay the groundwork for future studies using combinations of boron delivery agents for NCT of EGFR(+) gliomas.

Animals↗

PubMed2003

Boron neutron capture therapy: cellular targeting of high linear energy transfer radiation.

Boron neutron capture therapy (BNCT) is based on the preferential targeting of tumor cells with (10)B and subsequent activation with thermal neutrons to produce a highly localized radiation. In theory, it is possible to selectively irradiate a tumor and the associated infiltrating tumor cells with large single doses of high-LET radiation while sparing the adjacent normal tissues. The mixture of high- and low-LET dose components created in tissue during neutron irradiation complicates the radiobiology of BNCT. Much of the complexity has been unravelled through a combination of preclinical experimentation and clinical dose escalation experience. Over 350 patients have been treated in a number of different facilities worldwide. The accumulated clinical experience has demonstrated that BNCT can be delivered safely but is still defining the limits of normal brain tolerance. Several independent BNCT clinical protocols have demonstrated that BNCT can produce median survivals in patients with glioblastoma that appear to be equivalent to conventional photon therapy. This review describes the individual components and methodologies required for effect BNCT: the boron delivery agents; the analytical techniques; the neutron beams; the dosimetry and radiation biology measurements; and how these components have been integrated into a series of clinical studies. The single greatest weakness of BNCT at the present time is non-uniform delivery of boron into all tumor cells. Future improvements in BNCT effectiveness will come from improved boron delivery agents, improved boron administration protocols, or through combination of BNCT with other modalities.

Animals↗

PubMed2002

A physical dosimetry intercomparison for BNCT.

An intercomparison of physical dosimetry methods used at the Massachusetts Institute of Technology (MIT) and Brookhaven National Laboratory was completed to enable retrospective analysis of BNCT trials. Measurements were performed under reference conditions pertinent to clinical irradiations at the epithermal neutron beam facility of the Brookhaven Medical Research Reactor (BMRR) using procedures developed at MIT during similar trials. Thermal neutron flux was determined from gold foil activation experiments and good agreement was found between the depth profiles measured in-phantom by the two groups. At a depth of 3.5 cm where the measured flux is greatest, the ratio of the MIT/BMRR measurements is 1.01+/-0.10 if the same reporting procedures are applied. Photon and fast neutron absorbed dose rates were assessed using ionization chambers with separate graphite and A-150 plastic walls. Measurement of the in-phantom photon depth dose component agreed favorably with that previously reported by the BMRR group using thermoluminescent dosimeters. At a depth of 3.5 cm the ratio of the MIT measurements to those made by the BMRR group was 0.89+/-0.12. In-air measurements of the fast neutron and photon absorbed dose rates agreed within the limits of experimental uncertainty. Additional studies were performed in the ellipsoidal water phantom regularly used for beam characterizations at MIT. No significant differences in the thermal neutron flux measured in either a solid PMMA cube or an ellipsoidal shaped water phantom were observed on the central axis of the beam. This study confirms the reproducibility and uniformity of dosimetry measurements performed by the two independent groups undertaking BNCT trials in the USA and provides the physical data necessary to compare BMRR treatment protocols with those applied at Harvard-MIT.

Biophysical Phenomena↗