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

Barth, Rolf F.; Wu, Gong; Yang, Weilian; Binns, Peter J.; Riley, Kent J.; Patel, Hemant; Coderre, Jeffrey A.; Tjarks, Werner; Bandyopadhyaya, Achintya K.; Thirumamagal, B. T. S.; Ciesielski, Michael; Fenstermaker, Robert A.

doi:10.1016/j.apradiso.2004.05.004

Cited by 63 publications

(37 citation statements)

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“…Delivery of 10 B containing agents via liposomes conjugated to the anti-EGFR monoclonal antibody (MAb) cetuximab (C225) and L8A4, which is directly against EGFR vIII is an attractive delivery approach for BNCT, because of their high payload capacity (4,19). The use of EGFR-targeting boron containing bioconjugates as delivery agents for BNCT of brain tumors has been a major focus of our laboratories (4,(19)(20)(21)(22). A highly boronated polyamidoamine (PAMAM) dendrimer has been linked to either EGF, cetuximab or L8A4 for targeted delivery of 10 B to gliomas (23).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Cetuximab-Immunoliposomes via a Cholesterol-Based Membrane Anchor for Targeting of EGFR

et al. 2006

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The objective of the present study was to construct epidermal growth factor receptor (EGFR) targeting cetuximab immunoliposomes (ILs) for targeted delivery of boron compounds to EGFR(+) glioma cells for neutron capture therapy. The ILs were synthesized by using a novel cholesterolbased membrane anchor, maleimido-PEG-cholesterol (Mal-PEG-Chol), to incorporate cetuximab into liposomes by either surface conjugation or a post-insertion method. For post-insertion, transfer efficiency of MAb conjugates from micelles to liposome was examined at varying temperatures, mPEG 2000 -DSPE ratios, and micelle-to-liposome lipid ratios. Following this, the cetuximab-ILs were evaluated for targeted delivery of the encapsulated boron anion, dodecahydro-closododecaborate (2−) (B 12 H 12 2− ), to human EGFR gene transfected F98 EGFR glioma cells as potential delivery agents for boron neutron capture therapy (BNCT). In addition, cellular uptake of cetuximabILs, encapsulating a fluorescence dye, was analyzed by confocal fluorescence microscopy and flow cytometry, and boron content was quantified by ICP-MS. Much greater (~ 8-fold) cellular uptake of boron was obtained using cetuximab-ILs in EGFR(+) F98 EGFR compared with non-targeted human IgG-ILs. Based on these observations, we have concluded that cholesterol can serve as an effective anchor for MAb in liposomes and cetuximab-ILs are potentially useful delivery vehicles for BNCT of gliomas.

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Section: Introductionmentioning

confidence: 99%

Synthesis of Cetuximab-Immunoliposomes via a Cholesterol-Based Membrane Anchor for Targeting of EGFR

et al. 2006

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“…Animal irradiations were done with the reactor operating at a power between 4.0 and 4.8 MW. These took between 6.9 and 8.6 min to deliver a thermal neutron fluence of 2.64 Â 10 12 n cm À2 that matches previous dose prescriptions (13,15). After completion of BNCT, the animals were returned to The Ohio State University for clinical monitoring.…”

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confidence: 99%

“…We have investigated molecular targeting of EGFR or EGFRvIII using EGF (11 -13), or the monoclonal antibodies (mAb) cetuximab (14,15) and L8A4 (16,17), which have been linked to a heavily boronated polyamidoamine dendrimer. Cetuximab (Erbitux), known previously as IMC-C225, is a chimeric mouse-human mAb that originally was produced in the laboratory of Dr. John Mendelsohn (University of Texas M. D. Anderson Cancer Center, Houston, TX; ref.…”

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Molecular Targeting and Treatment of an Epidermal Growth Factor Receptor–Positive Glioma Using Boronated Cetuximab

Wu¹,

Yang²,

Barth³

et al. 2007

Clinical Cancer Research

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Purpose: The purpose of the present study was to evaluate the anti^epidermal growth factor monoclonal antibody (mAb) cetuximab (IMC-C225) as a delivery agent for boron neutron capture therapy (BNCT) of a human epidermal growth factor receptor (EGFR) gene-transfected rat glioma, designated as F98 EGFR . Experimental Design: A heavily boronated polyamidoamine dendrimer was chemically linked to cetuximab by means of the heterobifunctional reagents N-succinimidyl 3-(2-pyridyldithio)-propionate and N-(k-maleimido undecanoic acid)-hydrazide. The bioconjugate, designated as BD-C225, was specifically taken up by F98 EGFR glioma cells in vitro compared with receptornegative F98 wild-type cells (41.8 versus 9.1 Ag/g). For in vivo biodistribution studies, F98 EGFR cells were implanted stereotactically into the brains of Fischer rats, and 14 days later, BD-C225 was given intracerebrally by either convection enhanced delivery (CED) or direct intratumoral (i.t.) injection. Results: The amount of boron retained by F98 EGFR gliomas 24 h following CED or i.t. injection was 77.2 and 50.8 Ag/g, respectively, with normal brain and blood boron values <0.05 Ag/g. Boron neutron capture therapy was carried out at the Massachusetts Institute of TechnologyResearch Reactor 24 h after CED of BD-C225, either alone or in combination with i.v. boronophenylalanine (BPA). The corresponding mean survival times (MST) were 54.5 and 70.9 days (P = 0.017), respectively, with one long-term survivor (more than 180 days). In contrast, the MSTs of irradiated and untreated controls, respectively, were 30.3 and 26.3 days. In a second study, the combination of BD-C225 and BPA plus sodium borocaptate, given by either i.v. or intracarotid injection, was evaluated and the MSTs were equivalent to that obtained with BD-C225 plus i.v. BPA. Conclusions:The survival data obtained with BD-C225 are comparable with those recently reported by us using boronated mAb L8A4 as the delivery agent.This mAb recognizes the mutant receptor, EGFRvIII. Taken together, these data convincingly show the therapeutic efficacy of molecular targeting of EGFR using a boronated mAb either alone or in combination with BPA and provide a platform for the future development of combinations of high and low molecular weight delivery agents for BNCTof brain tumors.Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when nonradioactive boron-10 is irradiated with low energy (e V 0.025 eV) thermal neutrons to produce 11 B in an unstable form, which undergoes instantaneous nuclear fission to produce a-particles and recoiling lithium-7 nuclei. These high linear energy transfer particles have a range of 5 to 9 Am, thereby restricting their destructive effects to only those cells containing 10 B. To be

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“…The latter treatment dramatically decreased the number of VEGFR-2-positive cells in 4T1 tumors. 6 We found that s.c. injections of SLT-VEGF (1 Ag per mouse) on days 4 and 7 after tumor implantation before near-IR fluorescent imaging on day 13 decreased the selective accumulation of VEGF-BD/Cy5 by f10-fold (Fig. 5C -D).…”

Section: Near-ir Fluorescent Imaging Of Tumor Vasculature With Vegf-bmentioning

confidence: 69%

“…As we have recently shown, systemic treatment of 4T1 tumor-bearing mice with SLT-VEGF selectively eliminated only VEGFR-2-overexpressing cells and did not affect the majority of tumor endothelial cells expressing low to moderate levels of VEGFR-2. 6 Therefore, decreased VEGF-BD/Cy5 accumulation in SLT-VEGFtreated mice cannot be attributed to the reduced tumor vascularity.…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor selectively targets boronated dendrimers to tumor vasculature

Backer¹,

Gaynutdinov²,

Patel³

et al. 2005

Molecular Cancer Therapeutics

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

Cited by 63 publications

References 5 publications

Synthesis of Cetuximab-Immunoliposomes via a Cholesterol-Based Membrane Anchor for Targeting of EGFR

Synthesis of Cetuximab-Immunoliposomes via a Cholesterol-Based Membrane Anchor for Targeting of EGFR

Molecular Targeting and Treatment of an Epidermal Growth Factor Receptor–Positive Glioma Using Boronated Cetuximab

Vascular endothelial growth factor selectively targets boronated dendrimers to tumor vasculature

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