642 Molecular targeting of epidermal growth factor receptor (EGFR) positive gliomas for neutron capture therapy using boronated bioconjugates

Barth, Rolf F.; Wu, Gong; Yang, Weilian; Binns, Peter J.; Riley, Kent J.; Patel, Hemant; Coderre, Jeffrey A.; Tjarks, Werner; Ciesielski, Michael; Fenstermaker, Robert A.

doi:10.1016/s1359-6349(04)80650-5

Cited by 27 publications

(74 citation statements)

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“…Such molecular targets would minimize toxic effects on surrounding normal tissue. The epidermal growth factor receptor (Barth et al, 2002), platelet derived growth factor receptor (Hermanson et al, 1992), fibroblast growth factor receptor (Morrison et al, 1994), human epidermal receptor type 2 (Mineo et al, 2004), and interleukin-13 receptor (Mintz et al, 2002) have been shown to be upregulated in glioma cells. We have previously shown that human GBM cell lines express high levels of LDL receptors (Maletinska et al, 2000) and demonstrated that boronated protoporphryn is delivered to the SF-767 GBM cell line by LDL (Callahan et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Synthetic nano-low density lipoprotein as targeted drug delivery vehicle for glioblastoma multiforme

Nikanjam

Blakely

Bjornstad

et al. 2007

International Journal of Pharmaceutics

108

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The low density lipoprotein (LDL) receptor has been shown to be upregulated in GBM tumor cells and is therefore a potential molecular target for the delivery of therapeutic agents. A synthetic nano-LDL (nLDL) particle was developed and tested to determine its utility as a drug Collectively these data strongly suggest that the synthetic nano-LDLs described here are taken up by LDLR and can serve as a drug delivery vehicle for targeting GBM tumors via the LDLR.3

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Section: Discussionmentioning

confidence: 99%

Synthetic nano-low density lipoprotein as targeted drug delivery vehicle for glioblastoma multiforme

Nikanjam

Blakely

Bjornstad

et al. 2007

International Journal of Pharmaceutics

108

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“…Hydrogenated soy phosphatidylcholine (HSPC), methoxy-polyethyleneglycol 2000 (19). were cultured as a mononlayer in DMEM media supplemented with 100 units/mL penicillin, 100 µM/mL streptomycin, 200 mg/mL of G418 and 10% FBS in a humidified atmosphere containing 5% CO 2 at 37 °C.…”

Section: Experimental Procedures Materialsmentioning

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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“…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.…”

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confidence: 99%

“…F98 EGFR glioma cells expressing 10 5 receptor sites per cell, described previously by us in detail (12), were used for in vivo studies. This cell line, which has been stable for over 5 years, was produced by transfecting F98 wildtype (F98 WT ) cells with the human gene encoding wild-type EGFR (11). These cells were used to obviate an immune response directed against human EGFR, which we found occurred when cells expressing 10 6 receptor sites were implanted i.c.…”

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confidence: 99%

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

Wu¹,

Yang²,

Barth³

et al. 2007

Clinical Cancer Research

110

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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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642 Molecular targeting of epidermal growth factor receptor (EGFR) positive gliomas for neutron capture therapy using boronated bioconjugates

Cited by 27 publications

References 0 publications

Synthetic nano-low density lipoprotein as targeted drug delivery vehicle for glioblastoma multiforme

Synthetic nano-low density lipoprotein as targeted drug delivery vehicle for glioblastoma multiforme

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

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