Related Experiment Video
Updated: Jul 7, 2026
Nanoparticle Delivery of an Oligonucleotide Payload in a Glioblastoma Multiforme Animal Model
Published on: September 27, 2024
Molecular targeting and treatment of composite EGFR and EGFRvIII-positive gliomas using boronated monoclonal
Weilian Yang1, Gong Wu, Rolf F Barth
1Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA.
Purpose:
The purpose of the present study was to evaluate the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), cetuximab, (IMC-C225) and the anti-EGFRvIII mAb, L8A4, used in combination as delivery agents for boron neutron capture therapy (BNCT) of a rat glioma composed of a mixture of cells expressing either wild-type (F98(EGFR)) or mutant receptors(F98(npEGFRvIII)).
Experimental Design:
A heavily boronated polyamidoamine dendrimer (BD) was linked by heterobifunctional reagents to produce the boronated mAbs, BD-C225 and BD-L8A4. For in vivo biodistribution and therapy studies, a mixture of tumor cells were implanted intracerebrally into Fischer rats. Biodistribution studies were carried out by administering (125)I-labeled bioconjugates via convection-enhanced delivery (CED), and for therapy studies, nonradiolabeled bioconjugates were used for BNCT. This was carried out 14 days after tumor implantation and 24 h after CED at the Massachusetts Institute of Technology nuclear reactor.
Results:
Following CED of a mixture of (125)I-BD-C225 and (125)I-BD-L8A4 to rats bearing composite tumors, 61.4% of the injected dose per gram (ID/g) was localized in the tumor compared with 30.8% ID/g for (125)I-BD-L8A4 and 34.7% ID/g for (125)I-BD-C225 alone. The corresponding calculated tumor boron values were 24.4 mug/g for rats that received both mAbs, and 12.3 and 13.8 mug/g, respectively, for BD-L8A4 or BD-C225 alone. The mean survival time of animals bearing composite tumors, which received both mAbs, was 55 days (P < 0.0001) compared with 36 days for BD-L8A4 and 38 days for BD-C225 alone, which were not significantly different from irradiated controls.
Conclusions:
Both EGFRvIII and wild-type EGFR tumor cell populations must be targeted using a combination of BD-cetuximab and BD-L8A4. Although in vitro C225 recognized both receptors, in vivo it was incapable of delivering the requisite amount of (10)B for BNCT of EGFRvIII-expressing gliomas.
Insights
Combining cetuximab and L8A4 monoclonal antibodies for boron neutron capture therapy (BNCT) significantly improved survival in rats with mixed EGFR and EGFRvIII gliomas. Targeting both receptor types is crucial for effective BNCT treatment.
Area of Science:
- Oncology
- Radiotherapy
- Molecular Biology
Background:
- Gliomas often express both wild-type epidermal growth factor receptor (EGFR) and mutant EGFRvIII.
- Targeting these receptors is a key strategy in glioma treatment.
- Boron neutron capture therapy (BNCT) offers a targeted approach for cancer treatment.
Purpose of the Study:
- To evaluate the efficacy of cetuximab (anti-EGFR mAb) and L8A4 (anti-EGFRvIII mAb) as delivery agents for BNCT.
- To assess the combined use of these monoclonal antibodies (mAbs) in a rat glioma model with mixed receptor expression.
Main Methods:
- Heavily boronated polyamidoamine dendrimers (BD) were conjugated to cetuximab (BD-C225) and L8A4 (BD-L8A4).
- In vivo studies involved intracerebral implantation of mixed F98(EGFR) and F98(npEGFRvIII) glioma cells in Fischer rats.
- Biodistribution and therapy studies utilized (125)I-labeled and non-radiolabeled bioconjugates, respectively, administered via convection-enhanced delivery (CED) followed by BNCT.
Main Results:
- Combined administration of BD-C225 and BD-L8A4 resulted in 61.4% ID/g tumor localization, significantly higher than either mAb alone.
- Tumor boron concentrations were 24.4 mug/g for the combination therapy.
- Mean survival time increased to 55 days with combination therapy (P < 0.0001), compared to 36-38 days for single mAb treatments.
Conclusions:
- Targeting both EGFRvIII and wild-type EGFR expressing tumor cells is essential for effective BNCT.
- While cetuximab recognizes both receptors in vitro, it was insufficient alone for BNCT of EGFRvIII gliomas in vivo.
- Combination therapy with BD-cetuximab and BD-L8A4 demonstrates significant therapeutic potential for gliomas with mixed EGFR expression.
