Exploring gefitinib to enhance endocytosis of antibodies and nucleic acid aptamers targeting EGFR in glioblastoma
Abstract
Active targeting in drug delivery involves the binding of ligands to receptors present on the surface of targeted cells. Several conjugates are already in use or under development for active targeting of tumors, the most widely known being antibody–drug conjugates (ADC). They combine the specificity of monoclonal antibodies with the cytotoxicity of chemotherapeutic molecules. Nucleic acid based aptamers belong to another promising family of ligands able to deliver conjugated drugs, like cytotoxic compounds or siRNAs, by active targeting of tumor cells. The therapeutic efficacy of most conjugates largely depends on their endocytosis and vesicular trafficking. While combinatorial pharmacological and other strategies to enhance conjugate endocytosis have been and remain an active area of investigation, additional studies are necessary to fully unlock their therapeutic potential. In recent studies, we showed that gefitinib, a tyrosine kinase inhibitor directed against the epidermal growth factor receptor EGFR, induces a massive, non-physiological endocytosis of EGFR, known as gefitinib-mediated endocytosis (GME), in different glioblastoma cell lines. We thus hypothesized that besides promoting endocytosis of EGFR, gefitinib could also promote endocytosis of its ligands. In this study, we proved by quantitative fluorescence bioimaging, that gefitinib is indeed able to strengthen the endocytosis of fluorophore-conjugated EGFR-specific antibodies or aptamers. We also showed that the GME potentiates the toxicity of an antibody–drug conjugate (ADC) and the efficacy of an aptamer–siRNA conjugate (AsiC) in vitro. Our results underline the potential for developing new therapeutic combination with gefitinib, to enhance the delivery of ADC, AsiC and likely other conjugates targeting EGFR in glioblastoma, while limiting side effects on non-targeted cells. However, in vivo data emphasize the need for further optimization of combinatorial strategies to achieve meaningful clinical outcomes.
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BibTeX
@article{dancona2026exploring,
title = {{Exploring gefitinib to enhance endocytosis of antibodies and nucleic acid aptamers targeting EGFR in glioblastoma}},
author = {Charlène d'Ancona and Elisabete Cruz da Silva and Léa Denechere and Hélène Justiniano and Valérie Calco and Ludovic Richert and Romain Vauchelles and Dilara Sensoy and Candice Dussoulliez and Cendrine Seguin and Pascal Villa and François Daubeuf and Antoine Kichler and Sylvie Fournel and Halina Anton and Maxime Lehmann and Laurence Choulier},
journal = {Nanoscale},
year = {2026},
month = jun,
doi = {10.1039/d6nr00420b},
url = {https://hal.science/hal-05675895v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Exploring gefitinib to enhance endocytosis of antibodies and nucleic acid aptamers targeting EGFR in glioblastoma
AU - Charlène d'Ancona
AU - Elisabete Cruz da Silva
AU - Léa Denechere
AU - Hélène Justiniano
AU - Valérie Calco
AU - Ludovic Richert
AU - Romain Vauchelles
AU - Dilara Sensoy
AU - Candice Dussoulliez
AU - Cendrine Seguin
AU - Pascal Villa
AU - François Daubeuf
AU - Antoine Kichler
AU - Sylvie Fournel
AU - Halina Anton
AU - Maxime Lehmann
AU - Laurence Choulier
PY - 2026
DA - 2026/06/23
JO - Nanoscale
DO - 10.1039/d6nr00420b
UR - https://hal.science/hal-05675895v1
AB - Active targeting in drug delivery involves the binding of ligands to receptors present on the surface of targeted cells. Several conjugates are already in use or under development for active targeting of tumors, the most widely known being antibody–drug conjugates (ADC). They combine the specificity of monoclonal antibodies with the cytotoxicity of chemotherapeutic molecules. Nucleic acid based aptamers belong to another promising family of ligands able to deliver conjugated drugs, like cytotoxic compounds or siRNAs, by active targeting of tumor cells. The therapeutic efficacy of most conjugates largely depends on their endocytosis and vesicular trafficking. While combinatorial pharmacological and other strategies to enhance conjugate endocytosis have been and remain an active area of investigation, additional studies are necessary to fully unlock their therapeutic potential. In recent studies, we showed that gefitinib, a tyrosine kinase inhibitor directed against the epidermal growth factor receptor EGFR, induces a massive, non-physiological endocytosis of EGFR, known as gefitinib-mediated endocytosis (GME), in different glioblastoma cell lines. We thus hypothesized that besides promoting endocytosis of EGFR, gefitinib could also promote endocytosis of its ligands. In this study, we proved by quantitative fluorescence bioimaging, that gefitinib is indeed able to strengthen the endocytosis of fluorophore-conjugated EGFR-specific antibodies or aptamers. We also showed that the GME potentiates the toxicity of an antibody–drug conjugate (ADC) and the efficacy of an aptamer–siRNA conjugate (AsiC) in vitro. Our results underline the potential for developing new therapeutic combination with gefitinib, to enhance the delivery of ADC, AsiC and likely other conjugates targeting EGFR in glioblastoma, while limiting side effects on non-targeted cells. However, in vivo data emphasize the need for further optimization of combinatorial strategies to achieve meaningful clinical outcomes.
SN - 2040-3364
SN - 2040-3372
ER -