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Dual functionalized brain-targeting nanoinhibitors restrain temozolomide-resistant glioma via attenuating EGFR and
Xiangqi Meng1, Yu Zhao2, Bo Han1
1Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, 150086, Harbin, China.
Abstract:
Activation of receptor tyrosine kinase (RTK) protein is frequently observed in malignant progression of gliomas. In this study, the crosstalk activation of epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling pathways is demonstrated to contribute to temozolomide (TMZ) resistance, resulting in an unfavorable prognosis for patients with glioblastoma. To simultaneously mitigate EGFR and MET activation, a dual functionalized brain-targeting nanoinhibitor, BIP-MPC-NP, is developed by conjugating Inherbin3 and cMBP on the surface of NHS-PEG8-Mal modified MPC-nanoparticles. In the presence of BIP-MPC-NP, DNA damage repair is attenuated and TMZ sensitivity is enhanced via the down-regulation of E2F1 mediated by TTP in TMZ resistant glioma. In vivo magnetic resonance imaging (MRI) shows a significant repression in tumor growth and a prolonged survival of mice after injection of the BIP-MPC-NP and TMZ. These results demonstrate the promise of this nanoinhibitor as a feasible strategy overcoming TMZ resistance in glioma.
Insights
This study developed a novel nanoinhibitor (BIP-MPC-NP) to overcome temozolomide (TMZ) resistance in glioma by targeting both EGFR and MET pathways. The nanoinhibitor enhanced TMZ sensitivity and improved survival in preclinical models.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- Receptor tyrosine kinase (RTK) activation is common in malignant gliomas.
- Crosstalk between epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling contributes to temozolomide (TMZ) resistance in glioblastoma.
- TMZ resistance leads to poor patient prognosis.
Purpose of the Study:
- To develop a dual-functionalized, brain-targeting nanoinhibitor to simultaneously inhibit EGFR and MET activation.
- To evaluate the efficacy of the nanoinhibitor in overcoming TMZ resistance in glioma.
- To investigate the underlying mechanisms of enhanced TMZ sensitivity.
Main Methods:
- Development of a dual functionalized nanoinhibitor (BIP-MPC-NP) by conjugating Inherbin3 and cMBP onto modified nanoparticles.
- Assessment of BIP-MPC-NP's effect on DNA damage repair and TMZ sensitivity in TMZ-resistant glioma cells.
- In vivo studies using magnetic resonance imaging (MRI) to monitor tumor growth and survival in mice treated with BIP-MPC-NP and TMZ.
Main Results:
- BIP-MPC-NP effectively attenuated DNA damage repair and enhanced TMZ sensitivity in TMZ-resistant glioma.
- The nanoinhibitor mediated down-regulation of E2F1 via TTP.
- In vivo MRI demonstrated significant tumor growth repression and prolonged survival in treated mice.
Conclusions:
- Simultaneous inhibition of EGFR and MET using BIP-MPC-NP is a promising strategy to overcome TMZ resistance in glioma.
- The developed nanoinhibitor demonstrates potential for improved glioblastoma treatment outcomes.
- This approach offers a feasible strategy for enhancing therapeutic efficacy in recurrent or resistant gliomas.
