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The Toxic Effect and Mechanism of TMZ Combined with siHOXB9 on Glioblastoma Cells
Xiaoyu Liu1, Yunfei Liu1, Wenxuan Li1
1Department of Physical Science and Engineering, Beijing Jiaotong University, Beijing 100091, China.
Abstract:
Glioblastoma (GBM) represents a highly invasive primary malignant tumor within the central nervous system (CNS). Temozolomide (TMZ), a first-line chemotherapy agent for GBM treatment, has significant limitations, including drug resistance, poor water solubility, a short half-life, and notable toxic side effects. The innovation of the TMZ dosage form is pivotal for enhancing its therapeutic efficacy. In this study, solid lipid nanoparticles (SLN) loaded with Angiopep-2 (A2) and TMZ (TMZ-A2SLN), a nanopolymer featuring a solid spherical morphology and a particle size of approximately 100 nm, were constructed. The combined effect of TMZ-A2SLN and small-interfering RNA (siRNA) that can knock down the expression of the HOXB9 gene (siHOXB9) augmented the sensitivity of the glioma cell line U251 to TMZ. Under the combined effect, the viability of U251 cells was reduced by 77%. Meanwhile, the mortality rate increased by approximately 45%, and the cell apoptosis rate rose by around 36%. The number of cells arrested in the G2/M and S phases rose. Proteomic analysis indicates that TMZ-A2SLN might be implicated in the pro-inflammatory signaling cascade, tumor migration, invasion, and angiogenesis during the treatment of glioma cells. Moreover, HOXB9 may play a crucial regulatory role in the PPAR signaling pathway, the neural signaling pathway, the phospholipase D signaling pathway, the IL-17 signaling pathway, mineral absorption, and other pathways during glioma cell treatment.
Insights
This study developed novel solid lipid nanoparticles (SLN) to improve glioblastoma treatment. Combining these nanoparticles with siRNA targeting HOXB9 significantly enhanced chemotherapy effectiveness against glioma cells.
Area of Science:
- Oncology
- Nanotechnology
- Molecular Biology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options.
- Temozolomide (TMZ) is a first-line chemotherapy but faces challenges like drug resistance and toxicity.
- Novel drug delivery systems are needed to improve TMZ's therapeutic efficacy.
Purpose of the Study:
- To develop and evaluate solid lipid nanoparticles (SLN) loaded with Angiopep-2 (A2) and TMZ (TMZ-A2SLN).
- To investigate the combined effect of TMZ-A2SLN and HOXB9-targeting siRNA (siHOXB9) on glioma cells.
- To explore the underlying mechanisms of TMZ-A2SLN in glioma treatment.
Main Methods:
- Construction of TMZ-A2SLN with a particle size of approximately 100 nm.
- Treatment of U251 glioma cell line with TMZ-A2SLN and siHOXB9.
- Assessment of cell viability, mortality, apoptosis, and cell cycle.
- Proteomic analysis to identify involved signaling pathways.
Main Results:
- TMZ-A2SLN combined with siHOXB9 significantly reduced U251 cell viability by 77%.
- Combined treatment increased cell mortality by ~45% and apoptosis by ~36%.
- Cell cycle arrest was observed in G2/M and S phases.
- Proteomic analysis suggested TMZ-A2SLN involvement in inflammation, migration, invasion, and angiogenesis.
Conclusions:
- TMZ-A2SLN combined with siHOXB9 enhances TMZ sensitivity in glioma cells.
- HOXB9 plays a key regulatory role in multiple signaling pathways relevant to glioma.
- This nanomedicine approach holds promise for improved glioblastoma therapy.
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