Circadian-Tuned Peptide Drug/Gene Co-Delivery Nanocomplexes to Enhance Glioblastoma Targeting and Transfection
Ana R Neves1, Eric Vivès2, Prisca Boisguérin2
1RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal.
Abstract:
Glioblastoma is the most prevalent and aggressive form of brain malignancy. Actual treatments face several challenges due to its high aggressiveness and poor prognosis. The chemotherapeutic agent temozolomide (TMZ) has limited therapeutic efficacy, and mutations in the tumour protein p53 gene (TP53) have been associated with treatment resistance. Thus, this study aimed to explore an innovative therapeutic strategy to enhance treatment efficacy of GBM. Previously, our team had developed a WRAP5 cell-penetrating peptide (CPP) functionalized with a transferrin receptor ligand (Tf) for the targeted delivery of TMZ and a p53-encoding plasmid to glioma cells. Our research had elucidated the circadian oscillations of the clock genes in the U87 glioma cells by employing two different computational models and observed that T16 and T8 time points revealed the highest circadian activity for Bmal1 and Per2 genes, respectively. Similar analysis was conducted for the transferrin receptor, which revealed that T7 and T8 were the key time points for its expression. A confocal microscopy study indicated the highest intracellular uptake of complexes and p53 mRNA expression at T8, the time point with the highest Per2 and transferrin receptor expression. Following mRNA analysis, the evaluation of p53 levels confirmed transcriptional changes at the protein level, and that T16 appears to be a favourable time point for enhancing therapeutic efficacy in U87 glioblastoma cells. These findings suggested that synchronizing the complexes' administration with the biological clock of GBM cells may significantly improve glioblastoma therapeutics.
Insights
Synchronizing glioblastoma treatment with the U87 cell biological clock enhances drug delivery. Targeting the transferrin receptor and p53 gene expression at specific times improves therapeutic efficacy.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Chronobiology
Background:
- Glioblastoma (GBM) is an aggressive brain cancer with limited treatment options.
- Temozolomide (TMZ) efficacy is often hindered by drug resistance, particularly mutations in the tumor protein p53 (TP53) gene.
- Developing novel therapeutic strategies is crucial for improving GBM patient outcomes.
Purpose of the Study:
- To investigate a novel therapeutic strategy for enhancing glioblastoma treatment efficacy.
- To explore the potential of targeted delivery of temozolomide and a p53-encoding plasmid using a functionalized cell-penetrating peptide (CPP).
- To elucidate the role of circadian rhythms in optimizing glioblastoma therapy.
Main Methods:
- Utilized computational models to analyze circadian oscillations of clock genes (Bmal1, Per2) and transferrin receptor expression in U87 glioma cells.
- Developed a WRAP5 CPP functionalized with a transferrin receptor ligand (Tf) for targeted delivery of TMZ and p53 plasmid.
- Employed confocal microscopy to assess intracellular uptake and p53 mRNA expression at various time points.
- Validated transcriptional changes at the protein level for p53.
Main Results:
- Identified specific circadian time points (T8, T16) with high expression of key genes (Bmal1, Per2) and transferrin receptor.
- Observed maximal intracellular uptake and p53 mRNA expression at T8, coinciding with peak Per2 and transferrin receptor levels.
- Confirmed that T16 is a favorable time point for enhancing therapeutic efficacy, with observed changes at both mRNA and protein levels for p53.
Conclusions:
- Circadian rhythms significantly influence the expression of key genes and drug delivery targets in glioblastoma cells.
- Targeted delivery of therapeutic agents synchronized with the cellular biological clock can enhance treatment efficacy.
- This chronotherapy approach holds promise for improving outcomes in glioblastoma treatment.
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