O-methylguanine DNA methyltransferase (MGMT) is a crucial determinant of temozolomide (TMZ) sensitivity in patients with glioblastoma (GBM). The therapeutic potential of small interfering RNA (siRNA) targeting MGMT to enhance TMZ sensitivity has been hampered by serum nuclease degradation, off-target effects, poor accumulation at tumor sites, and low circulation in blood stream. In this study, we developed a framework nucleic acid-based nanoparticles (FNN), which is constructed from a six-helix DNA bundle, to encapsulate and protect siMGMT for improving TMZ sensitivity in GBM treatment. For better blood-brain barrier (BBB) penetration and GBM targeting, we conjugated Angiopep-2 (ANG) targeting modules to each end of the FNN. Nucleolin (NCL)-responsive locks were engineered along the sides of the six-helix DNA bundle, which safeguard siMGMT before tumor entry. Upon interaction with tumor-overexpressed NCL, these locks unlock, exposing siMGMT, this allows for effective suppression of MGMT, resulting in a significant improvement of TMZ therapeutic efficacy in GBM. This innovative strategy has the potential to transform the current treatment landscape for GBM.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.drup.2024.101122 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Protocatechuic aldehyde sensitizes BRAF-mutant melanoma cells to temozolomide through inducing FANCD2 degradation.
Med Oncol
January 2025
Engineering Research Center of Sichuan-Tibet Traditional Medicinal Plant, Chengdu University, Chengdu, 610106, China.
Temozolomide (TMZ)-based chemotherapy is a primary regimen for melanoma patients who have failed targeted therapy or immunotherapy. However, the low response rate of TMZ-based chemotherapy challenges the patients' prognosis. BRAF mutation is the most frequently mutated site in melanoma.
View Article and Find Full Text PDFTwo-Step Transfer Learning Improves Deep Learning-Based Drug Response Prediction in Small Datasets: A Case Study of Glioblastoma.
Bioinform Biol Insights
January 2025
Department of Pathology & Clinical Bioinformatics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
While deep learning (DL) is used in patients' outcome predictions, the insufficiency of patient samples limits the accuracy. In this study, we investigated how transfer learning (TL) alleviates the small sample size problem. A 2-step TL framework was constructed for a difficult task: predicting the response of the drug temozolomide (TMZ) in glioblastoma (GBM) cell cultures.
View Article and Find Full Text PDFFunctional germline variants in DNA damage repair pathways are associated with altered survival in adults with glioma treated with temozolomide.
Neuro Oncol
January 2025
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
Background: Temozolomide (TMZ) treatment has demonstrated, but variable, impact on glioma prognosis. This study examines associations of survival with DNA repair gene germline polymorphisms among glioma patients who did and did not have TMZ treatment. Identifying genetic markers which sensitize tumor cells to TMZ could personalize therapy and improve outcomes.
View Article and Find Full Text PDFLAT4 drives temozolomide induced radiotherapy resistance in glioblastoma by enhancing mTOR pathway activation.
Cancer Cell Int
December 2024
Department of Neurosurgery, Nanfang Hospital, Southern Medical University, 838 North Guangzhou Ave, Guangzhou, 510515, China.
Background: Glioblastoma multiforme (GBM) represents the most prevalent form of primary malignant tumor within the central nervous system. The emergence of resistance to radiotherapy and chemotherapy represents a significant impediment to advancements in glioma treatment.
Methods: We established temozolomide (TMZ)-resistant GBM cell lines by chronically exposing U87MG cell lines to TMZ, and dimethyl sulfoxide (DMSO) was used as placebo control.
The novel DNA cross-linking agent KL-50 is active against patient-derived models of new and recurrent post-temozolomide mismatch repair-deficient glioblastoma.
Neuro Oncol
December 2024
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago IL.
Article Synopsis
- Acquired resistance to temozolomide (TMZ) in glioblastoma patients, particularly those with DNA mismatch repair deficiencies, limits treatment effectiveness, prompting research into the new drug KL-50, which targets cancer cells in an MMR-independent manner.
- In studies, KL-50 significantly improved the median survival of mice with both naive and post-TMZ glioblastoma xenografts, showcasing its potential as a superior treatment option.
- Results indicate KL-50 may be particularly effective in MGMT and MMR-deficient tumors, offering hope for better management of recurrent glioblastoma after initial TMZ therapy.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!