Development and Applications of Mitochondria-Penetrating Peptide Conjugates in Glioblastoma Multiforme
Bibliographic record
Abstract
Glioblastoma multiforme (GBM) is an aggressive and treatment-refractory brain tumour characterized by high recurrence rates and poor patient outcomes. A major contributor to therapeutic resistance is the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), which counters the effects of the frontline alkylating agent temozolomide (Tmz). Mitochondria have emerged as key regulators of cancer cell survival, metabolic plasticity, and drug resistance – positioning them as an underexplored but promising therapeutic target. This thesis investigates the potential of mitochondria-penetrating peptide (MPP) conjugates to deliver DNA-damaging agents directly to mitochondria and overcome resistance in GBM. The first aim was to develop and characterize a mitochondria-targeted Tmz probe (mtTmz) and evaluate its ability to circumvent MGMT-mediated resistance. mtTmz exhibited enhanced cytotoxicity in GBM models, and mechanistic studies indicated that MGMT neither localized to mitochondria nor was upregulated in response to mtTmz-induced mtDNA damage. The second aim focused on engineering a mitochondria-targeted MGMT protein (mitoMGMT) to probe its role in mtDNA repair. Although successful mitochondrial localization was achieved, mitoMGMT failed to rescue cells from mtTmz cytotoxicity, suggesting the damage was irreparable. The third aim involved designing a radiolabeled MPP probe incorporating a diethylenetriaminepentaacetic acid (DTPA) chelator labeled with 111In. Initial in vivo imaging following intravenous injection showed rapid accumulation in the liver and kidneys with no blood-brain barrier (BBB) penetration, highlighting the limitations of systemic delivery. Subsequently, convection-enhanced delivery (CED) was employed and successfully achieved localized delivery and retention of the MPP probe in orthotopic GBM tumours, supporting the potential for therapeutic applications of MPP constructs via direct intracranial administration. Together, these studies demonstrate the promise of targeting mitochondrial vulnerabilities to circumvent resistance in GBM. By bypassing nuclear DNA repair mechanisms, MPP-drug conjugates offer a novel approach for delivering cytotoxic agents to resistant tumour cells. This work lays a foundation for the continued development of mitochondria-directed therapies in GBM and potentially other hard-to-treat cancers.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".