Pre-designed In situ Oncotherapeutic Nanohydrogel with Enhanced Efficacy for glioblastoma post-Resection

Glioblastoma multiforme (GBM) is a grade IV glioma, considered as the most aggressive brain tumor with an average five-year survival rate of 7.2% and projected mortality rate of 46.6% by 2040. The prognosis remains poor, not only due to the severity of the disease but also due to challenges in treatment modality and recurrence. Temozolomide (TMZ) is the preferred anticancer drug for GBM owing to its effectiveness in reducing relapse but the efficacy is compromised by substantial hurdle of drug resistance. My strategy is to overcome this challenge and revolutionize GBM treatment by addressing the obstacles associated with TMZ resistance and prioritizing patient compliance. I hypothesize that combining a small dose of NO-releasing NONOates will activate p53 and inhibit HIF-1, effectively blocking TMZ resistance pathway and significantly boosting therapeutic efficacy. Moreover, NO dilates tumor blood vessels, enhancing the permeation and retention effect (EPR) which increases biodistribution of TMZ within the tumor, promoting apoptosis and oncogenic stress signals thereby reducing the likelihood of tumor recurrence. While the combination of TMZ and NONOates offers numerous advantages for efficient delivery, a major challenge remains: ensuring the transport across the blood brain barrier (BBB) to the tumor site. Here, I also propose the development of an enzyme-triggered injectable hydrogel encapsulating NONOates and TMZ nanocrystals (NCs) designed for post-resection GBM. The enzymatic crosslinking process involves oxidative coupling of catechol groups of tyramine-modified biomolecules, while TMZ NCs will be fabricated via antisolvent co-sonoprecipitation method. The in-situ hydrogel forms rapidly, adhering stably to the resection site, ensuring a targeted and sustained release of TMZ and enhancing efficacy through the synergistic action of NONOates. The combination of NCs, NONOates and enzyme-triggered gelation provides a robust platform for targeted GBM therapy.