Development of Theranostic Hydrogels for MRI-guided Brain Tumor Treatment

Description

This study will develop a theranostic hydrogel for sustained delivery of brain cancer therapeutics locally while allowing non-invasive evaluation of drug distribution and tumor microenvironment via advanced MRI. The 5-year survival rate of brain cancer currently at 33% remains dismal1. In particular, treating the malignant brain tumors, e.g. glioblastoma multiforme(GBM), remains a daunting challenge despite substantial efforts to develop alternative therapies. The current standard of care is maximal surgical resection followed by radiotherapy and chemotherapy. Nevertheless, the complete surgical removal of the brain tumor is challenging and tumor recurrence is high. Recently, adjuvant treatments that deliver chemotherapeutics locally after tumor resection have received increasing attention and were shown to improve the survival rate of patients with newly diagnosed high-grade glioma and recurrent glioblastoma2, 3. This treatment benefits patients especially in aging societies such as Hong Kong, where patients are less tolerated to systemic chemotherapy4, 5. The current local chemotherapeutics use carmustine wafers2, but it suffers from short drug half-life and insufficient tissue contact. Furthermore, it lacks the ability to image the drug distribution in the brain and is unable to evaluate the drug efficacy in terms of alterations in tumor microenvironment, e.g. acidosis. Thus, a local adjuvant treatment using temozolomide (TMZ-a promising chemotherapeutics for brain tumors6) can improve patients’ tolerance to systemic chemotherapy by applying TMZ locally after tumor resection. These lead to an urgent need to develop a theranostic hydrogel to image-guide local TMZ treatments to improve the delivery of therapeutics for all brain tumor patients needing tumor resection3.Our hypothesis is thatlocal adjuvant treatment using theranostic hydrogel (TMZ-diaGel) will enable imaging of the distribution and amount of drug being deliveredin vivofor treatment monitoring, and will also provide a sustained release of drug, intimate tissue contact and physical support in the brain after tumor resection. In our preliminary study, we developed a new drug-loaded diaCEST hydrogel (TMZ-diaGel) for MRI to directly image the drug delivery at the tumor site and to monitor pH changes for treatment evaluation. CEST MRI is a sensitive molecular imaging approach for tracking specific moleculesin vivoand is available in clinical settings7-10. Our results showed that TMZ, the first-line treatment for GBM, had a natural CEST contrast for imaging drug delivery. The drug-loaded hydrogel could provide a sustained release for a week. Moreover, the hydrogel with nanosensor had a pH-sensitive CEST contrast for imaging acidosisin vivo. Our pilot study showed that the mechanical properties of injectable hydrogels can be customized to provide intimate tissue contact for local treatment. These include the specific morphology and stiffness of hydrogels which could support neural cell survival. Collectively, our preliminary results strongly suggested that the new TMZ-diaGel could allow the imaging of TMZ delivery, hydrogel location and acidosis in the microenvironment locally with distinctive CEST contrast, and could provide a sustained drug delivery and mechanical support at the surgical site for better recovery.In this proposed work, we will develop, optimize and evaluate theranostic hydrogels (TMZ-diaGel) to enhance the chemotherapy locally after brain tumor resection, and to monitor drug delivery and acidosis in a sensitive and high spatial resolution manner using the molecular CEST MRI. We will first develop the TMZ-diaGel and establish an optimal drug delivery and imaging platform. Then, we will systematically test our hypothesis by examining MRI readouts in clinical relevant brain tumor mouse models, particularly for detecting and monitoring drug delivery and treatments. Lastly, we will evaluate the efficacy of the theranostic hydrogel for its ability to improve therapeutic outcomes, e.g. CEST imaging of acidosis at the surgical site could help us to fine-tune the treatment to minimize tumor recurrence.