Self-Assembling Camptothecin Nanofiber Hydrogels as Adjunct Therapy for Intraoperative Treatment of Malignant Glioma

Project summary Malignant gliomas, including the most common type glioblastoma (GBM), are histologically heterogeneous and invasive tumors known as the most devastating neoplasms with high morbidity and mortality. Despite multimodal treatment including surgery, radiotherapy, and chemotherapy, the disease inevitably recurs and proves fatal. Local application of carmustine implants (Gliadel® wafers) as an adjunct to surgery and radiation therapy has been clinically proven to extend the survival time for patients with malignant gliomas, strongly suggesting that local chemotherapy after tumor resection presents a feasible and effective strategy to treat brain tumor patients. However, the rapid depletion of carmustine and low tissue penetration greatly limit the clinical benefits of Gliadel® wafers, which only extend the median survival of treated patients by six months compared to those untreated. This proposal aims to develop a novel type of self-assembling nanofiber hydrogels that use the anticancer drug camptothecin (CPT) as the molecular building blocks and that can be locally administered to the resection cavities after tumor removal, with the ultimate goal to achieve more effective treatments for patients diagnosed with malignant gliomas. We hypothesize that the proposed nanofiber hydrogels will spread across large tissue areas and sustainably release therapeutic agents for long-term cytotoxicity against glioma cells, thus leading to significantly extended survival time in our rodent model. To test our hypothesis, we outlined the proposed research activities in the three specific Aims, seeking to address the three key challenges in local delivery of therapeutic drugs into resection cavities: 1) the nanofiber gelation properties. The gel form enables prolonged retention in the delivery sites and also minimizes capillary loss of free drugs that would otherwise occur; 2) the sustained release of free drugs over a long period of time. The release rate and period are critical for effective elimination of glioma cells without causing devastating side effects; 3) diffusion across large tissue areas. In Aim 1, we will identify the key molecular parameters in the design of self-assembling CPT DAs to create CPT nanofibers of varying surface chemistries that would promote the formation of hydrogels upon contact with body fluids. Aim 2 is focused on the evaluation and fine-tuning of the drug release rate and mechanism, their ability to overcome the MDR mechanisms, as well as diffusion distance within organotypic tissues. In Aim 3, we will use an animal model to evaluate the nanofibers’ ability to diffuse across large tissue areas, pharmacokinetics, in vivo efficacy and toxicity of two already developed nanofiber hydrogels and also those to be developed in Aim 1 and Aim 2. Our ultimate goal is to develop a nanofiber hydrogel platform technology that will extend the survival time of rodents bearing human brain cancer, and translate this platform to a pre-clinical approach.