Functionalising peptide hydrogels to improve drug delivery for the treatment of glioblastoma

Abstract

Glioblastoma (GBM) is the most common and most aggressive primary brain tumour in adults, and its prognosis remains poor, with a near-universal fatality rate. This is due to a number of key obstacles in treating GBM, including: (i) the limited capacity for complete surgical resection due to risk of functional damage; (ii) the blood-brain barrier (BBB) preventing the systemic transport of many drugs into the brain, restricting treatment options; and (iii) the highly aggressive and infiltrative nature of GBM, which increases the likelihood of cancer cells remaining in the brain after treatment, responsible for high rates of recurrence. As such, one major avenue of interest for the improvement of GBM treatment outcomes is localised, post-operative drug delivery, to bypass the BBB and directly treat cells remaining at the resection margin. Biomaterials provide a promising vehicle for these delivery systems, due to their biocompatibility, biodegradability and capacity to mimic native tissue to support the area surrounding a surgical void. The overarching aim of this thesis is to develop a novel anticancer drug delivery system that, in conjunction with current surgical methods, may help to delay or prevent recurrence of GBM tumours. Using a tissue-specific self-assembling peptide (SAP) hydrogel as the delivery vehicle, here we developed an injectable and biocompatible drug delivery system that can be implanted post-operatively to release anticancer drugs directly at the site of resection. We demonstrate that the laminin-derived Fmoc-DDIKVAV SAP hydrogel used for neural applications has sequence-specific biocompatibility, supporting larger cell graft volumes with reduced immunoreactivity compared to alternative functional and non-functional sequences in the mouse brain in vivo. We also demonstrate that this Fmoc-DDIKVAV system is capable of supporting the culture of patient-derived GBM cell lines in vitro, maintaining cell viability and proliferation compared to the traditional 2D substrate used for GBM cell culture. We also show that the material's charge, and therefore the cellular response to the material, can be attenuated by altering the acid used to trigger self-assembly without affecting other key properties of the hydrogels. We show that three anticancer agents (CX-5461, PMR-116 and fucoidan) can be incorporated into the hydrogels without disrupting the hydrogel assembly mechanism or the anticancer activity of the drugs in GBM cells. In addition, we show that the method of drug incorporation has a major impact on the release rate of PMR-116, where release of shear encapsulated PMR-116 is approximately twice as fast as coassembled PMR-116 over 4 days. While both methods yield a linear release profile, this indicates that coassembly of drugs into the hydrogels provides the greatest potential for sustained release in the brain post-operatively. Collectively, these results demonstrate that Fmoc-SAP hydrogels are a promising material in the field of cancer research, both as a substrate for 3D culture of cancer cells and as an anticancer drug delivery vehicle for sustained, local drug release. This may help to improve treatment outcomes in GBM, bypassing the challenges posed by the BBB and reducing recurrence rates by treating cancer cells directly at the target site. Show more