Bypassing the Blood-Brain Barrier: Cucurbit[8]uril-based Hydrogels Towards Drug Delivery Reservoirs
Creators: name: Parkins, Christopher Charles
Publisher: name: Apollo - University of Cambridge Repository
Year: 2020
Subjects: cucurbit[8]uril
hydrogel
glioblastoma
gbm
ependymoma
glioblastoma multiforme
hyaluronic acid

description: Hydrogels formed from supramolecular crosslinking are an exciting class of soft materials that exhibit attractive properties lending themselves towards biomedical applications, specifically as drug delivery reservoirs. Dynamic crosslinks form materials that can be stimuli-responsive, shear-thinning and self-healing. It is the application of these materials in the local delivery of cargo to post-resection tumour cavities that is the focus of this thesis. In the first chapter the host-guest interactions of cucurbit[8]uril in aqueous assemblies, with a particular emphasis on those systems forming hydrogels, are summarised. The application of hydrogels towards delivery devices in glioblastoma and ependymoma are outlined and discussed. The second chapter focuses on the preparation of peptide-functionalised hyaluronic acid hydrogels dynamically crosslinked using the macrocylic host molecule cucurbit[8]uril (CB[8]). The host facilitates supramolecular crosslinks between the polymer chains drastically increasing the viscoelastic properties of the materials. By tuning the temporary chain entanglement (molecular weight) and the crosslinking density, control over the network mechanics, flow properties and relaxation is demonstrated. Matrix metalloproteinase cleavable linkers were introduced to produce environment-responsive networks that would lower the mechanical properties on demand. Conversely, light-triggered guest moieties were introduced to spatially and temporally modulate mechanical stiffness. The third chapter builds upon this initial work through the employment of peptide functionalised hyaluronic acid (HA(CF)) hydrogels as delivery devices. The binding dynamics of small-molecule chemotherapies is analysed through proton nuclear magnetic resonance (NMR) titrations and isothermal titration calorimetry (ITC). The in vitro and ex vivo release of each molecule from HA(CF) hydrogels is analysed using UV/vis spectroscopy, confocal microscopy and mass spectrometry imaging. Biocompatibility of the hydrogel and the constituents were demonstrated through a variety of in vitro viability and immunocytochemistry based assays. Moving forward, the in vivo validation of injectable HA(CF) hydrogels using patient derived xenografts (PDXs) of glioblastoma tumours, was undertaken in chapter four. The mechanical and viscoelastic properties of native human and mouse tissues are measured over 8 hours via oscillatory rheology under physiological conditions. Tissue stiffness matching of the hydrogels enables a significant survival impact of 45% (55.5 to 80.5 days) due to improved tissue apposition and subsequently increased local repurposed drug bioavailability. A relationship between the type of PDX tumour formed—a consequence of the heterogeneic nature of GB tumours—and changes in the initial survival is observed owing to greater local pressure from stiffer tumours. Chapter five highlights the utility of HA(CF) hydrogels within glioblastoma PDXs and supratentorial fusion-negative ependymoma resection models. Patient derived GB cells are transduced with luciferase reporter to monitor tumour growth in vivo. Resection surgery protocol is enhanced through the fluorescent tracking of the hydrogel following implantation. A synthetic dural patch is employed to prevent post-operative swelling and enhance drug delivery. The efficacy of HA(CF) hydrogels as delivery devices is scrutinised resulting in development points for further study. Finally, a concluding chapter summarises the work presented from hydrogel design, through in vitro validation, to in vivo implementation. This chapter outlines insight into the future work based on the work outlined, with emphasis on the surgical employment of the delivery device.