Supramolecular hydrogels enable co-delivery of chemotherapeutics with synergistic efficacy against patient-derived glioblastoma cells and spheroids

Abstract

Drug combinations have been shown to be highly effective in many cancer therapies but the ratios of the individual drugs must be adjusted carefully and formulated appropriately to ensure synergistic action. Here we assessed combinations of doxorubicin and gemcitabine for post-surgical treatment of IDH1 wild-type glioblastoma (GBM). 2D and 3D spheroid in vitro models of GBM were generated from patient-derived glioblastoma cells resected from brain tumour cores and invasive margins. Drug combinations were screened for synergy using the Chou–Talalay method and mechanisms of action investigated using measures of caspase 3/7-mediated apoptosis and γH2AX-mediated DNA damage. Single drug and drug combinations were formulated in a supramolecular hydrogel based on a peptide-functionalised hyaluronic acid backbone dynamically linked by cucurbit[8]uril-mediated host–guest interactions as an implantable drug-delivery vehicle. Drug efficacy data from in vitro assays demonstrated synergistic activity with doxorubicin and gemcitabine combinations in a molar ratio-dependent manner. These compounds were included in the drug screen as exemplars of DNA intercalators and nucleoside analogue respectively. Consistent with this, enhanced apoptosis and DNA damage were also observed in a synergistic manner. Overall, these drug-loaded hydrogels demonstrated potency and maintenance of synergy with drug-combination hydrogels, in an easy-to-administer in situ gelling formulation suitable for post-resection delivery to prevent GBM recurrence.