An adherent tissue-inspired hydrogel delivery vehicle utilised in primary human glioma models.

A physical hydrogel cross-linked via the host-guest interactions of cucurbit[8]uril and utilised as an implantable drug-delivery vehicle for the brain is described herein. Constructed from hyaluronic acid, this hydrogel is biocompatible and has a high water content of 98%. The mechanical properties have been characterised by rheology and compared with the modulus of human brain tissue demonstrating the production of a soft material that can be moulded into the cavity it is implanted into following surgical resection. Furthermore, effective delivery of therapeutic compounds and antibodies to primary human glioblastoma cell lines is showcased by a variety of in vitro and ex vivo viability and immunocytochemistry based assays.This work was supported by The Brain Tumour Charity (RG89672), the National Institute for Health Research Cambridge Biomedical Research Centre; the Higher Education Funding Council for England. We acknowledge the Human Research Tissue Bank and Biomedical Research Centre for the tissue being accessed through the Human Research Tissue Bank. The Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. MJR thanks the University of Cambridge Chemical Biology and Molecular Medicine PhD Training Programme for funding. CCP is thankful for the support of the EPSRC and the Brain Tumour Charity for funding. JHM acknowledges the support of the Gates Cambridge Scholarship programme. AKK was supported by a studentship from the John and Lucille van Geest Foundation

Local alkylating chemotherapy applied immediately after 5-ALA guided resection of glioblastoma does not provide additional benefit.

Grade IV glioma is the most common and aggressive primary brain tumour. Gross total resection with 5-aminolevulinic acid (5-ALA) guided surgery combined with local chemotherapy (carmustine wafers) is an attractive treatment strategy in these patients. No previous studies have examined the benefit carmustine wafers in a treatment programme of 5-ALA guided resection followed by a temozolomide-based chemoradiotherapy protocol. The objective of this study was to examine the benefit of carmustine wafers on survival in patients undergoing 5-ALA guided resection. A retrospective cohort study of 260 patients who underwent 5-ALA resection of confirmed WHO 2007 Grade IV glioma between July 2009 and December 2014. Survival curves were calculated using the Kaplan-Meier method from surgery. The log-rank test was used to compare survival curves between groups. Cox regression was performed to identify variables predicting survival. A propensity score matched analysis was used to compare survival between patients who did and did not receive carmustine wafers while controlling for baseline characteristics. Propensity matched analysis showed no significant survival benefit of insertion of carmustine wafers over 5-ALA resection alone (HR 0.97 [0.68-1.26], p = 0.836). There was a trend to higher incidence of wound infection in those who received carmustine wafers (15.4 vs. 7.1%, p = 0.064). The Cox regression analysis showed that intraoperative residual fluorescent tumour and residual enhancing tumour on post-operative MRI were significantly predictive of reduced survival. Carmustine wafers have no added benefit following 5-ALA guided resection. Residual fluorescence and residual enhancing disease following resection have a negative impact on survival

Mechanically matching the rheological properties of brain tissue for drug-delivery in human glioblastoma models.

Peptide functionalized hyaluronic acid (HACF) cross-linked by cucurbit[8]uril (CB[8]), a new class of drug-delivery reservoirs, is used to enable improved drug bioavailability for glioblastoma tumors in patient-derived xenograft (PDX) models. The mechanical and viscoelastic properties of native human and mouse tissues are measured over 8 h via oscillatory rheology under physiological conditions. Treatment with drug-loaded hydrogels allowed for a significant survival impact of 45 % (55.5-80.5 days). A relationship between the type of PDX tumor formed-a consequence of the heterogeneic nature of GB tumors-and changes in the initial survival is observed owing to greater local pressure from stiffer tumors. These biocompatible and tailorable materials warrant use as drug delivery reservoirs in PDX resection models, where the mechanical properties can be readily adjusted to match the stiffness of local tissue and thus have potential to improve the survival of GB patients.EPSRC Doctoral Training Grant, EPSRC reference EP/M508007/1 for lead author Chris Parkins. This work was supported by The Brain Tumour Charity (GN-000409), the National Institute for Health Research Cambridge Biomedical Research Centre and the Higher Education Funding Council for England. We acknowl- edge the Human Research Tissue Bank and Biomedical Research Centre for a portion of the tissue being accessed. The Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. CCP is thankful for the support of the EPSRC and the Brain Tumour Charity for funding. JHM acknowledges the support of the Gates Cambridge Trust and NIH OxCam Scholarship programme. LR and RJG thank the Mathile Family Foundation for funding