Prof. Oren Sherman

Melville Laboratory for Polymer Synthesis, Department of Chemistry, Cambridge University

Oren graduated from Cornell University in Ithaca, New York, with a BA in Chemistry in 1999. He completed a PhD in 2004 in olefin metathesis and controlled polymerisation, under the supervision of Professor Robert H. Grubbs at Caltech. After finishing his PhD, Oren moved to the Netherlands to work on supramolecular polymers with Professors E.W. Meijer and Rint P. Sijbesma at the Eindhoven University of Technology. In 2006, he moved to the University of Cambridge as a University Lecturer and Next Generation Fellow in the Melville Laboratory for Polymer Synthesis in the Department of Chemistry. In 2012, he was promoted to Reader in Supramolecular and Polymer Chemistry and in March 2013, he was appointed as the Director of the Melville Laboratory; Oren was promoted to Full Professor in 2015. His research focuses on dynamic supramolecular self-assembly at interfaces though the application of macrocyclic host-guest chemistry using cucurbit[n]urils in the development of novel supramolecular systems. The Scherman group exploits control over these molecular level interactions to design and fabricate soft materials with integrated function. Current research topics include microcapsules, drug-delivery systems, conservation and restoration of important historical artefacts and sensing and catalysis using self-assembled nanophotonic systems.

Abstract:

Glioblastoma multiforme (GBM) is the most common primary cancer in adults and one of the most aggressive cancers with extremely poor survival statistics owing to high rates of disease recurrence. GBM infiltrates the brain tissue diffusely making complete surgical excision impossible. Current standard of care involves surgical resection of the tumour, concomitant radiotherapy and alkylating chemotherapy, followed by adjuvant chemotherapy. Chemotherapeutic choices are limited on account of most drugs’ poor propensity to cross the blood brain barrier. Systemic treatment with unspecified concentrations of chemotherapy is ineffective and risks adverse side effects. A localised and sustained delivery of patient-tailored chemotherapy to the resection cavity walls could significantly enhance patient survival opportunities by circumventing the BBB to eradicate the local, residual disease.

We describe the utilisation of a peptide-functionalised hyaluronic acid hydrogel cross-linked by the host-guest interactions of cucurbit[8]uril (CB[8]) as a drug-delivery vehicle for the treatment of GBM. The resulting material (98 wt% water) exhibits extraordinary tailorability and biocompatibility and can be produced to closely match the rheological properties of GBM tumour tissue.[1-3] The shear-thinning and self-healing capability of the hydrogel is successfully achieved through the use of CB[8] as a supramolecular cross-linker,[4] allowing the hydrogel to mold itself to an ex vivo resection cavity, maintaining tight apposition whilst releasing therapeutic compounds up to 950 μm in 1 h. The hyaluronic acid cysteine-phenylalanine (HA-CF) hydrogel shows no toxicity towards in vitro cell lines, with up-regulation of inflammatory markers seen only in samples loaded with chemotherapeutics. Importantly, these supramolecular hydrogels demonstrate superior release properties compared to conventional carmustine-impregnated wafers, Gliadel^TM. HA-CF supramolecular hydrogels represent a class of physically cross-linked biocompatible materials that open a crucial window into post-operative treatment for glioma resection patients.

 

Figure 1. The hydrogel (blue) may be implanted in a tumour resection cavity via a syringe/needle. The hydrogel acts as a drug reservoir, delivering active chemotherapies through the cavity wall into the recurrence zone. The hydrogel consists of a hyaluronic acid functionalised with phenylalanine terminated peptides that bind in a 2:1 fashion with the CB[8] host providing shear-responsive crosslinks that allow for injection.

In vitro release studies of various drug compounds encapsulated in the hydrogel have been performed and efficacy against multiple patient-derived human GBM cell lines determined. In vivo experiments with a mouse model are currently underway. We envisage that access to such drug-delivery technology will lead to clinical studies in the near future with an overall goal to prevent disease recurrence and improve patient survival rates.

References:

[1] Rowland, M.J.; Appel, E.A.; Coulston, R.J.; Scherman, O.A. J. Mater. Chem. B, 2013, 1, 2904-2910.

[2] Rowland, M.J.; Atgie, M.; Hoogland, D.; Scherman, O.A. Biomacromolecules, 2015, 16, 2436-2443.

[3] Rowland, M.J.; Parkins, C.C.; McAbee, J.H.; Kolb, A.K.; Hein, R.; Loh, X.J.; Watts, C.; Scherman, O.A. Biomaterials 2018, 179, 199-208.

[4] Appel, E.A.; del Barrio, J.; Loh, X.J.; Scherman, O.A., Chem. Soc. Rev., 2012, 41, 6195-6214; Liu, J.; Lan, Y.; Scherman, O.A. et al., Acc. Chem. Res. 2017, 50, 208-217; Liu, J.; Tan, C.S.Y.; Lan, Y. Scherman, O.A., Macromol. Chem. Phys., 2016, 217, 319-332.