Research Update May 2016

Project Update                             Dr Helen Townley Personnel: Placement Students Giulia Spadafora and Lucy Taylor were working with us as undergraduate sandwich students from Bath University for the acamedic year 2014/2015 and Anna Evison for 2015/ 2016. The student’s projects concentrated on using the paediatric cancer cell lines RD and RH30 derived from Rhabdomyosarcomas. We have investigated the use of natural products as new chemotherapeutic agents, undertaken a screen of compounds from a library of compounds produced by Kiel University, Germany.  We are now following up lead compounds for their activity and mechanism of action. Doctoral training centre Mookie Bovornchutichai also worked with us for a term on dissolvable wafers for drug incorporation. Foreign visitors Florent Amiot was a vistor from a Paris University. He was synthesizing silica nanoparticles for peptide delivery. Course and Lectures HT was co-course leader at a workshop in Basel, Switzerland on targetted drug delivery, February 2016 HET is an invited speaker at the Clinical Applications of Nmanotechnology; Leeds, June 2016 Recently Accepted Publications: 1. Rachel Morrison, James Thompson, Luke Bird, Mark Hill, Helen Townley. Synthesis and characterization of polystyrene embolization particles doped with tantalum oxide nanoparticles for X-ray contrast. J. Mater Sci Mater Med. 2015; 26: 218 Our image of a fluorescently labelled microparticle was used on the front cover and the August Editorial was written about our article: http://static.springer.com/sgw/documents/1521148/application/pdf/JMSM+August+Editorial+HTownley+FINAL.pdf 2. Xinyue Huang & Helen Townley. Knockdown of ELMO1 in Paediatric Rhabdomyosarcoma Cells by Nanoparticle Mediated siRNA Delivery. Nanobiomedicine 2016, 3:4 This work described research into the delivery of RNAi molecules using a nanoparticulate system to downregulate the expression of the gene ELMO1 which is implicated in the metastasis of Rhabdomyosarcoma. 3. Charles Jeynes, Christopher Jeynes,  Vladimir Palitsin, Helen Townley Direct quantification of rare earth doped titania nanoparticles in individual human cells”, Nanotechnology. 2016 In Press. This work was a collaboration with the University of Surrey and the University of Exeter. We were able to use the Ion Beam centre to further analyze the properties of our nanoparticles. Manuscripts submitted for consideration: Rachel Morrison, Tiffany Lodge, Antonio Evidente, Robert Kiss, Helen Townley. The mechanism of cell death after exposure to Ophiobolin A varies by cancer cell origin. Submitted to Cell and Molecular Life Sciences Manuscripts in preparation: 1. Rachel Morrison, Malgorzata Rybak-Smith, James Thompson, Benedicte Thiebaut, Mark A. Hill, Helen E Townley Investigation of radiosensitizing doped titania nanoparticles under hypoxic conditions, and incorporation into an embolic microparticle Has been submitted to the legal department of our collaborators, Johnson Matthey Ltd., and will then be submitted to  the European Journal of Cancer. 2. Xinyue Huang, Michelle Potter, Ben S. Pilgrim, Ruchuta Ardkhean, Mikail A. Kabeshov, Georgina Dean, Tim D. W. Claridge, Matt Wiseman, Karl Morten, Timothy J. Donohoe, Helen E. Townley  The efficacy of the Quercetin analogue LY294002 is related to the bioenergetic profiles of the test cells in vitro. Grants being Finalized; due to start June 2016 Final contracts are being exchanged with Cristalia, a Brazilian Company, to work on a healthcare project using silica nanoparticles. Cindy Huang who received support from the Williams Fund during her DPhil project will be returning as a Postdoctoral researcher. Grants submitted for consideration by CRUK: Utilization of Amaryllidacae extracts as a potential source of novel chemotherapeutics for use in paediatric oncology PI: Helen Townley. Industrial collaboration with Agroceutical Products Ltd. Funds have been requested for a PDRA for 36 months This research proposal aims to capitalize on the potential for alkaloids found in the waste-stream after Galanthamine production from Narcissus to act as chemotherapeutic agents. The galanthamine is produced commerically by Agroceutical Products from Narcissus biomass for the treatment of Alzheimer’s disease. It is estimated that there are approximately 300 alkaloids present in the effluent, each of which may have chemotherapeutic activity either alone or in combination. There is precedent for alkaloids to have cytotoxic/ cytostatic activity e.g. vinblastine, vincristine, vindesine, and vinorelbine are based on Vinca alkaloids. We will therefore screen the alkaloids for activity against immortalized cancer cell lines. Studies in paediatric oncology are under-represented in cancer research programmes and we have selected to test the compounds against paediatric 8 sarcoma cell lines. The alkaloids will be tested both in isolation and in combination to test for synergistic interactions. We will use a random partition design to facilitate tractable experimental procedures and linear model analysis, and the high throughput liquid handling facility at the Target Discovery Institute in Oxford. The compounds showing the most promising activity will be investigated for mechanism of action. While the optimal drug ratios will be determined in the laboratory, in vivo individual drugs are likely metabolized independently and at different rates, possibly even resulting in a previously synergistic activity becoming antagonistic; a dire situation for the patient. We will therefore package the chosen alkaloids in nanoparticles so that a fixed ratio is delivered to the site of action in the tumour.   Nanoparticle delivery will also stabilize the compounds against degradation, allow passive targetting to tumours via the EPR mechanism, or allow for targetting moieties to be added to the surface.

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