Abstract
Glioblastoma multiforme is an aggressive, invasive brain tumour with a poor survival rate. Available treatments are ineffective and some tumours remain inoperable because of their size or location. The tumours are known to invade and migrate along white matter tracts and blood vessels. Here, we exploit this characteristic of glioblastoma multiforme by engineering aligned polycaprolactone (PCL)-based nanofibres for tumour cells to invade and, hence, guide cells away from the primary tumour site to an extracortical location. This extracortial sink is a cyclopamine drug-conjugated, collagen-based hydrogel. When aligned PCL-nanofibre films in a PCL/polyurethane carrier conduit were inserted in the vicinity of an intracortical human U87MG glioblastoma xenograft, a significant number of human glioblastoma cells migrated along the aligned nanofibre films and underwent apoptosis in the extracortical hydrogel. Tumour volume in the brain was significantly lower following insertion of aligned nanofibre implants compared with the application of smooth fibres or no implants.
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Acknowledgements
We would like to thank J. Leisen for his technical expertise with the MR scanner and J. Lyon and S. Nayebosadri for their assistance with the animal surgeries and immunohistochemistry. We would also like to acknowledge funding support for this project from National Institutes of Health EUREKA R01 CA153229 (NCI) (R.V.B.), the Georgia Research Alliance (R.V.B.), and Ian’s Friends Foundation (R.V.B.)
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R.V.B. conceived the tumour ‘exvasion’ strategy using nanofibre films towards an apoptosis-inducing hydrogel and was responsible for the overall study design. A.J. implemented the above strategy by means of the design of a nanofibre tumour guide and a hydrogel sink, and also performed the surgeries, designed the experiments and analysed the results. M.B. oversaw the smooth film control studies, as well as quantified the Ki-67+ staining and tumour volume. G.D.P. fabricated the polymer conduits and nanofibre films. C.M.V. designed and performed the collagen and cyclopamine collagen two-well depot Live/Dead experiments, based on a cyclopamine strategy suggested by T.J.M. V.J.M. assisted with animal surgeries and tissue sectioning. A.V. performed haematoxylin and eosin staining and helped with histological assessment. S.B.P. stably transfected the U87MG cells to express eGFP. B.B helped with surgical strategy.
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Jain, A., Betancur, M., Patel, G. et al. Guiding intracortical brain tumour cells to an extracortical cytotoxic hydrogel using aligned polymeric nanofibres. Nature Mater 13, 308–316 (2014). https://doi.org/10.1038/nmat3878
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DOI: https://doi.org/10.1038/nmat3878
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