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Guiding intracortical brain tumour cells to an extracortical cytotoxic hydrogel using aligned polymeric nanofibres

Nature Materials volume 13, pages 308–316 (2014)Cite this article

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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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Figure 1: Schematic and image of conduit inserted into a rat brain.
Figure 2: In vitro tumour cell migration on aligned nanofibre films versus smooth films.
Figure 3: Live/Dead assay for cell viability in hydrogels.
Figure 4: Glioblastoma cells in the conduit in vivo.
Figure 5: Proliferation of U87MG-eGFP cells in the brain and conduits.
Figure 6: Apoptosis staining of glioblastoma cells in the cyclopamine hydrogel-filled conduits.

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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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  1. Anjana Jain

    Present address: Present address: Department of Biomedical Engineering, Worcester Polytechnic Institute, 100 Institute Road, Worcester, Massachusetts 01609 USA,,

Authors and Affiliations

  1. Wallace H. Coulter Department of Biomedical Engineering Georgia Institute of Technology/Emory University School of Medicine, Neurological Biomaterials and Cancer Therapeutics Laboratory, 313 Ferst Drive, Atlanta Georgia 30332 USA,

    Anjana Jain, Martha Betancur, Gaurangkumar D. Patel, Chandra M. Valmikinathan, Vivek J. Mukhatyar, Ajit Vakharia, S. Balakrishna Pai & Ravi V. Bellamkonda

  2. Department of Neurosurgery Children’s Health Care of Atlanta Georgia 30342 USA,

    Barunashish Brahma

  3. Department of Pediatrics, Aflac Cancer And Blood Disorders Center Emory University School of Medicine Atlanta, Georgia 30322 USA,

    Tobey J. MacDonald

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Contributions

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.

Corresponding author

Correspondence to Ravi V. Bellamkonda.

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The authors declare no competing financial interests.

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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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