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Conformable hierarchically engineered polymeric micromeshes enabling combinatorial therapies in brain tumours

Nature Nanotechnology volume 16, pages 820–829 (2021)Cite this article

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Abstract

The poor transport of molecular and nanoscale agents through the blood–brain barrier together with tumour heterogeneity contribute to the dismal prognosis in patients with glioblastoma multiforme. Here, a biodegradable implant (μMESH) is engineered in the form of a micrometre-sized poly(lactic-co-glycolic acid) mesh laid over a water-soluble poly(vinyl alcohol) layer. Upon poly(vinyl alcohol) dissolution, the flexible poly(lactic-co-glycolic acid) mesh conforms to the resected tumour cavity as docetaxel-loaded nanomedicines and diclofenac molecules are continuously and directly released into the adjacent tumour bed. In orthotopic brain cancer models, generated with a conventional, reference cell line and patient-derived cells, a single μMESH application, carrying 0.75 mg kg−1 of docetaxel and diclofenac, abrogates disease recurrence up to eight months after tumour resection, with no appreciable adverse effects. Without tumour resection, the μMESH increases the median overall survival (∼30 d) as compared with the one-time intracranial deposition of docetaxel-loaded nanomedicines (15 d) or 10 cycles of systemically administered temozolomide (12 d). The μMESH modular structure, for the independent coloading of different molecules and nanomedicines, together with its mechanical flexibility, can be exploited to treat a variety of cancers, realizing patient-specific dosing and interventions.

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Fig. 1: Fabrication and hierarchical structure of the μMESH.
Fig. 2: In vitro functional characterization of the µMESH.
Fig. 3: In vitro pharmacological activity of the µMESH.
Fig. 4: Tissue transport performance of µMESH-released nanoparticles.
Fig. 5: Preclinical therapeutic efficacy of the µMESH.

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Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This project was partially supported by the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement 616695–POTENT (P.D.), and by the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement 754490–MINDED (P.D.). We thank the laboratory of D. De Pietri Tonelli for providing the U-87 MG GFP+ cells. We thank the Clean Room Facility in IIT and M. Francardi. P.D. and G.A.G. are grateful to Professor Sanjiv Sam Gambhir of Stanford University for catalysing and supporting the collaboration between their laboratories. We dedicate this work to the memory and legacy of Professor Sanjiv Sam Gambhir, who passed away on 18 June 2020.

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Authors and Affiliations

  1. Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Genoa, Italy

    Daniele Di Mascolo, Anna Lisa Palange, Rosita Primavera, Francesca Macchi, Tiziano Catelani, Federica Piccardi, Raffaele Spanò, Miguel Ferreira & Paolo Decuzzi

  2. Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA, USA

    Rosita Primavera

  3. Microscopy Facility, University of Milano-Bicocca, Milan, Italy

    Tiziano Catelani

  4. Electron Microscopy Facility, Fondazione Istituto Italiano di Tecnologia, Genoa, Italy

    Roberto Marotta

  5. Analytical Chemistry Lab, Fondazione Istituto Italiano di Tecnologia, Genoa, Italy

    Andrea Armirotti

  6. Neural Stem Cell Biology Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy

    Alberto L. Gallotti & Rossella Galli

  7. Department of Neurosurgery, Stanford University, Palo Alto, CA, USA

    Christy Wilson & Gerald A. Grant

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  1. Daniele Di Mascolo
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Contributions

D.D.M. and P.D. conceived the idea and designed the experiments. D.D.M. realized all the different platforms used, performed all the in vitro experiments, acquired optical and electron microscopy images, analysed all the data and performed statistical analyses. A.L.P. performed all the in vivo experiments. R.P. conducted the histological analyses and sample preparation. F.M. helped in the realization of the orthotopic tumour models. T.C. prepared samples for CLEM study. F.P. and R.S. helped with the in vivo experiments. A.L.G. and R.G. provided patient-derived GBM cells, transfected the cells with Luc+ and helped in developing the tumour model, and A.L.G. helped with cell inoculation. M.F. synthesized lipid-Cy5. R.M. performed cryo-EM analyses. A.A. performed liquid chromatography–mass spectrometry analyses. C.W. and G.A.G. performed time-course penetration experiments with µSPNs. D.D.M., P.D. and A.L.P. wrote the manuscript. P.D. supervised the whole project.

Corresponding author

Correspondence to Paolo Decuzzi.

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Competing interests

D.D.M. and P.D. are the coinventors on the pending patent WO2019193524A1—‘An implantable device for localized drug delivery, uses thereof and a manufacturing method thereof’ filed by the Fondazione Istituto Italiano di Tecnologia. The remaining authors declare no competing interests.

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Peer review information Nature Nanotechnology thanks Manish Aghi, Ravi Bellamkonda and Abhay Pandit for their contribution to the peer review of this work.

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Di Mascolo, D., Palange, A.L., Primavera, R. et al. Conformable hierarchically engineered polymeric micromeshes enabling combinatorial therapies in brain tumours. Nat. Nanotechnol. 16, 820–829 (2021). https://doi.org/10.1038/s41565-021-00879-3

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