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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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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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.
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.
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. (2021). https://doi.org/10.1038/s41565-021-00879-3