Conformable hierarchically engineered polymeric micromeshes enabling combinatorial therapies in brain tumours

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\u2009mg\u2009kg−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\u2009d) as compared with the one-time intracranial deposition of docetaxel-loaded nanomedicines (15\u2009d) or 10 cycles of systemically administered temozolomide (12\u2009d). 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. Surgical resection is the primary treatment strategy for glioblastoma multiforme, but the infiltrating nature of the tumour, coupled with its heterogeneity and the presence of the blood–brain barrier that hampers drug delivery, contributes to recurrence and poor prognosis. Here the authors engineer a mechanically flexible mesh that can adhere to the tumour resected cavity and release a combination of nanomedicines and small molecules in a controlled and sustained manner for tumour therapy.