Nanotherapeutics for neurosurgically-applied drug delivery

Abstract

Abstract Despite multimodal treatment, the median survival of Glioblastoma multiforme (GBM) remains less than 15 months, in considerable part due to diffusely infiltrative disease. Better treatment methods are necessary to eradicate residual tumour burden remaining beyond the resection cavity boundary. Based on an increasing understanding of GBM intra-tumour heterogeneity, the capability to deliver multiple therapeutic moieties from single formulations is clinically-relevant. It is hypothesised that incorporating drug-loaded polymer pro-drugs, which are capable of transcytotic ‘hopping’, into a biodegradable microparticulate paste will lead to efficacious local delivery. Here we report the formulation of numerous self-assembling cytocompatible nanoparticles, based on different linear and branched polymeric architectures. The polymers were synthesised by ring opening polymerisation with organic catalysts, leading to controlled reaction kinetics and greater potential biomedical applicability. We demonstrated that copolymerisation of a monomer with functional capability enabled the successful conjugation of doxorubicin to the polymer chain. We hypothesised that polymers with a greater degree of branching over traditional linear structures would lead to greater drug loading, and successfully tested this hypothesis through the encapsulation of olaparib. We will discuss strategies to incorporate: i) pH-sensitive linkers to the polymeric backbone, which would allow controlled drug release in acidic microenvironments; ii) multiple combined chemotherapeutics, including doxorubicin and olaparib. Future work will assess the efficacy of the polymer pro-drugs against primary GBM lines derived from the invasive margin and safety/efficacy using orthotopic syngeneic allografts. This is the first study incorporating polymer pro-drugs of this type into an existing localised micro-scale delivery system for GBM therapies.