Exploiting the anticancer effects of a nitrogen bisphosphonate nanomedicine for glioblastoma multiforme

Lynn N Jena,Nicholas J Dunne,Sreekanth Pentlavalli,James F Burrows,Emma M Mcerlean,Niamh E Buckley,Kim Glass,Vicky L Kett,Jonathan A Coulter,Helen O Mccarthy,Lindsey A Bennie

doi:10.1186/s12951-021-00856-x

Abstract

Glioblastoma multiforme (GBM) is an incurable aggressive brain cancer in which current treatment strategies have demonstrated limited survival benefit. In recent years, nitrogen-containing bisphosphonates (N-BPs) have demonstrated direct anticancer effects in a number of tumour types including GBM. In this study, a nano-formulation with the RALA peptide was used to complex the N-BP, alendronate (ALN) into nanoparticles (NPs) < 200 nm for optimal endocytic uptake. Fluorescently labelled AlexaFluor®647 Risedronate was used as a fluorescent analogue to visualise the intracellular delivery of N-BPs in both LN229 and T98G GBM cells. RALA NPs were effectively taken up by GBM where a dose-dependent response was evidenced with potentiation factors of 14.96 and 13.4 relative to ALN alone after 72 h in LN229 and T98G cells, respectively. Furthermore, RALA/ALN NPs at the IC50, significantly decreased colony formation, induced apoptosis and slowed spheroid growth in vitro. In addition, H-Ras membrane localisation was significantly reduced in the RALA/ALN groups compared to ALN or controls, indicative of prenylation inhibition. The RALA/ALN NPs were lyophilised to enhance stability without compromising the physiochemical properties necessary for functionality, highlighting the suitability of the NPs for scale-up and in vivo application. Collectively, these data show the significant potential of RALA/ALN NPs as novel therapeutics in the treatment of GBM.

Highlights

Glioblastoma multiforme (GBM) is the most malignant primary brain tumour, derived from glial cells
RALA/nitrogen-containing bisphosphonates (N-BPs) NPs were prepared according to a mass ratio of RALA to BP using ALN monosodium trihydrate dissolved in TE buffer prior to NP formulation, to achieve an optimal electrochemical state for effective RALA complexation
LN229 and T98G cells treated with RALA/ALN NPs exhibited a significant decrease in the cell viability in vitro, as demonstrated by the apoptosis and clonogenic assay

Summary

Introduction

Glioblastoma multiforme (GBM) is the most malignant primary brain tumour, derived from glial cells. GBM rarely colonise regions external to the central nervous system (CNS) [1]. Post-diagnosis, median survival remains low at 6.9 months and the 5-year overall survival rate is less than 9.8% despite multimodal therapy [2]. Radiotherapy plus adjuvant temozolomide chemotherapy represent the standard of care for newly diagnosed GBM patients [3]. GBM recurs in up to 90% of cases that leads to patient death [4]. To prolong tumour control and patient survival, novel therapeutic strategies are required

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