The malignant brain cancer, glioblastoma multiforme (GBM), is heterogeneous, infiltrative, and associated with chemo-and radioresistance. Despite pharmacological advances, prognosis is poor. Delivery into the brain is hampered by the blood-brain barrier (BBB), which limits the efficacy of both conventional and novel therapies at the target site. Current treatments for GBM remain palliative rather than curative; therefore, innovative delivery strategies are required and nanoparticles (NPs) are at the forefront of future solutions. Since the FDA approval of Doxil® (1995) and Abraxane (2005), the first generation of nanomedicines, development of nano-based therapies as anti-cancer treatments has escalated. A new generation of NPs has been investigated to efficiently deliver therapeutic agents to the brain, overcoming the restrictive properties of the BBB. This review discusses obstacles encountered with systemic administration along with integration of NPs incorporated with conventional and emerging treatments. Barriers to brain drug delivery, NP transport mechanisms across the BBB, effect of opsonisation on NPs administered systemically, and peptides as NP systems are addressed. Keywords BBB. Cell penetrating peptides. Drug delivery. GBM. Nanoparticle. RALA Abbreviations Au PENP P o l y e t h y l e n e i m i n e-e n t r a p p e d g o l d nanoparticles Au Gold BBB Blood-brain barrier Bcl-2 B cell lymphoma-2 BCRP Breast cancer resistance protein BMEC Brain microvascular endothelial cell c(RGD) Cyclic (arginine-glycine-aspartic acid) peptide C h o l-P C L-LNP PEGylated cleavage lipopeptide CNS Central nervous system CPP Cell penetrating peptide D M-P C L-LNP Dimyristoyl anchored PEGylated MMPcleavable lipopeptide DSPE 1 , 2-D i s t e a r o y l-s n-g l y c e r o-3phosphoethanolamine DTC Dithiolane-functionalized trimethylene carbonate EB

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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.

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.