157 Intranasal delivery of liposomal saccharide-linked diethyldithiocarbamates: formulation development and free drug assessment

Abstract

The treatment success of Glioblastoma (GBM) remains poor, with lack of success being attributed to both the presence of the blood-brain barrier and chemoresistance. The development of intranasal delivery alongside the use of a novel anticancer agent could provide a more direct and successful route to the brain with less significant limitations. This study introduces a novel cancer agent, saccharide linked diethyldithiocarbamates (Sa-DDC), which has shown promising anticancer activity in vitro as well as encouraging aerosolization properties, and explores its use in the development of an encapsulated form for GBM treatment. The cytotoxicity of unencapsulated Sa-DDC was assessed through an MTT assay and initial aerosiliation properties were evaluated using a Spraytec to assess the droplet size produced. HSPC-based liposomes were formulated using the ethanol based proliposome method with high pressure homogenisation for size reduction. Further characterisation, using dynamic light scattering, assessed their size, polydispersity index (PDI) and zeta potential. The encapsulation efficiency was determined using ultrafiltration and ultracentrifugation in combination. In vitro assessment of the cytotoxicity of Sa-DDC via an MTT viability assay gave an IC50 of ∼ 8 µM on a GBM cell line. Initial results from the Spraytec analysis showed droplet sizes of the free drug in saline of < 200 µm. Given the promising results from the unencapsulated drug, the development of a liposomal formulation was carried out. The resulting liposomes produced sizes of < 140 nm with a PDI <0.25 and a zeta potential of ∼ -20 mV and an encapsulation efficiency of ∼40-50%. The promising activity of saccharide-diethyldithiocarbamate compounds and further successful encapsulation highlight a potential for their use intranasally, and comparisons between the free drug and encapsulated are ongoing.