Suppressed XIAP and cIAP expressions in human brain cancer stem cells using BV6-and GDC0152-encapsulated nanoparticles

Background: Smac mimetics functioned against inhibitors of apoptosis proteins (IAP) often fail to achieve sufficient ability in glioblastoma multiforme (GBM) treatment due to the obstruction of the blood-brain barrier (BBB). Methods: BV6-and GDC0152-encapsulated solid lipid nanoparticles (SLNs) with surface transferrin (Tf) and folic acid (FA) (BV6-GDC0152-Tf-FA-SLNs) were developed to downregulate IAP in U87MG cells and human brain cancer stem cells (HBCSCs) for GBM treatment. Significant findings: An increase in stearic acid (SA) level enlarged SLNs with improved entrapment of BV6 and GDC0152. H-1 NMR study revealed hydrogen bonding between SA and the two IAP antagonists, supporting controlled release of BV6 and GDC0152 from SLNs. Increasing sodium dodecyl sulfate concentration reduced the size of SLNs, and raised the particle stability. Conjugated Tf and FA on SLNs favored permeating the BBB as corroborated from decreased transendothelial electrical resistance, and raised BBB permeability of propidium iodide, BV6 and GDC0152. The ability of BV6-GDC0152-Tf-FA-SLNs to target IAP in U87MG cells and HBCSCs was validated from the downregulated XIAP and cIAP-1 expressions and upregulated caspase-3 expression in immunofluorescence staining, flow cytometry and western blot analysis. Hence, Tf-and FA-grafted SLNs can be an effective colloidal delivery system to deliver BV6 and GDC0152 across the BBB, facilitate IAP targeting, and enhanced drug bioavailability of the two Smac mimetics in GBM cells for potential clinical trials.

Automated summary

By encapsulating BV6 and GDC0152 in solid lipid nanoparticles with surface transferrin and folic acid modifications, the efficacy of these two Smac mimetics in glioblastoma multiforme treatment can be enhanced, allowing for targeted drug delivery and release in GBM cells.