Etoposide-loaded lipopolymer nanoparticles promote Smac minetic activity against inhibitor of apoptosis protein for glioblastoma treatment.

Encapsulated BV6 and SM164, two bivalent second mitochondria-derived activator of caspase (Smac) mimetics, in etoposide (ETO)-lipopolymer nanoparticles (NPs) have been developed to deplete inhibitor of apoptosis proteins (IAP), impair DNA, and produce antagonistic effects on glioblastoma multiforme (GBM) in nude mice. The NPs, composed of cocoa butter (CB) and polyvinyl alcohol (PVA), were stabilized by glycerol monostearate and Pluronic F-127, and grafted with transferrin (Tf) and wheat germ agglutinin (WGA) to dock the blood-brain barrier (BBB) and degenerated dopaminergic neurons. The dual-targeting NPs increased the BBB permeability of BV6, SM164 and ETO via recognizing Tf receptor (TfR) and N-acetylglucosamine that are abundantly expressed on brain microvascular endothelial cells. The sustained release of BV6, SM164 and ETO from CB-PVA-NPs for 48 h resulted in a reduction of about 40 % in the viability of U87MG cells and human brain cancer stem cells. Hematoxylin and eosin staining of the brain in GBM mice revealed atypical mitosis of cancer cells and a considerable decrease in tumor cell density after treatment with Tf-WGA-BV6-SM164-ETO-NPs. Compared to untreated mice, the current ETO preparation carrying Smac mimetics reduced cellular IAP-1 expression to about 33 % and X-linked IAP expression to about 42 %, while enhanced about 3.8-fold caspase-3, indicating the effectiveness of the nanocarriers in accelerating apoptosis of GBM cells. Tf-WGA-CB-PVA-NPs can be promising to upgrade BV6 and SM164 activity by ETO in clinical trials for GBM management.