Targeted eradication of glioblastoma via venom decapeptide-conjugated dendrimers: Inducing nuclear translocation and autophagic cell death.

Glioblastoma (GBM) is the most prevalent and aggressive primary central nervous system (CNS) neoplasm. Herein, we developed a nanoparticle (NP) drug delivery system by conjugating a scorpion venom-derived decapeptide Ctir9495 (C9) to a polyamidoamine (PAMAM) dendrimer, where 4-(bromomethyl) phenylboronic acid (PBA) modified PAMAM is used as a drug carrier due to its small size and favorable tumor penetration. This decapeptide-conjugated dendrimer, G5C9, targeted human GBM cells and displayed enhanced cell internalization. The G5C9 complex targeted GBM cells presumably by binding to the overexpressed surface sialic acid, resulting in rapid endocytosis and endolysosome formation. This induced cell cycle arrest, blocked tumor cell proliferation, colony formation and migration, resulting in autophagosome lysosome-based apoptotic GBM cell death. G5C9 suppressed GBM cell proliferation via enhanced nuclear translocation of the transcription factor EB (TFEB), a master regulator of the autophagosome lysosome pathway, by disrupting mTORC1 activity and downregulating the PI3K/AKT/mTOR signaling axis. This G5C9 complex exhibited potent activity against GBM xenografts in vivo. Hence, our delivery strategy not only enhances the uptake of this venom decapeptide-conjugated dendrimers into GBM, but also offers a novel modality to target and eradicate GBM.