Abstract
Cancer cells demonstrate elevated expression levels of the inhibitor of apoptosis proteins (IAPs), contributing to tumor cell survival, disease progression, chemo-resistance, and poor prognosis. Smac/DIABLO is a mitochondrial protein that promotes apoptosis by neutralizing members of the IAP family. Herein, we describe the preparation and in vitro validation of a synthetic mimic of Smac/DIABLO, based on fluorescent polyethylene glycol (PEG)-coated silica-core nanoparticles (NPs) carrying a Smac/DIABLO-derived pro-apoptotic peptide and a tumor-homing integrin peptide ligand. At low μM concentration, the NPs showed significant toxicity towards A549, U373, and HeLa cancer cells and modest toxicity towards other integrin-expressing cells, correlated with integrin-mediated cell uptake and consequent highly increased levels of apoptotic activity, without perturbing cells not expressing the α5 integrin subunit.
Highlights
Apoptosis, or programmed cell death, is an essential process in the homeostasis of multicellular organisms
Monodispersed fluorescent silica-core/polyethylene glycol (PEG)-shell NPs functionalized with azide moieties and incorporating the dye rhodamine B triethoxysilane (RhB-TES) [44] (Figure 1A) were expediently obtained using a direct micelle-assisted method [45]
These nanostructures were formed by the condensation of the silica precursor TEOS in an aqueous acid environment in the presence of co-aggregates composed by a 10:1 mixture of the tri-block surfactant copolymer Pluronic® F127 (PF127) and its diazide derivative PF127–(N3)2 [43]
Summary
Programmed cell death, is an essential process in the homeostasis of multicellular organisms. Caspase-3, -7 and -9 activity is regulated by the inhibitor of apoptosis proteins (IAPs) [1,2]. BIRs are protein-interacting modules with distinct binding properties, necessary for the anti-apoptotic activity [4,5,6]. IAP-mediated caspase inhibition is depressed by the second mitochondria-derived activator (Smac)/direct inhibitor of apoptosis-binding protein with low pI (DIABLO), a mitochondrial protein that is translocated to the cytoplasm in apoptotic conditions [9]. Structural analysis proved that the N-terminal sequence of Smac/DIABLO is essential for its function in the interaction with the BIR domain of IAP [10]. Peptides derived from the N-terminal sequence of Smac/DIABLO may represent attractive anticancer molecules
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