Abstract
Specifically designed and functionalized nanoparticles hold great promise for biomedical applications. Yet, the applicability of nanoparticles is critically predetermined by their surface functionalization and biodegradability. Here we demonstrate that amino-functionalized polystyrene nanoparticles (PS-NH2), but not amino- or hydroxyl-functionalized silica particles, trigger cell death in hepatocellular carcinoma Huh7 cells. Importantly, biodegradability of nanoparticles plays a crucial role in regulation of essential cellular processes. Thus, biodegradable silica nanoparticles having the same shape, size and surface functionalization showed opposite cellular effects in comparison with similar polystyrene nanoparticles. At the molecular level, PS-NH2 obstruct and amino-functionalized silica nanoparticles (Si-NH2) activate the mTOR signalling in Huh7 and HepG2 cells. PS-NH2 induced time-dependent lysosomal destabilization associated with damage of the mitochondrial membrane. Solely in PS-NH2-treated cells, permeabilization of lysosomes preceded cell death. Contrary, Si-NH2 nanoparticles enhanced proliferation of HuH7 and HepG2 cells. Our findings demonstrate complex cellular responses to functionalized nanoparticles and suggest that nanoparticles can be used to control activation of mTOR signaling with subsequent influence on proliferation and viability of HuH7 cells. The data provide fundamental knowledge which could help in developing safe and efficient nano-therapeutics.
Highlights
The fast nanotechnology advancements in recent years resulted in the development of numerous nanomaterials, which often possess complex structures and surface functionalization[1,2,3]
It has been shown that specific proteins present in the original protein corona are retained on NPs until they accumulate in lysosomes[37]
Similar physicochemical characteristics of the particles and the low polydispersity index (PDI) allowed us to analyze the role of the surface charge on the protein corona formation and subsequent pathophysiological responses of cancer cells (Fig. 2B)
Summary
The fast nanotechnology advancements in recent years resulted in the development of numerous nanomaterials, which often possess complex structures and surface functionalization[1,2,3]. Targeting lysosomes to trigger lysosomal leakage may be utilized for cancer therapy Such an approach could be associated with fewer side effects and higher therapeutic efficacy due to evasion of common resistance mechanisms[16]. We and others have shown previously that amino-functionalized NPs can induce lysosomal swelling and result into cancer cell death[12,13,18,19]. MTOR as well as some of the targets of the mTOR kinase signaling are overexpressed or mutated in cancer, and it is regarded as a promising target for anticancer treatment[20,21] It is worth noting here, that mTOR inhibitors display favorable pharmacological profiles and are well tolerated comparing to conventional anticancer therapy[22]
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