Abstract
BackgroundAutophagy regulation through exogenous materials has aroused intensive attention to develop treatment protocols according to diverse human diseases. However, to the best of our knowledge, few examples have been reported to selectively control autophagy process and ultimately achieve efficient therapeutic potential.ResultsIn this study, monolayers of poly (acryloyl-l, d and racemic valine) (l-PAV-AuNPs, d-PAV-AuNPs and l/d-PAV-AuNPs) chiral molecules were anchored on the surfaces of gold nanoparticles (PAV-AuNPs), and the subsequent chirality-selective effects on autophagy activation were thoroughly studied. The cytotoxicity induced by PAV-AuNPs towards MDA-MB-231 cells (Breast cancer cells) was achieved mainly through autophagy and showed chirality-dependent, with d-PAV-AuNPs exhibiting high autophagy-inducing activity in vitro and in vivo. In contrast, the PAV-AuNPs exhibited autophagy inactivation for normal cells, e.g., 3T3 fibroblasts and HBL-100 cells. The chirality-selective autophagy activation effect in MDA-MB-231 cells was likely attributed to the chirality-variant ROS generation, cellular uptake and their continuous autophagy stimulus. Furthermore, the intratumoral injection of d-PAV-AuNPs could largely suppress the tumor growth but exhibit negligible toxicity in vivo.ConclusionsAs the first exploration on stereospecific NPs for autophagy induction, this work not only substantiates that chiral polymer coated NPs can selective induce autophagy-specific in cancer cells and achieve a high tumor eradication efficiency in vivo, but also opens up a new direction in discovering unprecedented stereospecific nanoagents for autophagy-associated tumor treatment.
Highlights
Autophagy regulation through exogenous materials has aroused intensive attention to develop treatment protocols according to diverse human diseases
Characterization by transmission electron microscope (TEM) analysis showed that PAV-autophagy-inducing gold nanoparticles (AuNPs) were approximately spherical in shape and had an average-diameter of 15 nm (Fig. 1b), regardless of surface chirality
The UV–Vis-NIR spectra exhibited that PAV-AuNPs had a surface plasmon resonance (SPR) peak of 521 nm (Fig. 1c)
Summary
Chiral PAV molecules, composed of valine (one of the eight essential amino acids of human body), were grafted on the AuNPs through the thioester-Au bond [17] (Fig. 1a). The activation of autophagy induced by PAV-AuNPs in 3T3 fibroblasts and HBL-100 cells still were not observed (Fig. 2c and Additional file 1: Figure S2), irrespective of the surface chirality. We speculate that the selective activation of autophagy induced by the PAV-AuNPs between cancer cells and normal cells was possibly attributed to the differences of biomolecules or proteins in their membranes, which may influence their interactions with the NPs (i.e., cellular uptake). The d-PAV-AuNPs treated group presented more immunofluorescence of LC3-II than l-PAV-AuNPs treated one (Fig. 5e) These results suggested that the in vivo activation of autophagy is chirality-dependent, with d-PAV-AuNPs are more effectively inducing autophagy in vivo. Our anticancer depot especially the d-PAVAuNPs could be used as an efficient anticancer agent for future clinic application, which was demonstrated by the largely tumor suppression and negligible toxicity in vitro and in vivo
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