Carbonic anhydrase (CA) IX overexpresses exclusively on cell membranes of hypoxic tumors, regulating the acidic tumor microenvironment. Small molecules of CA inhibitor modified with short peptide successfully achieve CA IX–targeted self-assembly that localizes CA inhibitors on hypoxic cancer cell surfaces and enhances their inhibition efficacy and selectivity. CA IX–related endocytosis also promotes selective intracellular uptake of these nanofibers under hypoxia, in which nanofiber structures increase in size with decreasing pH. This effect subsequently causes intracellular acid vesicle damage and blocks protective autophagy. The versatility of tunable nanostructures responding to cell milieu impressively provokes selective toxicities and provides strategic therapy for hypoxic tumors. Moreover, in vivo tests demonstrate considerable antimetastatic and antiangiogenesis effects in breast tumors, and particularly remarkable enhancement of antitumor efficacy in doxorubicin administration. With its biocompatible components and distinctive hypoxia therapies, this nanomaterial advances current chemotherapy, providing a new direction for hypoxic cancer therapy.
Cellular uptake and exocytosis of SWCNTs are fundamental processes determining their intracellular concentration and effects. Despite the great potential of acid-oxidized SWCNTs in biomedical field, understanding of the influencing factors on these processes needs to be deepened. Here, we quantitatively investigated uptake and exocytosis of SWCNTs in three lengths-630 (±171) nm (L-SWCNTs), 390 (±50) nm (M-SWCNTs), and 195 (±63) nm (S-MWCNTs) in macrophages. The results showed that the cellular accumulation of SWCNTs was a length-independent process and non-monotonic in time, with the most SWCNTs (3950 fg/cell) accumulated at 8 h and then intracellular SWCNTs dropped obviously with time. The uptake rate of SWCNTs decreased with increasing concentration, suggesting that intracellular SWCNTs accumulation is a saturable process. After refreshing culture medium, we found increasing SWCNTs in supernatant and decreasing intracellular SWCNTs over time, confirming the exocytosis occurred. Selective inhibition of endocytosis pathways showed that the internalization of SWCNTs involves several pathways, in the order of macropinocytosis> caveolae-mediated endocytosis> clathrin-dependent endocytosis. Intriguingly, clathrin-mediated endocytosis is relatively important for internalizing shorter SWCNTs. The dynamic processes of SWCNTs uptake and exocytosis and the mechanisms revealed by this study may render a better understanding on SWCNT toxicity and facilitate the design of CNT products with mitigated toxicity and desired functions.
Molecular self-assembly makes it feasible to harness the structures and properties of advanced materials via initial molecular design. To develop short peptide-based hydrogels with stimuli responsiveness, we designed here short amphiphilic peptides by engineering protease cleavage site motifs into self-assembling peptide sequences. We demonstrated that the designed Ac-ISLKG-NH and Ac-ISLGK-NH self-assembled into fibrillar hydrogels and that the Ac-ISLKG-NH hydrogel showed degradation in response to MMP-2 but the Ac-ISLGK-NH hydrogel did not. The cleavage of Ac-ISLKG-NH into Ac-IS and LKG-NH was found to be mechanistically responsible for the enzymatic degradation. Finally, when an anticancer peptide G(IIKK)I-NH (G3) was entrapped into Ac-ISLKG-NH hydrogels, its release was revealed to occur in a "cell-demanded" way in the presence of HeLa cells that overexpress MMP-2, therefore leading to a marked inhibitory effect on their growth on the gels.
The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/smll.201907665. Engineered nanomaterials (ENMs) are used in food additives, food packages, and therapeutic purposes owing to their useful properties, Therefore, human beings are orally exposed to exogenous nanomaterials frequently, which means the intestine is one of the primary targets of nanomaterials. Consequently, it is of great importance to understand the interaction between nanomaterials and the intestine. When nanomaterials enter into gut lumen, they inevitably interact with various components and thereby display different effects on the intestine based on their locations; these are known as location-oriented effects (LOE).
The intestinal LOE confer a new biological-effect profile for nanomaterials, which is dependent on the involvement of the following biological processes: nanomucus interaction, nano-intestinal epithelial cells (IECs) interaction, nanoimmune interaction, and nano-microbiota interaction. A deep understanding ofNM-induced LOE will facilitate the design of safer NMs and the development of more efficient nanomedicine for intestine-related diseases. Herein, recent progress in this field is reviewed in order to better understand the LOE of nanomaterials. The distant effects of nanomaterials coupling with microbiota are also highlighted. Investigation of the interaction of nanomaterials with the intestine will stimulate other new research areas beyond intestinal nanotoxicity. www.advancedsciencenews.com
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