2019) Chitosan nanoparticles induced the antitumor effect in hepatocellular carcinoma cells by regulating ROSmediated mitochondrial damage and endoplasmic reticulum stress, Artificial Cells, Nanomedicine, and Biotechnology, 47:1, 747-756, ABSTRACTIn recent years, numerous studies have confirmed the role of chitosan nanoparticles (CS NPs) as a promising drug delivery carrier for improving the efficiency of anticancer drug in the treatment of cancer. However, the possible biological effects of CS NPs on tumour cells and underlying mechanisms are still unclear. Recently, reactive oxygen species (ROS)-mediated cell apoptosis has been implicated in the regulation of cell death. In this study, we found that CS NPs induced the massive generation of ROS and resulted in apoptosis of hepatocellular carcinoma cells (SMMC-7721) through activating the mitochondrial pathway and endoplasmic reticulum stress. These results suggest an important role of ROS in CS NPs-induced cancer cell death. ARTICLE HISTORY

There is a close relationship between autophagy and apoptosis during cancer cell death. We used chitosan nanoparticles (CS NPs) to explore the effects of internalized NPs on the induction of autophagy and to confirm the role of autophagic responses elicited by nanomaterials on the tumour cell's fate. CS NPs at nontoxic concentrations ranging from 10-100 μg/mL triggered the induction of autophagy. With the addition of CS NPs, the aggregation of endogenous LC3 was significantly enhanced and acidic autophagic bodies had been accumulated. CS NPs significantly triggered the occurrence of autophagy by increasing the ratio of LC3 II to LC3 I and CS NPs-mediated autophagy was implicated in reactive oxygen species (ROS) generation and the ROS scavenger N-acetylcysteine (NAC) attenuated CS-induced autophagy. The addition of blank NPs produced a negative effect on cytotoxicity and cellular apoptosis of free Dox, and with the pre-treatment of chloroquine (CQ) as a known autophagy inhibitor, the inhibition rates of cells treated with the combination of Dox and blank CS NPs had been significantly increased. The findings demonstrated that CS NPs have the ability to induce protective autophagy via ROS generation and they were believed to inhibit tumour cell death.

Mitochondria as an important organ in eukaryotic cells produced energy through oxidative phosphorylation and also played an important role in regulating the apoptotic signal transduction process. Importantly, mitochondria like nuclei also contained the functional DNA and were very sensitive to anticancer drugs which could effectively inhibit the synthesis of nucleic acid, especially the production of DNA. In this work, we designed novel triphenyl phosphine (TPP)-conjugated chitosan (CS) nanoparticles (NPs) for efficient drug delivery to cell mitochondria. The results showed that compared with free doxorubicin (Dox), Dox-loaded TPP-NPs were specifically distributed in mitochondria of tumor cells and interfered with the function of mitochondria, thus resulted in the higher cytotoxicity and induced the significant cell apoptosis effect. Taken together, triphenyl phosphine-conjugated chitosan nanoparticles may become a promising mitochondria-targeting nanocarrier candidate for enhancing antitumor effects.

Artemisinin and its derivatives were considered to exert a broad spectrum of anti-cancer activities, and they induced significant anti-cancer effects in tumor cells. Artemisinin and its derivatives could be absorbed quickly, and they were widely distributed, selectively killing tumor cells. Since low concentrations of artesunate primarily depended on oncosis to induce cell death in tumor cells, its anti-tumor effects were undesirable and limited. To obtain better anti-tumor effects, in this study, we took advantage of a new nanotechnology to design novel artesunate-loaded bovine serum albumin nanoparticles to achieve the mitochondrial accumulation of artesunate and induce mitochondrial-mediated apoptosis. The results showed that when compared with free artesunate’s reliance on oncotic death, artesunate-loaded bovine serum albumin nanoparticles showed higher cytotoxicity and their significant apoptotic effects were induced through the distribution of artesunate in the mitochondria. This finding indicated that artesunate-loaded bovine serum albumin nanoparticles damaged the mitochondrial integrity and activated mitochondrial-mediated cell apoptosis by upregulating apoptosis-related proteins and facilitating the rapid release of cytochrome C.

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