Delivery of Arsenic Trioxide by Multifunction Nanoparticles To Improve the Treatment of Hepatocellular Carcinoma

• Published in: ACS applied materials & interfaces 2020-02, Vol.12 (7), p.8016-8029
• Main Authors: Wu, Qirun, Chen, Xiaowei, Wang, Peng, Wu, Qiong, Qi, Xun, Han, Xiangjun, Chen, Lufeng, Meng, Xianwei, Xu, Ke
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Arsenic Trioxide - administration & dosage; Arsenic Trioxide - pharmacology; Arsenic Trioxide - therapeutic use; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Cell Movement - drug effects; Cell Proliferation - drug effects; Delayed-Action Preparations; Drug Carriers - chemistry; Drug Liberation; Hep G2 Cells; Humans; Hyperthermia, Induced - instrumentation; Hyperthermia, Induced - methods; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Liver Neoplasms - therapy; Male; Membrane Potential, Mitochondrial - drug effects; Mice; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Mitochondria - drug effects; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Particle Size; Xenograft Model Antitumor Assays; Zirconium - chemistry
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.9b22802

Arsenic trioxide (ATO) is effective in the treatment of hematological malignancies and solid tumors. However, its toxicity and side effects are severe, posing an obstacle in its clinical application. A controlled-release ATO carrier with mitochondrial targeting was constructed in this study. The safety and efficacy in vitro were investigated using a hemolysis test, cytotoxicity, proliferation, migration, apoptosis, and other changes in cell behavior. The safety and efficacy were further evaluated in vivo by hematoxylin–eosin staining, terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling staining, and blood testing in tumor-bearing mice. Immunohistochemically and western blotting experiments were conducted to explore the mechanism of combination therapy of material-based chemotherapy and microwave hyperthermia in vitro. We demonstrated that the nano-zirconia (ZrO2) loading platform may be used to administer the ATO, with local precision-controlled release and mitochondrial targeting. Furthermore, we showed the safety of this approach for delivering high doses of ATO. In addition, we explored this new method in combination with in vitro microwave heat therapy, providing a potentially novel intravenous approach to chemotherapy. We described a new non-invasive treatment that improved the efficacy of ATO chemotherapy against hepatocellular carcinoma through nano-ZrO2 carriers.