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

Abstract

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.

Augmented EPR effect post IRFA to enhance the therapeutic efficacy of arsenic loaded ZIF-8 nanoparticles on residual HCC progression

“…However, the poor bioavailability and narrow drug safety window of ATO severely restrict its clinical applications [ 23 ]. Specifically, as a water-soluble drug, ATO shows low delivery efficiency and rapid renal elimination, which inhibit its accumulation in the tumor site [ 24 – 26 ]. Therefore, to achieve the desired therapeutic effect, a large dose of ATO is required, but this high dose can lead to serious hepatotoxicity and nephrotoxicity [ 23 , 26 ].…”

Iodide Analogs of Arsenoplatins—Potential Drug Candidates for Triple Negative Breast Cancers

“…The toxicities of APs are comparable to the toxicity of ATO, except for AP-5, which is significantly more toxic than ATO. Although ATO showed potency against many solid tumors in vitro [ 44 ], ATO suffers from rapid renal clearance in vivo [ 45 , 46 , 47 ]; therefore, an intense search to develop methods to deliver ATO to solid tumors is ongoing [ 12 , 47 , 48 , 49 ]. APs may be a simple solution to this problem, as they can deliver platinum and arsenic pharmacophores simultaneously.…”

Nanomaterials responding to microwaves: an emerging field for imaging and therapy

“…Interestingly, zirconium dioxides have also been suggested as drug delivery vehicles. 103 In this study, ZrO 2 nanospheres were loaded with the cancer therapeutic arsenic trioxide (which functions through the damage of the mitochondria), as well as the mitochondrial targeting ligand TPP (triphenylphosphine). The composites were also modified with tetradecanol for temperature sensitive release upon the application of microwave hyperthermia.…”