Zirconia‐Platinum Nanohybrids for Ultrasound‐Activated Sonodynamic‐Thermodynamic Bimodal Therapy by Inducing Intense Intracellular Oxidative Stress

Abstract

The therapeutic exploration of nano‐zirconia semiconductor largely remains untouched in the field of fundamental science to date. Here, a robust nano‐sonosensitizer of ZrO2−x@Pt is strategically formulated by in situ growth of Pt nanocrystal onto the surface of oxygen‐deficient ZrO2−x. Compared to 3.09 eV of nano‐ZrO2−x, the bandgap of ZrO2−x@Pt Schottky junction is narrowed down to 2.74 eV. The band bending and bandgap narrowing enables an enhanced e−/h+ separation in the presence of aPt electron sink, which facilitates a high yield of singlet oxygen (1O2) and hydroxyl radicals (·OH) under ultrasound (US) irradiation. Moreover, nanozyme Pt with catalase‐mimic activity can promote 1O2 generation by relieving the hypoxic tumor microenvironment. Upon further modification of 2,2′‐azobis[2‐(2‐imidazolin‐2‐yl)propane] dihydrochloride (AIPH), US‐stimulated local thermal shock can disintegrate AIPH to create cytotoxic alkyl radicals (•R). US‐triggered reactive oxygen species generation and hyperthermia‐induced alkyl radical production lead to severe and irreversible tumor cell death. Such combinatorial sonodynamic‐thermodynamic therapy benefits the tumor eradication and metastasis inhibition at the animal level, with the aid of immunogenetic cell death and immune checkpoint blockade. Taken together, this proof‐of‐concept paradigm expands the medical use of nano‐zirconia and provides useful insights for its therapeutic perspectives.

Advances in Nanodynamic Therapy for Cancer Treatment

“…This combination of ROS and thermally induced alkyl radicals leads to irreversible degradation of tumor cells. In cellular experiments, the "ZPA + US + H 2 O 2 " treatment resulted in the strongest green fluorescence of CRT on the membrane of 4T1 cells, the highest level of HMGB1 fluorescence attenuation, and the lowest intracellular ATP levels, with the highest extracellular ATP content [41]. These results suggest that under the enhanced action of SDT, ZPA induces ICD, triggering the secretion of multiple DAMPs, which is conducive to reversing immune suppression and improving anti-tumor efficacy.…”

Ultrasound-Based Micro-/Nanosystems for Biomedical Applications

“…The generation of ROS triggered by ultrasound and the hyperthermia-induced production of alkyl radicals result in severe and irreversible tumor cell death (Figure 50e, f). 1088 Based on Fenton or Fenton-like reactions, CDT creates serious oxidative damage without requiring outside stimulation by converting intracellular overexpressed H 2 O 2 into highly lethal •OH in the tumor microenvironments. 1089 Due to the hypoxic environment in solid tumors, SDT exhibits a diminished therapeutic effect.…”

“…(f) Weight of the solid tumor dissected on day 14. Reprinted with permission from ref . Copyright 2022 John Wiley and Sons.…”

Surface Chemistry of Biologically Active Reducible Oxide Nanozymes

“…In support of this, a Li et al provided evidence of catalytic activity using 𝛼-amylase, an enzyme involved in the breakdown of sucrose via a (hydroxyapatite) HA-ZrO 2 nanocomposite. [100] The enzyme's activity was compared to the standard K M values of amylase. A lower value of K M led to an increase in nanocomposite enzyme efficiency.…”