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

• Published in: Small (Weinheim an der Bergstrasse, Germany) Germany), 2022-09, Vol.18 (38), p.e2203080-n/a
• Main Authors: Li, Yongcan, Huang, Jiansen, Yu, Honglian, Zhao, Yinmin, Xu, Zhigang, Kang, Yuejun, Xue, Peng
• Format: Article
• Language: English
• Subjects: Apoptosis; Catalase; Cell death; Combinatorial analysis; Energy gap; Hydroxyl radicals; Hyperthermia; Nanocrystals; Nanotechnology; nano‐sonosensitizers; nano‐zirconia; reactive oxygen species; Singlet oxygen; sonodynamic therapy; Thermal shock; thermodynamic therapy; Thermodynamics; Tumors; Ultrasonic imaging; Zirconium dioxide
• ISSN: 1613-6810; 1613-6829
• DOI: 10.1002/smll.202203080

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. A ZrO2−x@Pt/AIPH nanotherapeutic platform established by the conjugation of 2,2′‐azobis[2‐(2‐imidazolin‐2‐yl)propane] dihydrochloride onto ZrO2−x@Pt Schottky junction is successfully applied for the promoted sonodynamic/thermodynamic therapy under ultrasound activation. Apart from the primary tumor inhibition, this therapeutic regimen is also devoted to restraining the distant metastasis with the aid of a PD‐1/PD‐L1 immune checkpoint blockade.