Carrier-free nanoprodrug for p53-mutated tumor therapy via concurrent delivery of zinc-manganese dual ions and ROS

• Published in: Bioactive materials Vol. 20; pp. 404 - 417
• Main Authors: Wang, Jinping, Qu, Chang, Shao, Xinyue, Song, Guoqiang, Sun, Jingyu, Shi, Donghong, Jia, Ran, An, Hailong, Wang, Hongjun
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.02.2023; KeAi Publishing; KeAi Communications Co., Ltd
• Subjects: Carrier-free nanoprodrug; Mn-ZnO2 nanoparticle; p53-mutated tumor therapy; Reactive oxygen species; Wild-type p53 protein; Reactive oxygen species; p53-mutated tumor therapy; Mn-ZnO2 nanoparticle; Wild-type p53 protein; Carrier-free nanoprodrug
• DOI: 10.1016/j.bioactmat.2022.06.005
• ISSN: 2452-199X

Human cancers typically express a high level of tumor-promoting mutant p53 protein (Mutp53) with a minimal level of tumor-suppressing wild-type p53 protein (WTp53). In this regard, inducing Mutp53 degradation while activating WTp53 is a viable strategy for precise anti-tumor therapy. Herein, a new carrier-free nanoprodrug (i.e., Mn-ZnO2 nanoparticles) was developed for concurrent delivery of dual Zn-Mn ions and reactive oxygen species (ROS) within tumor to regulate the p53 protein for high anti-tumor efficacy. In response to the mild tumor acidic environment, the released Zn2+ and H2O2 from Mn-ZnO2 NPs induced ubiquitination-mediated proteasomal degradation of Mutp53, while the liberative Mn2+ and increased ROS level activated the ATM-p53-Bax pathway to elevate WTp53 level. Both in vitro and in vivo results demonstrated that pH-responsive decomposition of Mn-ZnO2 NPs could effectively elevate the intracellular dual Zn-Mn ions and ROS level and subsequently generate the cytotoxic hydroxyl radical (•OH) through the Fenton-like reaction. With the integration of multiple functions (i.e., carrier-free ion and ROS delivery, tumor accumulation, p53 protein modulation, toxic •OH generation, and pH-activated MRI contrast) in a single nanosystem, Mn-ZnO2 NPs demonstrate its superiority as a promising nanotherapeutics for p53-mutated tumor therapy. Schematic illustration of the sysnthesis of carrier-free nanoprodrugs for p53-mutated tumor therapy by co-delivering zinc-manganese dual ions and ROS to modulate Mutp53 degradation and WTp53 activation. [Display omitted] •Demonstrate the efficacy of multifunctional nanoparticles in degrading mutant p53 while activating wide-type p53.•Develop “carrier-free nanoprodrug” for pH-induced delivery of dual ions (Zn2+, Mn2+) and H2O2 with reduced side effects.•Readily extend the simple, green, yet efficient synthesis route to other ion-doped metal peroxide nanoparticles.