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

ABSTRACT: 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.

SUBMITTER: Wang J

PROVIDER: S-EPMC9218170 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

Wang Jinping J Qu Chang C Shao Xinyue X Song Guoqiang G Sun Jingyu J Shi Donghong D Jia Ran R An Hailong H Wang Hongjun H

Bioactive materials 20220618

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>i.e</i>., Mn-ZnO<sub>2</sub> nanoparticles) was developed for concurrent delivery of dual Zn-Mn ions and reactive oxygen species (ROS) within tumor to regulate the p53 prot ...[more]

PMID: 35784636

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Project description:Dual functional drug carrier has been a modern strategy in cancer therapy because it is a platform to elicit additive and synergistic effects through combination therapy. Photo-activated external stimuli such as reactive oxygen species (ROS) also ensure adequate drug delivery in a precise temporal and spatial manner. However, current ROS-responsive drug delivery systems usually require tedious synthetic procedures. A facile one-pot approach has been reported herein, to obtain self-assembled polymeric nanocarriers (NCs) for simultaneous paclitaxel (PTX)- and Rose Bengal (RB)-loading to achieve combined chemo-photodynamic therapy and controlled drug release in responsive to a light-induced ROS stimulus. To encapsulate these hydrophobic and hydrophilic drugs, chitosan (CTS), branched polyethylenimine (bPEI) and polyvinyl alcohol (PVA) were selected and fabricated into nanoblended matrices through an oil-in-water emulsion method. The amphiphilic properties of CTS permit simultaneous entrapment of PTX and RB, while the encapsulation efficiency of RB was further improved by increasing the amount of short-chain bPEI. During the one-step assembly process, bovine serum albumin (BSA) was also added to condense the cationic tripolymer mixtures into more stable nanocarriers (BNCs). Hyaluronic acid (HA) was subsequently grafted onto the surface of BNCs through electrostatic interaction, leading to the formation of HA-BSA/CTS/PVA/bPEI-blended nanocarriers (HBNCs) to achieve an efficient prostate-cancer-cell uptake. Importantly, in response to external light irradiation, HBNCs become destabilized owing to the RB-mediated photodynamic action. It allows an on-demand dual-payload release to evoke a simultaneous photodynamic and chemo treatment for cancer cell eradication. Thus, HBNCs present a new promising approach that exhibits a specific vulnerability to RB-induced photosensitization. The consequent dual-cargo release is also expected to successfully combat cancer through a synergistic anti-tumor effect.

Dataset Information

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

Publications

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

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