Ultrafast self-assembled supramolecular nanoparticles for enhanced chemodynamic therapy and ferroptosis through lactic acid metabolism regulation

• Published in: Chemical engineering journal (Lausanne, Switzerland : 1996) Switzerland : 1996), 2023-09, Vol.471, p.144563, Article 144563
• Main Authors: Meng, Qi, Tan, Jia, Tong, Weifang, Chen, Changxiao, Liu, Zhendong, Liu, Sainan, Wang, Meifang, Cheng, Ziyong, Ding, Binbin, Ma, Ping'an, Lin, Jun
• Format: Article
• Language: English
• Subjects: Enhanced chemodynamic therapy; Ferroptosis; GSH depletion; Lactic acid metabolism; Ultrafast self-assemble
• ISSN: 1385-8947; 1873-3212
• DOI: 10.1016/j.cej.2023.144563

FCP NPs are prepared through the coordination of Fe3+ and CHCA by one-pot ultrafast self-assembled method and can release Fe2+ and CHCA in the presence of overexpressed GSH. CHCA enhances Fe2+-guided CDT by regulating lactate metabolism to improve intracellular acidity, resulting in apoptosis. Besides, FCP NPs depleted intracellular GSH and downregulated GPX4 expression which further caused ferroptosis. Therefore, the as-prepared FCP NPs exhibits excellent antitumor efficiency in vitro and in vivo. ToC: The main procedure for the synthesis and antitumor mechanism of ultrafast self-assembled supramolecular nanoparticles FCP NPs. [Display omitted] •FCP NPs were prepared by one-pot ultrafast self-assembled method which is simple and fast.•FC NPs solved the problem of insufficient water solubility of CHCA, and greatly increased the drug loading rate, up to 83.5%.•FCP NPs enhanced CDT by regulating lactate metabolism to improve intracellular acidity, resulting in apoptosis and ferroptosis. Chemodynamic therapy (CDT) is an antitumor strategy based on the Fenton response. However, the mild acidity in the tumor microenvironment (TME) limits the efficiency of the Fenton response. Lactic acid has the potential to regulate pH in TME by regulating its metabolism. α-cyano-4-hydroxycinnamic acid (CHCA) can block lactate transport and induce lactate accumulation in cells, thus enhancing intracellular acidity. Nevertheless, CHCA is insoluble in water and the existing nanodrug delivery systems have complex synthesis and low drug-loading. Herein, we use Fe3+ and CHCA to form ultrahigh drug-loading supramolecular nanoparticles (FC NPs) by an ultrafast self-assembly strategy at room temperature for only 5 min. Polyethylene glycol (PEG) modified FC (FCP) NPs undergo lactate metabolism regulation-enhanced CDT in tumor cells to generate toxic hydroxyl radicals to induce apoptosis. Besides, glutathione is consumed and glutathione peroxidase 4 is down-regulated to induce ferroptosis due to the oxidation of Fe3+. In vitro and in vivo experiments show FCP induced synergetic effect of CDT and ferroptosis as well as the excellent therapeutic effect compared with either CHCA or Fe3+ alone. We believe that the ideal design of the CHCA supramolecular nanosystem will provide more revelations on the future research about CDT and lactate metabolism therapy.