Tumor microenvironment-activated, immunomodulatory nanosheets loaded with copper(II) and 5-FU for synergistic chemodynamic therapy and chemotherapy

Yi Xia; Muge Gu; Jiayu Wang; Xiangqi Zhang; Tianyi Shen; Xiaoying Shi; Wei-En Yuan

doi:10.1016/j.jcis.2023.09.042

Tumor microenvironment-activated, immunomodulatory nanosheets loaded with copper(II) and 5-FU for synergistic chemodynamic therapy and chemotherapy

J Colloid Interface Sci. 2024 Jan;653(Pt A):137-147. doi: 10.1016/j.jcis.2023.09.042. Epub 2023 Sep 9.

Authors

Yi Xia¹, Muge Gu¹, Jiayu Wang¹, Xiangqi Zhang¹, Tianyi Shen¹, Xiaoying Shi¹, Wei-En Yuan²

Affiliations

¹ Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, China; Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China; National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai 200240, China.
² Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, China; Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China; National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: yuanweien@sjtu.edu.cn.

PMID: 37713912
DOI: 10.1016/j.jcis.2023.09.042

Abstract

The tumor microenvironment (TME) has a redox state that differs greatly from normal tissues, as characterized by the overexpression of H₂O₂ and glutathione (GSH). To address the GSH-related restrictions on chemodynamic therapy (CDT) efficacy, we have developed a Cu(II)-based CDT strategy. In this study, a novel organic-inorganic hybrid drug delivery system (LDH/HA/5-FU) was conceived and prepared by the intercalation of 5-FU into the interlayer of copper-aluminum layered double hydroxide (CuAl-LDH) via ion exchange strategy and the adsorption of hyaluronic acid (HA) on the surface of CuAl-LDH. Taking advantage of the pH-degradable property of CuAl-LDH and the CD44-targeting property of HA, the formed LDH/HA/5-FU nanosheets could specifically target tumor cells' overexpressing CD44 receptor, rapidly release Cu(II) and 5-FU in tumor cells, inducing tumor cell apoptosis and cuproptosis, and long-term intracellular GSH depletion and toxic hydroxyl radicals (·OH) generation could be achieved through the cyclic catalytic reaction of Cu(I)/Cu(II). Meanwhile, peritumoral injection of LDH/HA/5-FU nanosheets might function as an adjuvant to increase the levels of antitumor tumor-associated macrophages (TAMs) and T cells. In vivo experiments further verified that the intelligently designed LDH/HA/5-FU nanosheets successfully promoted the immune systems, with an excellent inhibition efficacy towards tumors by combining Cu-based CDT and chemotherapy, showing promising potential for solid tumor treatments.

Keywords: Chemodynamic therapy; Chemotherapy; CuAl-layered double hydroxide; Immune regulation; Tumor.