Tumor-activatable biomineralized nanotherapeutics for integrative glucose starvation and sensitized metformin therapy. (November 2021)

• Record Type: Journal Article
• Authors: Wen, Hong; Fei, Yang; Cai, Ruisi; Yao, Xuemei; Li, Yanan; Wang, Xuan; Xue, Chencheng; Hu, Yan; Li, Menghuan; Luo, Zhong
• Is Part Of: Biomaterials. Volume 278(2021)
• Publication Date: 2021-11
• Subjects: Sensitized metformin therapy -- Tumor starvation -- Biomineralized nanoplatforms -- MCL-1-Depdent tumor survival cascade -- Combinational tumor therapy; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2021.121165
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Metformin is a clinically-approved anti-diabetic drug with emerging antitumor potential, but its antitumor activity is highly susceptible to local glucose abundance. Herein, we construct a nanotherapeutic platform based on biocompatible constituents to sensitize tumor cells for metformin therapy via cooperative glucose starvation. The nanoplatform was synthesized through the spontaneous biomineralization of glucose oxidase (GOx) and metformin in amorphous calcium phosphate nanosubstrate, which was further modified with polyethylene glycol and cRGD ligands. This biomineralized nanosystem could efficiently deliver the therapeutic payloads to tumor cells in a targeted and bioresponsive manner. Here GOx could catalyze the oxidation of glucose into gluconic acid and H2 O2, thus depleting the glucose in tumor intracellular compartment while accelerating the release of the entrapped therapeutic payloads. The selective glucose deprivation would not only disrupt tumor energy metabolism, but also upregulate the PP2A regulatory subunit B56δ and sensitize tumor cells to the metformin-induced CIP2A inhibition, leading to efficient apoptosis induction via PP2A-GSK3β-MCL-1 axis with negligible side effects. This study may offer new avenues for targeted tumor therapy in the clinical context.