Tumor-activatable biomineralized nanotherapeutics for integrative glucose starvation and sensitized metformin therapy
| Autor: | Menghuan Li, Ruisi Cai, Yan Hu, Zhong Luo, Xuan Wang, Chencheng Xue, Yanan Li, Xuemei Yao, Hong Wen, Yang Fei |
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| Rok vydání: | 2021 |
| Předmět: |
Drug
media_common.quotation_subject Biophysics Bioengineering Context (language use) Biomaterials Glucose Oxidase chemistry.chemical_compound Downregulation and upregulation Cell Line Tumor Neoplasms medicine Animals Humans Glucose oxidase media_common biology Hydrogen Peroxide Protein phosphatase 2 Metformin Glucose chemistry Mechanics of Materials Ceramics and Composites biology.protein Gluconic acid Cancer research Intracellular medicine.drug |
| Zdroj: | Biomaterials. 278:121165 |
| ISSN: | 0142-9612 |
| DOI: | 10.1016/j.biomaterials.2021.121165 |
| Popis: | 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 H2O2, 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. |
| Databáze: | OpenAIRE |
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