Anti-alcoholism drug disulfiram for targeting glioma energy metabolism using BBB-penetrating delivery of fixed-dose combination. (June 2022)

• Record Type: Journal Article
• Authors: Zhao, Pengfei; Qu, Jingkun; Wu, Aihua; Wang, Shuang; Tang, Xueping; Ou, Ante; Zhang, Jiaxin; Xu, Yi; Zhao, Qiang; Huang, Yongzhuo
• Is Part Of: Nano today. Volume 44(2022)
• Publication Date: 2022-06
• Subjects: Fixed-dose codelivery -- Glioma -- Energy metabolism -- Tumor immune microenvironment -- Disulfiram -- Shikonin -- Immunogenic cell death -- Tumor-associated macrophage; 2-DG 2-deoxyglucose -- ALDH1L1 aldehyde dehydrogenase 1 family member L1 -- ATP adenosine triphosphate -- BBB blood-brain barrier -- BCEC brain capillary endothelial cells -- BMDM bone marrow-derived macrophage -- BSA NP bovine serum albumin nanoparticle -- BSA/LF NP albumin/lactoferrin hybrid nanoparticle -- CI combination index -- CRT calreticulin -- CTLs cytotoxic T lymphocytes -- DC dendritic cells -- DHFR dihydrofolate reductase -- DSF disulfiram -- FA fluoroacetate -- GM-CSF granulocyte-macrophage colony-stimulating factor -- HMGB-1 high mobility group box 1 -- IC50 semi-inhibitory concentration -- ICD immunogenic cell death -- IFN-γ interferon-gamma -- IL-4 interleukin-4 -- LF lactoferrin -- Lipo-Clo clodronate liposomes -- LPS lipopolysaccharide -- LRP-1 low-density lipoprotein-related protein-1 -- M-CSF macrophage colony-stimulating factor -- Metf metformin -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- MTX methotrexate -- MΦ macrophage -- NADH the reduced form of nicotinamide adenine dinucleotide -- PHGDH phosphoglycerate dehydrogenase -- PKM2 pyruvate kinase isozyme type M2 -- SHK shikonin -- SPARC secreted protein acidic and rich in cysteine -- TAMs tumor-associated macrophages -- TGF-β1 transforming growth factor-beta1 -- THF tetrahydrofolate -- TIME tumor immune microenvironment -- TNF-α tumor necrosis factor-alpha -- Tregs regulatory T cells; Nanotechnology -- Periodicals; Nanosciences -- Périodiques; 620.505
• DOI: 10.1016/j.nantod.2022.101448
• Languages: English
• ISSNs: 1748-0132

Abstract

Highlights: It was demonstrated a two-pronged strategy of ATP energy depletion for anti-glioma. It was revealed that the ATP depletion by ALDH1L1 inhibition is a new molecular mechanism of disulfiram. A BBB-penetrating protein-based nanohybrid was developed to achieve a fixed-dose ratio delivery for combination therapy. Graphical Abstract: ga1 Abstract: The interconnection between tumor metabolism and the immune microenvironment governs the progression of glioma. It was revealed that the metabolic enzymes ALDH1L1 and PKM2 were overexpressed in glioma. We discovered that the anti-alcoholism drug disulfiram (DSF) can intervene in the tumor energy metabolism by inhibiting ATP supply via an alternative pathway, of which ALDH1L1 is an essential enzyme in the 10-formyl-tetrahydrofolate-NADH-ATP metabolism axis. We thus proposed a dual-inhibition strategy by using a combination therapy of a PKM2 inhibitor shikonin (SHK) and an ALDH1L1 inhibitor DSF. By simultaneously inhibiting glycolysis and NADH-ATP metabolism, the ATP generation in the tumor cells can be efficiently cut down. A BBB-penetrating hybrid albumin/lactoferrin nanosystem (termed BSA/LF NP) was developed for biomimetic codelivery of DSF/SHK for anti-glioma therapy. Due to the overexpression of SPARC and LRP-1 in both the BBB and glioma cells, the BSA/LF NP could efficiently enter the glioma. More importantly, it can deliver a fixed-dose ratio of DSF and SHK to the glioma, providing a basis for synergistic effect in combination therapy. The BSA/LF NP effectively prolonged the survival of glioma mice by interactive modulation of energy metabolism (via both glycolysis and NADH-ATP pathways) and immune microenvironment. The work provided a promising glioma-targeting strategy for a fixed-dose combination and a potent ATP-depletion treatment.