Two-in-One Nanoparticle Formulation to Deliver a Tyrosine Kinase Inhibitor and microRNA for Targeting Metabolic Reprogramming and Mitochondrial Dysfunction in Gastric Cancer

Yu-Li Lo; Tse-Yuan Wang; Chun-Jung Chen; Yih-Hsin Chang; Anya Maan-Yuh Lin

doi:10.3390/pharmaceutics14091759

Two-in-One Nanoparticle Formulation to Deliver a Tyrosine Kinase Inhibitor and microRNA for Targeting Metabolic Reprogramming and Mitochondrial Dysfunction in Gastric Cancer

Pharmaceutics. 2022 Aug 23;14(9):1759. doi: 10.3390/pharmaceutics14091759.

Authors

Yu-Li Lo^{1

2}, Tse-Yuan Wang¹, Chun-Jung Chen^{3

4}, Yih-Hsin Chang⁵, Anya Maan-Yuh Lin^{2

6}

Affiliations

¹ Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
² Faculty of Pharmacy, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
³ Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan.
⁴ Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung 404, Taiwan.
⁵ Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
⁶ Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan.

Abstract

Dysregulational EGFR, KRAS, and mTOR pathways cause metabolic reprogramming, leading to progression of gastric cancer. Afatinib (Afa) is a broad-spectrum tyrosine kinase inhibitor that reduces cancer growth by blocking the EGFR family. MicroRNA 125 (miR-125) reportedly diminishes EGFRs, glycolysis, and anti-apoptosis. Here, a one-shot formulation of miR-125 and Afa was presented for the first time. The formulation comprised solid lipid nanoparticles modified with mitochondrial targeting peptide and EGFR-directed ligand to suppress pan-ErbB-facilitated epithelial-mesenchymal transition and mTOR-mediated metabolism discoordination of glycolysis-glutaminolysis-lipids. Results showed that this cotreatment modulated numerous critical proteins, such as EGFR/HER2/HER3, Kras/ERK/Vimentin, and mTOR/HIF1-α/HK2/LDHA pathways of gastric adenocarcinoma AGS cells. The combinatorial therapy suppressed glutaminolysis, glycolysis, mitochondrial oxidative phosphorylation, and fatty acid synthesis. The cotreatment also notably decreased the levels of lactate, acetyl-CoA, and ATP. The active involvement of mitophagy supported the direction of promoting the apoptosis of AGS cells, which subsequently caused the breakdown of tumor-cell homeostasis and death. In vivo findings in AGS-bearing mice confirmed the superiority of the anti-tumor efficacy and safety of this combination nanomedicine over other formulations. This one-shot formulation disturbed the metabolic reprogramming; alleviated the "Warburg effect" of tumors; interrupted the supply of fatty acid, cholesterol, and triglyceride; and exacerbated the energy depletion in the tumor microenvironment, thereby inhibiting tumor proliferation and aggressiveness. Collectively, the results showed that the two-in-one nanoparticle formulation of miR-125 and Afa was a breakthrough in simplifying drug preparation and administration, as well as effectively inhibiting tumor progression through the versatile targeting of pan-ErbB- and mTOR-mediated mitochondrial dysfunction and dysregulated metabolism.

Keywords: microRNA; mitochondrial dysfunction; mitochondrial targeting; nanoparticle; tumor metabolism reprogramming; tyrosine kinase inhibitor.

Abstract

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