Mitochondrion-Directed Nanoparticles Loaded with a Natural Compound and a microRNA for Promoting Cancer Cell Death via the Modulation of Tumor Metabolism and Mitochondrial Dynamics

Abstract

Mitochondrial dysfunction may cause cancer and metabolic syndrome. Ellagic acid (abbreviated as E), a phytochemical, possesses anticancer activity. MicroRNA 125 (miR-125) may regulate metabolism. However, E has low aqueous solubility, and miR-125 is unstable in a biological fluid. Hence, this study aimed to develop nanoparticle formulations for the co-treatment of miR-125 and E. These nanoparticles were modified with one mitochondrion-directed peptide and a tumor-targeted ligand, and their modulating effects on mitochondrial dysfunction, antitumor efficacy, and safety in head and neck cancer (HNC) were evaluated. Results revealed that miR-125- and E-loaded nanoparticles effectively targeted cancer cells and intracellular mitochondria. The co-treatment significantly altered cellular bioenergetics, lipid, and glucose metabolism in human tongue squamous carcinoma SAS cells. This combination therapy also regulated protein expression associated with bioenergenesis and mitochondrial dynamics. These formulations also modulated multiple pathways of tumor metabolism, apoptosis, resistance, and metastasis in SAS cells. In vivo mouse experiments showed that the combined treatment of miR-125 and E nanoparticles exhibited significant hypoglycemic and hypolipidemic effects. The combinatorial therapy of E and miR-125 nanoparticles effectively reduced SAS tumor growth. To our best knowledge, this prospective study provided a basis for combining miRNA with a natural compound in nanoformulations to regulate mitochondrial dysfunction and energy metabolism associated with cancer.

Potential roles and molecular mechanisms of phytochemicals against cancer

“…However, due to the various bottlenecks, especially the poor pharmacokinetics and low potency of natural phytochemicals, future studies should focus on promoting the bioavailability of phytochemicals with new formulations or developing more potent analogues, such as nano-based drug delivery systems, 24 phytochemical-loaded chitosan-pectin core-shell nanoparticles, 26 glycosylation agents, 110 and functional snacks containing encapsulated phytochemicals, 111 to enhance the polarity and lighten the weak pharmacokinetic profile of natural products, facilitating their anti-cancer efficacy and even their conversion from bench to bedside. Furthermore, more studies should aim at designing and fabricating a novel nanocomplex for co-encapsulating two or multiple phytochemicals, which enable them to have synergistic anti-cancer potency.…”

“…Phytochemicals, with natural plants being their potential sources and which include flavonoids, polyphenols, terpenoids, alkaloids, saponins, coumarins and so on, could target diverse signaling pathways, which may be a favorable way to block cancer progression and chemotherapy drug resistance. 15–38…”

Subcellular delivery of lipid nanoparticles to endoplasmic reticulum and mitochondria

“…Specifically, Irinotecan was efficiently delivered to the tumor mitochondria for targeted killing, while miR-200 suppressed tumor metastasis and increased tumor cell sensitivity to chemotherapy. Similarly, KLA-modified lipid nanoparticles were reported to load phytochemical agent Ellagic acid and miR-125 for a combinatorial therapy with effective inhibition of human tongue squamous carcinoma SAS cells (Lo et al, 2020).…”

Regulation of Mitochondrial Quality Control by Natural Drugs in the Treatment of Cardiovascular Diseases: Potential and Advantages

“…Natural drugs and active ingredients can also regulate MQC by modulating mitophagy, which may become a new strategy in the treatment of CVDs (Feng et al, 2017;Lo et al, 2020). Catalpol (CTL) increases myocardial mitophagy induced by glucose starvation and plays a protective role in the cardiomyocytes.…”

“…As described above, natural drugs can control the quality of mitochondria by regulating their fission/fusion and energy metabolism, and autophagy, maintaining normal mitochondrial function (Takanashi et al, 2017;Arauna et al, 2019). As such, the effect of natural drugs on mitochondrial function has been investigated in previous studies on the material basis of natural drugs (Zhou H. et al, 2018;Lo et al, 2020). As shown in Figure 1 and Table 2, various natural drugs and active ingredients can protect mitochondrial function and structure by regulating MQC, and their effectiveness has been preliminarily verified in experimental studies of coronary atherosclerotic heart disease (CHD), acute myocardial infarction (AMI), heart failure (HF), myocardial I/R injury, and other CVDs.…”