Issue 44, 2023

Carbonized polymer dots derived from metformin and l-arginine for tumor cell membrane- and mitochondria-dual targeting therapy

Abstract

Metformin has demonstrated antitumor potential in clinical studies; however, achieving optimal antitumor effects requires administering an extremely safe medication dose. To enhance the efficacy and reduce dosage requirements, we propose the creation of large-molecule drugs through the combination of small-molecule drugs. In this study, we developed novel polymer dots, referred to as MA-dots, with sizes of approximately 5 nm, featuring dual targeting capabilities for tumor cell membranes and mitochondria. MA-dots were synthesized using metformin and L-arginine via a rapid microwave-assisted method. Notably, the resulting MA-dots (with a half maximal inhibitory concentration (IC50) of 93.60 μg mL−1) exhibited more than a 12-fold increase in antitumor activity compared to the raw metformin material (IC50 = 1159.00 μg mL−1) over a 24-hour period. In addition, our MA-dots outperformed most metformin-derived nanodrugs in terms of antitumor efficacy. Furthermore, oral gavage treatment with MA-dots led to the suppression of A549 (lung cancer cell lines) tumor growth in vivo. Mechanistic investigations revealed that MA-dots bound to the large neutral amino acid transporter 1 (LAT1) proteins, which are overexpressed in malignant tumor cell membranes. Moreover, these MA-dots accumulated within the mitochondria, leading to increased production of reactive oxygen species (ROS), mitochondrial damage, and disruption of energy metabolism by modulating the 5'-adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in tumor cells. This cascade of events triggers cell-cycle arrest and apoptosis. In summary, this study presented a rapid method for fabricating a novel nanoderivative, MA-dots, capable of both tumor targeting and exerting tumor-suppressive effects.

Graphical abstract: Carbonized polymer dots derived from metformin and l-arginine for tumor cell membrane- and mitochondria-dual targeting therapy

Supplementary files

Article information

Article type
Paper
Submitted
17 avq 2023
Accepted
12 okt 2023
First published
18 okt 2023

Nanoscale, 2023,15, 17922-17935

Carbonized polymer dots derived from metformin and L-arginine for tumor cell membrane- and mitochondria-dual targeting therapy

M. Chen, Y. Li, Y. Liu, B. Jia, X. Liu and T. Ma, Nanoscale, 2023, 15, 17922 DOI: 10.1039/D3NR04145J

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