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

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.