PMID- 37902070
OWN - NLM
STAT- MEDLINE
DCOM- 20231117
LR  - 20231117
IS  - 2040-3372 (Electronic)
IS  - 2040-3364 (Linking)
VI  - 15
IP  - 44
DP  - 2023 Nov 16
TI  - Carbonized polymer dots derived from metformin and L-arginine for tumor cell 
      membrane- and mitochondria-dual targeting therapy.
PG  - 17922-17935
LID - 10.1039/d3nr04145j [doi]
AB  - 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 (IC(50)) of 
      93.60 mug mL(-1)) exhibited more than a 12-fold increase in antitumor activity 
      compared to the raw metformin material (IC(50) = 1159.00 mug 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.
FAU - Chen, Manling
AU  - Chen M
AD  - Institute of Clean Energy Chemistry, Key Laboratory for Green Synthesis and 
      Preparative Chemistry of Advanced Materials, College of Chemistry, Liaoning 
      University, Shenyang 110036, Liaoning, P. R. China. liuxue@lnu.edu.cn.
FAU - Li, Yang
AU  - Li Y
AD  - Department of Cell Biology, Key Laboratory of Cell Biology of Ministry of Public 
      Health, Key Laboratory of Medical Cell Biology of Ministry of Education, China 
      Medical University, Shenyang 110122, Liaoning, P. R. China.
FAU - Liu, Yangcheng
AU  - Liu Y
AD  - School of Pharmaceutical Science, Liaoning University, Shenyang 110036, Liaoning, 
      P. R. China.
FAU - Jia, Baohua
AU  - Jia B
AD  - School of Science, STEM College, RMIT University, Melbourne, VIC 3000, Australia. 
      tianyi.ma@rmit.edu.au.
FAU - Liu, Xue
AU  - Liu X
AUID- ORCID: 0000-0001-5187-0354
AD  - Institute of Clean Energy Chemistry, Key Laboratory for Green Synthesis and 
      Preparative Chemistry of Advanced Materials, College of Chemistry, Liaoning 
      University, Shenyang 110036, Liaoning, P. R. China. liuxue@lnu.edu.cn.
FAU - Ma, Tianyi
AU  - Ma T
AUID- ORCID: 0000-0002-1042-8700
AD  - School of Science, STEM College, RMIT University, Melbourne, VIC 3000, Australia. 
      tianyi.ma@rmit.edu.au.
LA  - eng
PT  - Journal Article
DEP - 20231116
PL  - England
TA  - Nanoscale
JT  - Nanoscale
JID - 101525249
RN  - 9100L32L2N (Metformin)
RN  - 94ZLA3W45F (Arginine)
RN  - 0 (Reactive Oxygen Species)
SB  - IM
MH  - Humans
MH  - *Metformin/pharmacology
MH  - Cell Line, Tumor
MH  - *Lung Neoplasms/drug therapy
MH  - Cell Membrane/metabolism
MH  - Mitochondria/metabolism
MH  - Arginine
MH  - Apoptosis
MH  - Cell Proliferation
MH  - Reactive Oxygen Species/metabolism
EDAT- 2023/10/30 12:41
MHDA- 2023/11/17 15:24
CRDT- 2023/10/30 06:37
PHST- 2023/11/17 15:24 [medline]
PHST- 2023/10/30 12:41 [pubmed]
PHST- 2023/10/30 06:37 [entrez]
AID - 10.1039/d3nr04145j [doi]
PST - epublish
SO  - Nanoscale. 2023 Nov 16;15(44):17922-17935. doi: 10.1039/d3nr04145j.