Development of nanocontainers for the delivery of 2,4-dinitrophenol derivatives to the liver in the treatment of non-alcoholic fatty liver disease and type 2 diabetes
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Faculty of Chemistry, Mikhail Vasilyevich Lomonosov Moscow State University, Moscow, Russia
MIREA Russian Technological University, Moscow, Russia
National University of Science and Technology (MISIS), Moscow, Russia
Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University, Moscow, Russia
Publication date: 2022-05-27
Public Health Toxicol 2022;2(Supplement 2):A13
Type 2 diabetes mellitus (DM-2) and non-alcoholic fatty liver disease (NAFLD) are two of the most urgent problems of medicine nowadays. According to the World Health Organization forecasts, by 2030 these diseases will take the 7th place among all causes of death. Clinics use a number of drugs aimed at treating DM-2, but there is no drug treatment for NAFLD.
Thus, the development of a drug for the prevention and treatment of NAFLD and CD-2 is relevant. One of the promising molecules that can be effective and safe in the treatment of these diseases is 2,4-dinitrophenol, which changes the activity of mitochondria. The mechanism of action of 2,4-dinitrophenol is to transfer a proton across the mitochondrial membrane, dissipating the mitochondrial proton gradient and promoting thermal dissipation of energy resulting from the oxidation of the mitochondrial substrate, which leads to accelerated fat oxidation. Previously, 2,4-dinitrophenol was widely used as a weight loss agent, but was discontinued due to the occurrence of fatal hyperthermia. In order to remove the established side effects from its use, the task arose to develop an effective formulation of this molecule for targeted delivery to the liver.
The aim of this work is to develop nanocontainers of 2,4-dinitrophenol derivatives with controlled release in the liver for oral administration. To solve the problem, we used esters and alkyl derivatives of 2,4-dinitrophenol, as well as aromatic polycyclic nitroalcohols based on naphthol-1 and benzylphenol, loaded into nanoparticles based on polylactic-co-glycolic acid (PLGA).
Polymer micelles have a number of advantages such as high stability, simplicity of preparation and delayed prolonged release. The efficiency of encapsulation of 2,4-dinitrophenol derivatives increases up to 30 times compared to the free molecule, and slow release from the nanocontainer is observed. Using the analysis of ATP-luciferin-luciferase, the effectiveness of derivatives was shown in comparison with free 2,4-dinitrophenol. In addition, in vitro testing of the formulations showed a prolonged inhibition of ATP synthesis due to the prolonged release of the active molecules.
The obtained results open up the prospects for further application of polymeric micelles of 2,4-dinitrophenol derivatives as a harm-free drug treatment for DM-2 and NAFLD.
The work was performed using equipment of the Moscow University Program of the development. This study was supported in part by M.V. Lomonosov MSU Reg. Theme 121041500039-8.
The study was supported by the Russian Science Foundation (Grant Number: 20-73-00333).