| Autor: |
Vlasova KY; Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia.; School of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Ostroverkhov P; Department of Chemistry and Technology of Biologically Active Compounds, Medical and Organic Chemistry, Lomonosov Institute of Fine Chemical Technologies MIREA-Russian Technological University (RTU MIREA), 119571 Moscow, Russia., Vedenyapina D; Department of Chemistry and Technology of Biologically Active Compounds, Medical and Organic Chemistry, Lomonosov Institute of Fine Chemical Technologies MIREA-Russian Technological University (RTU MIREA), 119571 Moscow, Russia., Yakimova T; Faculty of Materials Science, Lomonosov Moscow State University, 119991 Moscow, Russia., Trusova A; Faculty of Materials Science, Lomonosov Moscow State University, 119991 Moscow, Russia., Lomakina GY; School of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Vodopyanov SS; College of New Materials and Nanotechnologies, National University of Science and Technology (MISIS), 119049 Moscow, Russia., Grin M; Department of Chemistry and Technology of Biologically Active Compounds, Medical and Organic Chemistry, Lomonosov Institute of Fine Chemical Technologies MIREA-Russian Technological University (RTU MIREA), 119571 Moscow, Russia., Klyachko N; School of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia., Chekhonin V; Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia.; V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia., Abakumov M; Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia.; College of New Materials and Nanotechnologies, National University of Science and Technology (MISIS), 119049 Moscow, Russia.; V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia. |
| Abstrakt: |
Mitochondrial uncoupler 2,4-dinitrophenol (2,4-DNP) is a promising antidiabetic and antiobesity agent. Its clinical use is limited by a narrow dynamic range and accumulation in non-target sensitive organs, which results in whole-body toxicity. A liposomal formulation could enable the mentioned drawbacks to be overcome and simplify the liver-targeted delivery and sustained release of 2,4-DNP. We synthesized 2,4-DNP esters with carboxylic acids of various lipophilic degrees using carboxylic acid chloride and then loaded them into liposomes. We demonstrated the effective increase in the entrapment of 2,4-DNP into liposomes when esters were used. Here, we examined the dependence of the sustained release of 2,4-DNP from liposomes on the lipid composition and LogP oct of the ester. We posit that the optimal chain length of the ester should be close to the palmitic acid and the lipid membrane should be composed of phospholipids with a certain phase transition point depending on the desired release rate. The increased effect of the ATP synthesis inhibition of the liposomal forms of caproic and palmitic acid esters compared to free molecules in liver hepatocytes was demonstrated. The liposomes' stability could well be responsible for this result. This work demonstrates promising possibilities for the liver-targeted delivery of the 2,4-DNP esters with carboxylic acids loaded into liposomes for ATP synthesis inhibition. |
