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Liposomal Form of 2,4-Dinitrophenol Lipophilic Derivatives as a Promising Therapeutic Agent for ATP Synthesis
Kseniya Yu Vlasova1,2, Petr Ostroverkhov3, Daria Vedenyapina3
1Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University, 117997 Moscow, Russia.
Abstract:
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 LogPoct 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.
Insights
Liposomal formulations enhance the delivery of 2,4-dinitrophenol (2,4-DNP) for antidiabetic and antiobesity treatments. This approach improves liver targeting and sustained release, overcoming toxicity issues of free 2,4-DNP.
Area of Science:
- Biochemistry
- Pharmacology
- Drug Delivery
Background:
- Mitochondrial uncoupler 2,4-dinitrophenol (2,4-DNP) shows potential for treating diabetes and obesity.
- Clinical application of 2,4-DNP is hindered by toxicity due to its narrow therapeutic window and off-target organ accumulation.
Purpose of the Study:
- To develop a liposomal formulation for liver-targeted delivery and sustained release of 2,4-DNP.
- To investigate the impact of esterification and liposomal composition on 2,4-DNP release kinetics and efficacy.
Main Methods:
- Synthesis of 2,4-DNP esters with varying lipophilicity.
- Encapsulation of 2,4-DNP esters into liposomes with controlled lipid composition.
- Evaluation of liposomal 2,4-DNP release rates and ATP synthesis inhibition in liver hepatocytes.
Main Results:
- Esterification significantly increased 2,4-DNP entrapment into liposomes.
- Liposomal release rate was dependent on ester lipophilicity (LogPoct) and liposome lipid composition.
- Liposomal 2,4-DNP esters demonstrated enhanced ATP synthesis inhibition in liver cells compared to free 2,4-DNP, attributed to liposome stability.
Conclusions:
- Liposomal delivery of 2,4-DNP esters offers a promising strategy to improve therapeutic efficacy and reduce toxicity.
- Optimized ester chain length and liposome formulation are key for controlling 2,4-DNP release and targeting.
- This approach facilitates liver-targeted delivery and sustained release of 2,4-DNP for potential antidiabetic and antiobesity applications.
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