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Sustained-release mitochondrial protonophore reverses nonalcoholic fatty liver disease in rats
Guangfei Wei1, Xu Song1, Yao Fu1
1Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
Abstract:
As a mitochondrial uncoupler, 2,4-dinitrophenol (DNP) is proven therapeutically effective against nonalcoholic fatty liver disease (NAFLD) by uncoupling oxidation and phosphorylation. However, a major factor that impedes the clinical application of DNP is the significant side effects derived from its frequent hyperthermia and even death. In this study, we developed an injectable liquid crystal gel (DNP-LC-gel) to reduce the toxicity of DNP. DNP-LC-gel achieved sustained release and maintained DNP plasma concentration at an effective drug level. In a rat model of NAFLD, DNP-LC-gel treated rats reduced hepatic steatosis, liver triglyceride content, plasma triacylglycerol (TG) and total cholesterol (TC) content. Compared with DNP solution (DNP-soln), rats after DNP-LC-gel treatment showed no body temperature toxicity and local irritation. All results above indicated that DNP-LC-gel has a great potential for NAFLD therapy.
Insights
A novel injectable liquid crystal gel (DNP-LC-gel) effectively treats nonalcoholic fatty liver disease (NAFLD) by providing sustained release of 2,4-dinitrophenol (DNP), reducing liver fat and improving lipid profiles without toxic side effects.
Area of Science:
- Biochemistry
- Pharmacology
- Materials Science
Background:
- 2,4-dinitrophenol (DNP) is a mitochondrial uncoupler effective for nonalcoholic fatty liver disease (NAFLD).
- DNP's clinical use is limited by severe side effects, including hyperthermia and mortality.
- Developing safer drug delivery systems for DNP is crucial for NAFLD treatment.
Purpose of the Study:
- To develop an injectable liquid crystal gel (DNP-LC-gel) to mitigate DNP toxicity.
- To evaluate the efficacy and safety of DNP-LC-gel in a rat model of NAFLD.
Main Methods:
- Formulation of an injectable liquid crystal gel (DNP-LC-gel) for sustained DNP release.
- Administration of DNP-LC-gel and DNP solution (DNP-soln) to a rat model of NAFLD.
- Assessment of liver steatosis, triglyceride, triacylglycerol (TG), and total cholesterol (TC) levels.
- Monitoring of body temperature and local irritation.
Main Results:
- DNP-LC-gel demonstrated sustained release of DNP, maintaining effective plasma drug concentrations.
- Treatment with DNP-LC-gel significantly reduced hepatic steatosis and liver triglyceride content in NAFLD rats.
- DNP-LC-gel administration led to decreased plasma TG and TC levels.
- Animals treated with DNP-LC-gel exhibited no hyperthermia or local irritation, unlike DNP-soln.
Conclusions:
- Injectable DNP-LC-gel offers a promising therapeutic strategy for NAFLD.
- The DNP-LC-gel formulation enhances DNP's safety profile by reducing toxicity.
- This delivery system has significant potential for clinical application in NAFLD management.
