Megalin-targeting and ROS-responsive elamipretide-conjugated polymeric prodrug for treatment of acute kidney injury

Area of Science:

• Biomedical Engineering
• Pharmacology
• Nephrology

Background:

• Acute kidney injury (AKI) is a critical condition linked to kidney dysfunction and mortality.
• Reactive oxygen species (ROS) surge during ischemia-reperfusion injury, a key factor in AKI pathogenesis.
• Mitochondria are major ROS sources in AKI, making mitochondrial-targeted antioxidant therapy a promising strategy.

Purpose of the Study:

• To synthesize and evaluate a novel, low molecular weight, Megalin receptor-targeted polymeric prodrug for AKI treatment.
• To overcome the challenge of nanodrug size limitations in reaching renal tubules, the primary site of AKI damage.
• To deliver the antioxidant elamipretide specifically to renal tubular epithelial cells and their mitochondria.

Main Methods:

• Synthesis of a low molecular weight chitosan-thioketal-elamipretide (LMWC/TK/Ela) polymeric prodrug.
• Utilizing Megalin receptor targeting for enhanced accumulation in renal tubules.
• Assessing the prodrug's ability to cross the glomerular barrier and release elamipretide responsively.

Main Results:

• The developed LMWC/TK/Ela prodrug is soluble and capable of crossing the glomerular filtration barrier.
• The prodrug successfully targets renal tubular epithelial cells, a key site for AKI.
• The prodrug releases the potent antioxidant elamipretide, mitigating ROS in the target cells.

Conclusions:

• A novel Megalin receptor-targeted polymeric prodrug (LMWC/TK/Ela) was successfully synthesized for AKI.
• This approach enables effective delivery of antioxidants to renal tubules, overcoming size limitations of conventional nanodrugs.
• The targeted delivery and ROS mitigation offer a promising therapeutic strategy for AKI relief.