Targeted delivery of acrolein scavenger hydralazine in spinal cord injury using folate-linker-drug conjugation

Oxidative stress has been shown to play a critical pathogenic role in functional loss after spinal cord injury (SCI). As a direct result of oxidative stress, lipid peroxidation-derived aldehydes have emerged as key culprits that sustain secondary injury and contribute significantly to pathological outcomes. Acrolein, a neurotoxin, has been shown to be elevated in SCI and can result in post-SCI neurological deficits. Reducing acrolein has therefore emerged as a novel and effective therapeutic strategy in SCI. Previous studies have revealed that hydralazine, an FDA approved blood pressure lowering medication, when administered after SCI shows strong acrolein scavenging capabilities and significantly improves cellular and behavioral outcomes. However, while effective at scavenging acrolein, hydralazine's blood pressure lowering activity can have a detrimental impact on neurotrauma patients. Here, our goal was to preserve the acrolein scavenging capability while mitigating the effect of hydralazine on blood pressure. We accomplished this using a folate-targeted delivery system to deploy hydralazine to the folate receptor positive inflammatory site of the cord injury. Using a model of rat SCI, we found that this system is effective for targeting the injury site, and that folate targeted hydralazine can scavenge acrolein without significantly impacting blood pressure.