Intravesical Administrated Pirfenidone@polydopamine Nanoparticles Decrease Bladder Inflammation And Improve Bladder Functions After Spinal Cord Injury

Background:The bladder lose its connection with the pontine voiding center because of spinal cord injury,so patients with spinal cord injury are usually accompanied by bladder storage and voiding dysfunction,resulting in urinary retention and ultimately kidney damage.At the same time,spinal cord injury can also cause changes in bladder morphology,such as bladder inflammation and bladder remodeling,which are in need of effective treatment,but currently,there is no specific drug for the treatment of bladder dysfunction and bladder remodeling caused by spinal cord injury.The current treatments are usually symptomatic treatment of detrusor overactivity.Patients with spinal cord injury often require clean intermittent catheterization,so intravesical administration is suitable for these patients.Methods:Pirfenidone is small molecule drug that have the effect of anti-inflammatory and anti-fibrotic.In order to improve the penetration of pirfenidone into the bladder wall,it is necessary to modified pirfenidone with polydopamine(PDA).In this study,a PFD@PDA NPs system was designed and constructed.PFD@PDA NPs was used to intravesical instillation in an animal model to observe the penetration effect of the system in urothelial barrier and its effects on bladder dysfunction,bladder inflammation and remodeling in animals with spinal cord injury.Results:PFD@PDA NPs could effectively penetrate the bladder wall after intravesical instillation and be preserved in bladder tissue for at least two days.Meanwhile,PFD@PDA NPs had less cytotoxicity.PFD@PDA NPs significantly improved urodynamic parameters in a rat model of spinal cord injury after 14 days of intravesical instillation:decreased baseline pressure,micturition interval,perfusion volume between micturition;decreased residual urine volume and bladder weight ratio in spinal cord injury rats.In addition,PFD@PDANPs could effectively alleviate bladder inflammation and bladder remodeling induced by spinal cord injury:PFD@PDA NPs inhibited the expression of pro-inflammatory cytokines,reduced the proportion of pro-inflammatory macrophages,reduced the level of oxidative stress,inhibited epithelial hyperplasia and abnormal hypertrophy of detrusor muscle in bladder after spinal cord injury.Conclusions:The findings clearly demonstrate that intravesical instillation of PFD@PDA NPs was an effective treatment to inhibit chronic inflammation,prevent bladder remodeling,and improve bladder function.