Sulfhydryl functionalized hyaluronic acid hydrogels attenuate cyclophosphamide-induced bladder injury

Clinical management of cyclophosphamide (CYP) results in numerous side effects including hemorrhagic cystitis (HC), which is characterized by inflammation and oxidative stress damage. Intravesical hyaluronic acid (HA) supplementation, a therapeutic method to restore barrier function of bladder, avoid the stimulation of metabolic toxicants on bladder and reduce inflammatory response, has shown good results in acute or chronic bladder diseases. However, there are unmet medical needs for the treatment of HC to temporarily restore bladder barrier and reduce inflammation. Herein, sulfhydryl functionalized HA (HA-SH) and dimethyl sulfoxide (DMSO) were used to prepared a hydrogel system for optimizing the treatment of HC. We systematically evaluated the physicochemical of hydrogels and their roles in a rat model of CYP-induced HC. The prepared hydrogels exhibited outstanding gel forming properties, injectability, and biosafety. Swelling and retention studies showed that hydrogels were stable and could prolong the residence time of HA in the bladder. Histopathology and vascular permeability studies indicated that the hydrogels significantly attenuated bladder injury caused by CYP administration. Moreover, the hydrogels also showed excellent anti-inflammation and anti-oxidation properties. In conclusion, these data suggest that intravesical instillation of HA-SH/DMSO hydrogels reduces CYP-induced bladder toxicity and this work provides a new strategy for the prevention and early treatment of HC.