Nanomedicine-embedded Hydrogel Improves Chemotherapy Of Bladder Cancer

Objective:A suitable hydrogel(Gel)formulation was screened and nanomedicine with enhanced penetration was prepared.The physical and chemical characteristics of Gel,the principle of nanomedicine permeation,the degradation and release behavior in vitro,and the drug retention and permeation performance of composite systems in vivo were studied.Methods:The Gel was prepared based on the chemically crosslink between chitosan(CS)and oxidized dextran(ODEX).The optimal gel formulation was selected by gel time and rheological properties.Moreover,the basic physical and chemical properties and the adhesion strength to the bladder mucosa of Gel were investigated.The epirubicin(EPI)-loaded chitosan nanoparticles(NP/EPI)were prepared by ionic gel method.The basic morphology,particle size and surface charge of NP/EPI were studied.The transepithelial resistance meter combined with a modified Transwell chamber was used to explore the principle of mucosal permeability of NP/EPI.In addition,NP/EPI was incorporated into the CS solution,and then mixed with the ODEX solution through a double-tube injection system to prepare a composite system consisting of nanomedicine and gel(Gel-NP/EPI).The degradation and drug release behavior of Gel-NP/EPI in vitro were studied in the simulated urine with different pH.Laser confocal microscopy was used to measure the retention time of drugs on the bladder mucosa and the penetration of drugs into the bladder wall.Result:The screened Gel was suitable for bladder perfusion(gel time of 66.3s).Gel has suitable mechanical strength(storage modulus of 670.0 Pa)and it could firmly adhere to the bladder mucosa after perfusion(shear adhesion of 11.2 kPa).The prepared NP/EPI was spherical,which had uniform size,hydrodynamic radius(R_h)of 109.0±1.3 nm and surface charge of 11.3±2.1 mV.NP/EPI could enhance the mucosal penetration of drugs by opening the tight junctions between cells.Gel-NP/EPI prepared by the double-tube injection system was slowly degraded in vitro and the degradation rate was accelerated as the pH value of the degradation solution decreased.In addition,the same phenomenon was also observed in the drug release behavior of Gel-NP/EPI in vitro.In vivo,Gel-NP/EPI significantly prolonged the retention time of drugs in the bladder and a weak EPI fluorescence signal could be detected even after120 h.Gel-NP/EPI could also promote the penetration of drugs and maintain high concentrations of EPI in the bladder wall for an extended period of time.Conclusion:1.The screened gel was suitable for bladder perfusion and could firmly adhere the bladder wall;2.The prepared NP/EPI had a uniform particle size and a positive charge,which could open the tight connection between cells and promote the mucosal penetration of drugs;3.Gel-NP/EPI slowly degraded and released the drugs in vitro,which could significantly prolong the action time of drugs in the body,promote the penetration of drugs,and maintain long-term high-concentration drugs exposure in the bladder wall.