| Background:Bladder cancer is one of the most prevalent cancers originating from the urinary tract and causes high levels of morbidity and mortality worldwide.The mainstay standard treatment for NMIBC management is transurethral resection of bladder tumor combined with the post-surgery intravesical instillation chemotherapy(IIC),which could drastically reduce the risks of the recurrence and chance of progression.Currently,the efficiency of clinical intravesical instillation chemotherapy has been greatly compromised by the toxicological and physiological factors.First,the residence of free drugs inside bladder is quite short due to the voiding of urine,so that continuous infusion is required to maintain high drug concentration,which may result in urethral injury,increased expense,and occurrence of drug-resistance.Second,as the result of lacking tumor-selective target ability,the chemotherapy drugs kill the tumor cells accompanying with also damaging normal cells,which may result in side effects.Third,due to the weak penetration of the chemotherapy drugs for the tumor,the tumor cells located in the deep tissues remain undamaged,leading to increase the risk of the recurrence or progression for bladder cancer.The above-mentioned problems in the process of intravesical instillation chemotherapy have been affecting clinicians and patients.How to solve the above problems has become a hot topic of research.New formulations that could specifically and efficiently kill bladder cancer cells are in urgent need to overcome the low residence efficiency.The combination of mucoadhesive nanocarriers and cancer cell selective prodrugs could address these limitations.Extensive efforts have been devoted in the past decade to develop stimuliresponsive drug delivery systems based on the endogenous stimulus for the tumor microenvironment.In our previous study,we have confirmed the ROS activated gambogic acid prodrug is safe and efficient for intravesical instillation chemotherapy of bladder cancer.However,the insignificant endogenous stimulus differences between cancer cells and normal cells in most cases and the high local drug concentration make it essential to develop new drugs with broader selectivity-window.Herein,based on the statistically different NQO1 expression between cancerous and normal bladder tissues,the reactive oxygen species(ROS)activatable epirubicin prodrug and highly potent NQO1 substrate,KP372-1,were co-delivered using a GSH-responsive mucoadhesive nanocarrier.Method:Based on this hypothesis,this project has studied in detail for the expression of NQO1 in tumor tissue and normal tissue,and the preparation and characterization of ROS/GSH dual-responsive prodrug nano-drugs,characterization of ROS production capacity of prodrug NPs in vivo and in vitro,in vitro cytotoxicity,apoptosis and cell cycle arrest of NPs,and tumor penetration mediated by transcytosis of NPs.The antitumor effect on an orthotopic mouse bladder cancer model,as well as the safety of NPs drugs were also studied in detail.Results:It has been confirmed by the research that after endocytosis,epirubicin could be promptly activated by the NQO1-dependent ROS production caused by KP372-1,and specifically inhibite the proliferation of bladder cancer cells.Since KP372-1 is 10 times more potent than some commonly used NQO1 substrates,for example β-lapachone,the cascade drug activation could occur under much lower drug concentration,which could greatly lower the toxicity in normal cells and broaden the selectivity-window during intravesical bladder cancer chemotherapy.In addition to the anti-tumor effect,the nanodrugs prepared by our research group have higher safety than free drugs.Conclusion:To sum up,the co-delivery system based on GSH-responsive mucoadhesive nanocarrier to simultaneously deliver KP372-1 and a ROS-activatable prodrug of epirubicin in this study has better targeted tumor inhibition for intravesical instillation chemotherapy and with better biosafety.The application prospect is broad. |
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