Construction And Effect Study Of A Bladder Cancer Targeting Self-assembly Drug Delivery System

Bladder cancer is currently the most common malignant tumor of the urinary system,and most(approximately 90%)are urothelial carcinomas(hereinafter referred to simply as bladder cancer).According to the development stage,bladder cancer can be divided into non-muscle-invasive bladder cancer and muscle-invasive bladder cancer.At present,the treatment of bladder cancer varies profoundly depending on the clinical stage and associated risk factors.The front-line treatment for non-muscle invasive bladder cancer,located in the mucosal layer,is transurethral resection.However,because the tumor can hardly be completely removed by resection,the five-year recurrence rate of bladder cancer is as high as 70%.As for the muscle-invasive bladder cancer,tumor cells have disseminated to the lamina propria,even the detrusor muscle,neither the diseased tissue can be effectively removed by surgery,nor can the tumor development be suppressed simply by intravesical drug delivery treatment.Generally,cystectomy,with or without adjuvant systemic chemotherapy,is the front-line treatment for muscle-invasive bladder cancer.However,due to the limited treatment options and poor clinical prognosis caused by chemotherapy,patients with muscle-invasive bladder cancer have a survival rate of only 50% within five years,and 15% for disseminated muscle-invasive bladder cancer.In order to develop a bladder cancer targeting self-assembled drug delivery system and improve the clinical treatment effect of bladder cancer,the fusion protein Lectinm HFBI was constructed and expressed in E.coli.This fusion protein will have both the properties of protein Lectin and m HFBI.m HFBI,the mutant of hydrophobin HFBI,can self-assemble to carry drugs.Lectin is the N-terminal mannose-binding domain of FimH,the type 1 adhesin at pilus tip of uropathogenic Escherichia coli(UPEC),which can specifically bind to the plaque protein Uroplakin Ia on the surface of bladder cancer cells and then mediate the endocytosis of drugs.Then the receptor targeting property and self-assembly ability of the fusion protein Lectin-m HFBI have been verified by high-resolution laser confocal microscopy,transmission electron microscopy and other methods.Finally,take doxorubicin as a model drug,the targeting drug delivery capability of the fusion protein Lectin-m HFBI was tested in vitro and in vivo respectively.Given that the drug delivery system can target bladder cancer cells and break through the blood-urine barrier,reduce the side effects caused by traditional administration,it is expected to be applied to systemic administration or intravesical drug delivery of bladder cancer treatment,which may also contribute greatly to the treatment of other bladder-related diseases.Besides,this study provides new ideas and tools for applications that require a breach of the blood-urine barrier,such as carrying gene editing tools to break through the blood-urinary barrier for gene therapy,as well as the image diagnosis of bladder.