爆破触发多层穿透的复合载药体系增强膀胱灌注疗效

Bladder permeability barrier (BPB) decrease the efficacy of intravesical treatment for non-muscle invasive bladder cancer (NMIBC). The main structure of BPB contain the glycosaminoglycan layer (GAG layer), uroplakins layer (UP layer) and umbrella cell layer. The current using drugs and drug carriers are unable to penetrate the three layers of BPB all at once, such reduced the drug penetration in bladder and drug accumulation in tumor. The research proposed a drug delivery system for enhancing drug penetration in bladder wall and drug retention in bladder tumors, the system is blasting triggered and multilayer penetration. The drug delivery system is composed of micro-liposome loaded with nano-liposome and sulfur hexafluoride. The micro-liposome targeted bind to glycosaminoglycan and penetrate GAG layer. The micro-liposome would release cationic nano-liposome by ultrasound triggered blasting, the cationic nano-liposome could penetrate UP layer and umbrella cell layer. Finally, the nano-liposome active targeted to bladder cancer, release mitomycin and surviving siRNA for combination therapy. The multilayer penetration /active targeted drug delivery system would enhance drug penetration in bladder wall and drug retention in tumor. Thus, it increased the efficacy of intravesical treatment for NMIBC.

膀胱渗透屏障(BPB)是限制非肌层浸润性膀胱癌(NMIBC)术后膀胱灌注疗效的主要因素。构成BPB的主要结构是糖胺聚糖层（GAG层)、尿空斑蛋白层（UP层）和伞状细胞层。目前临床上膀胱灌注的药物及当前研究的药物载体都无法同时穿透BPB三层结构，限制了药物在膀胱组织的穿透及在肿瘤蓄积。本课题拟构建爆破触发多层穿透的复合载药体系来增加药物在膀胱的穿透及在肿瘤蓄积。该复合载药体系由微米脂质体载纳米脂质体及六氟化硫气体构成。微米脂质体将靶向结合糖胺聚糖并穿透GAG层，超声爆破触发微米脂质体释放所载纳米阳离子脂质体，带正电的纳米粒吸附穿透UP层，并将通过细胞旁途径进一步穿透伞状细胞层，最后，纳米粒主动靶向结合膀胱癌细胞，释放所载丝裂霉素及生存素siRNA，联合起效杀伤膀胱癌。该逐层穿透、主动靶向的载药体系可增加药物对膀胱组织穿透及在肿瘤蓄积，以期增强膀胱灌注疗效。

本研究从目前膀胱灌注效率低导致非肌层浸润性膀胱癌术后复发率居高不下这一临床重点难题出发，基于膀胱渗透屏障（BPB）是限制目前非肌层浸润性膀胱癌术后膀胱灌注疗效的主要因素，本课题构建了有效穿透BPB的爆破触发多层穿透的复合载药体系，该复合载药体系由微米脂质体载纳米脂质体及六氟化硫气体构成，采用薄膜法+水化法制备。膀胱灌注该复合载药体系后，微米脂质体依靠其表面修饰的麦胚凝集素与膀胱粘膜表面的糖胺聚糖层靶向结合，采用超声触发爆破释放所载纳米阳离子脂质体，带正电纳米粒脂质体吸附穿透膀胱粘膜层，依靠纳米阳离子脂质表面修饰的RGD主动靶向结合膀胱癌细胞，释放所载药物，杀伤膀胱癌。研究结果显示，该复合载药体系显著提高灌注药物在膀胱及其肿瘤组织的蓄积，显著增强灌注药物的抗肿瘤效应。本研究利用该爆破触发多层穿透的复合载药体系增加所载药物对膀胱组织的穿透及蓄积，增强膀胱灌注疗效。希望为目前膀胱灌注效率低导致非肌层浸润性膀胱癌术后复发率居高不下这一临床关键难点提供解决新思路。