携抗PSMA多肽的靶向载多西紫杉醇微泡治疗前列腺癌的实验研究

While lacking tumor-targeting function, the conventional chemotherapy often induces severe side effects and has poor treatment efficacy, which significantly hinders the improvement in treating prostate cancer. As a newly developed technology, the targeted drug-delivery microbubbles combined with ultrasound-targeted microbubble destruction technology can be used for local drug delivery. The targeted drug-delivery microbubbles can bind specifically to the tumor due to its targeting function, achieve the desired drug concentration at the particular targeted tissue and minimize side effects. Consequently, the therapeutic effect of anticancer drugs would be significantly improved and the idea of targeted therapy would be realized. At present, the research about the targeted drug-delivery microbubble is still at the initial stage. Its application in prostate cancer treatment is not yet fully understood. In our previous studies, we have obtained non-targeted docetaxel-carrying liposome microbubbles and synthesized anti-PSMA peptide that is specific against the prostate cancer. Based on these results, the aim of the current study is to produce targeted docetaxel-carrying microbubbles and to improve the formula of microbubble by in vitro and vivo experiments. Furthermore, we will select and evaluate the ultrasound parameters for the optimized processing of the drug delivery. Our study will provide theoretical basis for the targeted drug-delivery microbubbles technology and new ideas for the targeted treatment of prostate cancer.

常规化疗药物缺乏靶向性、毒副作用大、疗效差的现状已成为阻碍前列腺癌治愈率提高的关键因素。靶向载药微泡联合超声辐照作为一种新型的药物递送方式可以实现局部定位释药，且其具有主动寻靶功能，能与肿瘤组织特异性结合，通过提高肿瘤局部药物浓度、降低全身毒副作用来显著提高抗肿瘤药物的治疗效果，从而有望实现真正意义上的靶向治疗。目前，对靶向载药微泡的研究尚处于起步阶段，其在前列腺癌药物治疗中的价值尚未明确，因此，本课题拟在前期成功制得普通载药微泡和具良好前列癌靶向性的抗PSMA多肽的基础上构建靶向载药微泡，通过系列体外和体内实验，调整微泡配方获得靶向性、载药量、显像性、稳定性最佳的靶向载药微泡，并筛选适宜超声辐照条件，评价超声辐照靶向载药微泡对前列腺癌的治疗作用，为研究基于靶向超声微泡的药物定位控释技术提供理论依据，同时为前列腺癌的靶向治疗技术提供新的思路。

常规化疗药物缺乏靶向性、毒副作用大、疗效差的现状已成为阻碍前列腺癌治愈率提高的关键因素。靶向载药微泡联合超声辐照作为一种新型的药物递送方式可以实现局部定位释药，且其具有主动寻靶功能，能与肿瘤组织特异性结合，通过提高肿瘤局部药物浓度、降低全身毒副作用来显著提高抗肿瘤药物的治疗效果，从而有望实现真正意义上的前列腺癌靶向治疗。.本项目拟在前期成功制得普通载药微泡和具良好前列癌靶向性的抗PSMA多肽的基础上构建携抗PSMA多肽的靶向载多西紫杉醇脂质微泡造影剂，通过系列体外和体内实验，调整微泡配方获得靶向性、载药量、显像性、稳定性最佳的靶向载药微泡，并筛选适宜超声辐照条件，评价超声辐照靶向载药微泡对前列腺癌的治疗作用。.本项目采用缩合反应和薄膜水化法制备合成携抗PSMA多肽的靶向载多西紫杉醇脂质微泡造影剂。靶向载药微泡最优制备方案为磷脂与多西紫杉醇质量比为10:1，磷脂胆固醇质量比为4:1，超声时间为60s，超声功率为400W。靶向载药微泡呈球形分布均匀，平均粒径为(1.31±0.29)μm；平均电位为(-20.1±0.25)mV；包封率为(86.76±0.84)%；载药量为(6.87±0.36)%。4℃可存放3天，超声辐照后具突释性。体外细胞靶向结合试验显示靶向载药微泡可与表达PSMA的人前列腺癌LNcap细胞呈特异性结合。体外超声显像实验示靶向载药微泡在灰阶超声模式及造影模式下均呈明亮高回声，且回声强度随微泡造影剂浓度的增加而升高。体内超声显像示LNCaP荷瘤裸鼠在注射靶向载药微泡造影剂后，裸鼠肿瘤组织呈明显增强显影。体外前列腺癌细胞抑制实验结果显示适宜超声辐照参数为载药微泡药物浓度2.0μg/mL、超声时间60s，超声声强0.75w/cm2，占空比30%。体内靶向治疗实验结果显示靶向载药微泡联合超声辐照能有效介导药物释放，明显抑制肿瘤生长，具有较强的体内靶向抑瘤效果。.本项目为研究基于靶向超声微泡的药物定位控释技术提供理论依据，同时为前列腺癌的靶向治疗技术提供新的思路。