pH响应型碳酸钙复合纳米粒子作为诊疗一体化制剂在超声显影及肝癌联合治疗中的应用

Ultrasound-guided radiofrequency ablation (RFA) is becoming one of the most important methods for conquering hepatocellular carcinoma. However, it is difficult for RFA to extensively and completely ablate the tumor, which leading high rate of local recurrence. Besides, due to their large size (1-8 μm), the ultrasound contrast microbubbles are predominantly located invascular systems and do not permeate into host tumoral environments, which hard to accurately show the minute lesions of tumor. Thus, the shortcoming limited microbubbles’ application for diagnosis and therapy of tumor..Herein, we aim to develop a theranostic CaCO3-Mn-Dox nanoparticle that can generate CO2 bubbles at tumoral acidic pH. And this project is focused on solving: (1) Preparing uniform hybrid nanoparticles with good enough colloidal stability for longer circulation time in blood. (2) The generated CO2 bubbles could enhance the ultrasonic echo signal which can be applied for tumor specific recognition combined with the enhanced MRI signal of Mn2+ .（3）CaCO3-Mn-Dox nanoparticle that can generate Ca2+ and trigger the release of anticancer drug doxorubicin at tumoral acidic pH, which combined with RFA could reducing local recurrence rate of tumor. Therefore, the developed tumor-pH-activated nanocarrier based on biodegradable CaCO3 theranostic nanoparticles, which can provide us with new thinking and method for the clinic comprehensive treatment of hepatocelluar carcinoma.

超声引导下的射频消融（RFA）已成为肝癌重要治疗方法。然而RFA难以大范围、彻底消灭肿瘤，导致其局部复发率较高；此外，临床使用的超声造影微泡粒径较大（1-8微米），无法穿透血管内皮间隙，难以显示微小病灶，严重限制其对肿瘤疾病的诊断与治疗。.本项目基于碳酸钙纳米粒子在肿瘤微酸性环境下分解并产生CO2的原理，通过气体-弥散法构建了CaCO3-Mn-DOX诊疗一体化纳米制剂，重点解决：（1）制备粒径均一、长循环且具有pH响应性的复合纳米粒子；（2）CO2产生的超声回波信号，联合Mn2+产生MRI增强信号，提高对肿瘤部位的特异性识别能力；(3) CaCO3分解过程产生Ca2+，可增加肿瘤局部离子浓度，并触发抗癌药物盐酸阿霉素的释放，联合射频消融提高肿瘤治疗效率，降低毒副作用。本研究有望提供一种肿瘤微环境响应型诊疗一体化纳米制剂，用于提高肝癌的诊疗效果，降低其局部复发率。

临床使用的超声造影微泡粒径较大（1-8微米），无法穿透血管内皮间隙，难以显示微小病灶，严重限制其对肿瘤疾病的诊断与治疗。本项目利用气体-弥散法制备一种肿瘤微环境响应性诊疗一体化纳米制剂。实验结果证明该碳酸钙纳米粒子可有效负载亲水性的盐酸阿霉素及吲哚菁绿，当其处于低pH环境时，可显著提高MRI以及超声显影信号，这归功于二氧化碳的产生以及Mn2+的释放，同时起到快速释放药物的作用。因此，CaCO3-Mn@ICG\DOX NPs具有非常好的应用前景。与此同时，本项目利用薄荷醇受热易挥发-气化的特点，通过乙醇注入化法将其与光热转换剂IR-780共负载于纳米脂质体中，制备了多重影像介导的诊疗一体化制剂，实现了荧光、光声以及超声增强成像介导光热消融治疗的目的，此外，薄荷醇气化过程产生微泡的空化效应进一步提高热消融范围，提高对肿瘤细胞杀伤效果。达到多重影像引导选择性增强消融肿瘤的目的，在临床上具有潜在的应用价值。