载普鲁士蓝诊疗一体化靶向分子探针多模态显像及靶向治疗分化型甲状腺癌研究

Thyroid nodules are a common clinical problem worldwide. When the results of fine needle aspiration cytology (FNAC) are equivocal, indeterminate or suspicious of malignancy, ultrasonic molecular imaging can provide help for the diagnosis of thyroid carcinoma and differential diagnosis of benign and malignant thyroid nodules. The micro-size of MBs used clinically do not allow effective extravasation into tumor tissue, which have limitations in diagnosis of thyroid cancer and identification of benign and malignant thyroid nodule. Based on previous studies, in this project, we will adopt lipidosome for the elaborate integration with Prussian blue nanoparticles (PB NPs) and phase-convertible perfluoropentane (PFP) core to construct a theranostic molecular probe, which is targeted by the monoclonal antibody HBME-1. The theranostic molecular probe combine the capability of enhanced ultrasound imaging of PFP with the capability of enhancing photoacoustic and magnetic resonance imaging and photothermal-conversion capability of PB NPs, which could target the differentiated thyroid cancer cells specially and multimodal imaging of differentiated thyroid cancer in ultrasonic, photoacoustic and magnetic resonance imaging at the molecular level and in vivo. In the meantime, the theranostic molecular probe could realize the noninvasive photothermal therapy of differentiated thyroid cancer, visualization in monitoring treatment effects and provide a new way for the diagnosis and differential diagnosis and non-invasive treatment of differentiated thyroid cancer.

甲状腺结节是普遍的世界性临床问题，在细针穿刺活检结果为不确定良恶性时，超声分子成像可以为甲状腺癌的诊断及甲状腺结节的良恶性鉴别诊断提供帮助。但临床普遍应用的超声造影剂为微米级别，无法穿透肿瘤毛细血管内皮细胞间隙，对甲状腺癌的诊断及甲状腺结节良恶性的鉴别诊断存在局限性。本课题基于前期研究基础，采用磷脂为成膜材料，包裹普鲁士蓝纳米粒子和相变材料全氟戊烷（PFP），表面连接分化型甲状腺癌表面特异性单克隆抗体HBEM-1，制备载普鲁士蓝诊疗一体化靶向分子探针，可以特异性的靶向分化型甲状腺癌细胞，结合PFP的增强超声显影能力和普鲁士蓝光声、磁共振显像和光热特性，以期在分子水平及在体实现超声、光声、磁共振多模态显影分化型甲状腺癌，同时实现分化型甲状腺癌无创光热治疗，可视化在体监控治疗效果，为分化型甲状腺癌的诊断及鉴别诊断、无创治疗提供了新的思路。

单一治疗方式在治疗伴有并发症的转移性病变方面有局限性。尽管新出现的免疫治疗显示出初步的成功，但实体肿瘤通常是免疫抑制的，导致无效的抗肿瘤免疫反应和免疫治疗抵抗。多种治疗方式的合理组合有可能成为一种有效治疗癌症的新策略。在此基础上，我们设计了一种基于“纳米靶向细胞”的鸡尾酒疗法，利用poly(lactic-co-glycolic) acid (PLGA)包裹光热转化剂普鲁士蓝(PB)，化疗药物多西紫杉醇(DTX)和免疫佐剂咪喹莫特(R837)，制备纳米粒（P-PDR），再利用癌细胞膜包裹P-PDR，制备出人工纳米靶向细胞（M@P-PDR）。所设计的M@P-PDRs因为癌细胞膜的修饰，通过静脉注射表现出令人满意的同源的靶向能力。且M@P-PDRs显示出优异的光声成像（PA）/磁共振成像（MR）双模成像性能，结合其靶向性，可以精确的进行肿瘤PA/MR双模成像，并且可以精确指导原发肿瘤的光热治疗（PTT）。M@P-PDRs中的PB可以将光能转化成热能，激光辐照PB触发PTT，R837和DTX从M@P-PDRs中释放出来，同时凋亡或坏死的肿瘤细胞释放肿瘤相关抗原(TAAs)。释放的TAAs与免疫佐剂R837共同促进树突状细胞（DCs）的成熟，化疗药物DTX使M2型促癌TAMs向和M1型抑癌TAMs极化，两者均促进细胞因子的分泌，从而有效激活T细胞反应，攻击原发肿瘤。上述过程促进细胞毒性T淋巴细胞（CTLs）浸润，治疗远处转移，从而原发肿瘤和转移肿瘤明显受到抑制。综上所述，纳米靶向细胞（M@ P-PDR）的鸡尾酒疗法，可以实现在光声（PA）/磁共振（MR）双模态成像引导下的靶向诊断与治疗一体化，对原发肿瘤和转移肿瘤产生光热/化疗/免疫治疗“三效合一”的协同治疗效果，为肿瘤制造了一场“末日风暴”。