用于恶性肿瘤治疗的放射性靶向纳米胶囊的研制及其应用研究

Anaplastic Thyroid Cancer (ATC) is a form of highly malignant thyroid cancer, which has very limited therapeutic outcome due to its resistance to common radioiodine (I-131) therapy. Currently, extensive efforts have been devoted to exploring drugs that can activate the downstream pathway of ATC, whereas severe adverse effects and poor patient tolerance to those drugs are observed. Our group has long been working on the development of nanomedicine for cancer treatments, and previously we have found that targeted delivery of I-131 conjugated nanocarriers significantly inhibited the proliferation of breast cancer cells, as well as suppressed the growth of the breast tumor. This project aims to develop radiotherapy for ATC with the protein nanocapsule technology. Briefly, I-131 will be first conjugated onto the bovine serum albumin nanocapsule (nBSA), which is proved to be highly biocompatible as a drug carrier. Subsequently, suramin, an inhibitor of the epidermal growth factor receptor (EGFR) pathway will be further conjugated on nBSA for site-specific delivery. The resulting suramin-I-131-nBSA nanocomplex are expected to achieve active targeting by suramin and tumor suppression by I-131, simultaneously. Such design that integrates two therapeutic purposes in one form of nanomedicine, offers a new approach for the treatment of ATC, opening possibilities of future clinical applications.

未分化型甲状腺癌(ATC)是一种恶性程度高，常规碘(131I)放射治疗无效的肿瘤疾病，临床上缺乏有效的治疗方法。目前，国内外研究热点集中在开发能够激活ATC下游通路的药物上，但这类药物副作用明显，病人的耐受性差。本课题组长期从事纳米药物的研发，于前期工作中发现靶向投递131I标记的纳米载药系统(纳米胶囊)可以明显抑制乳腺癌细胞的增殖，并实现了对乳腺癌病灶的抑制作用。本项目拟将蛋白纳米胶囊技术应用于ATC的放射治疗。131I标记的牛血清白蛋白(BSA)纳米胶囊将作为表皮生长因子及受体通路的抑制剂苏拉明(Suramin)的载体。通过化学方法相互结合，制备靶向型的抗肿瘤生长的生物制剂，该药物将同时发挥Suramin的靶向定位及其本身抗肿瘤增殖作用和131I内照射杀伤肿瘤细胞的双重治疗功效。本研究旨在为ATC综合治疗提供新的思路和技术平台，并为其临床应用提供分子水平的理论依据。

未分化型甲状腺癌（ATC）是侵袭性最高的实体肿瘤之一，对放疗、化疗均不敏感，患者预后极差，目前仍缺乏安全有效的治疗策略。在此项目中，本小组选用牛血清白蛋白BSA为核心、MPC为壳层，以Iodogen法电荷吸附131I和Anlotinib使其装载在纳米载体上，通过表征其理化特性，成功构建了131I标记的负载多激酶抑制剂Anlotinib的MPC纳米载体131I-nBSA-Anlotinib。Anlotinib的特异靶向定位功能，可以直接将治疗性核素131I运送至ATC 病灶部位，同时Anlotinib兼具抑制肿瘤细胞增殖的功效。本小组使用未分化型甲状腺癌细胞株8305和C643，观察制备的纳米载体对上述细胞株的转移和侵袭能力、应激和细胞凋亡、131I摄取和流出率等体外疗效；同时成功构建ATC裸鼠模型，通过SPECT/CT显像及脏器活度检测分析该纳米载体的生物学分布及药代动力学特征；评价动物体内的治疗效果，并进行生物安全性检测。体外细胞研究发现：两组细胞对经纳米载体运载的131I摄取率明显高于游离131I；nBSA-Anlotinib与131I联用存在放疗增敏的功效，本项目首次发现其可能机制有3条：1、Anlotinib可以激活野生型P53通路，增加促凋亡因子P21和Bax表达量；2、Anlotinib通过抑制EGFR下游通路PI3K/Akt/mTOR表达，进而降低HIF-1α表达量，进而达到降低放疗抵抗的作用；3、突变型P53对VEGFR的抑制剂Anlotinib敏感度增加。同时动物体内显像研究发现：靶向纳米颗粒主要靶向分布在肿瘤组织内，可以达到5天持续存在；另外纳米材料组裸鼠肿瘤体积和重量均显著小于对照组，以此实现了通过纳米载体同时将兼具靶向定位与治疗双重作用的药物精准投递至肿瘤表面，达到对肿瘤的生物靶向治疗与核素内照射治疗协同功效，为ATC提供新的治疗策略。

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