Fan Yongzeng, Xiong Yalan, Wang Xinhong, Chen Jiahao, Fang Danzhou, Huang Jiahui, Yuan Gengbiao
Department of Nuclear Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Emergency, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Front Oncol. 2023 Jan 27;13:1030105. doi: 10.3389/fonc.2023.1030105. eCollection 2023.
Aggressive thyroid carcinoma (ATC) usually loses radioiodine avidity to iodine-131 (I) due to the downregulation of sodium/iodide symporter (NIS). The expression of thyroid stimulating hormone receptor (TSHR) is more persistent than NIS and the administration of recombinant human thyroid stimulating hormone (rhTSH) promotes de novo NIS synthesis. Hence, exploring methods integrating I with rhTSH might be a feasible therapeutic strategy for selective delivery of I into thyroid cancer to fortify the effect of radioiodine ablation.
The I, poly (lactic-co-glycolic acid) (PLGA) and rhTSH were used to synthesize of the I-PLGA-rhTSH nanoparticles. The characteristics of the I-PLGA-rhTSH nanoparticles was determined using a light microscopy, scanning electron microscopy (SEM), autoradiography and immunofluorescence (IF) staining. The diameter of the I-PLGA-rhTSH nanoparticles was measured with a Mastersizer 3000, and the encapsulation efficiency (EF) of I in I-PLGA-rhTSH nanoparticles and the radioactivity of a single nanoparticle were determined. Then, the mouse tumor xenograft model was established, and the biodistribution and effect of I-PLGA-rhTSH nanoparticles on apoptosis of thyroid cance cells were investigated in vivo. Thereafter, the role of I-PLGA-rhTSH nanoparticles in cell viability using cell counting kit-8 and lactate dehydrogenase (LDH) release assays. Subsequently, the underlying mechanism of I-PLGA-rhTSH nanoparticles in reducing cell viability was assessed using immunostaining, boyden invasion assays and phalloidin staining.
Our results showed that the method of developing nanoparticles-encapsulated I using poly (lactic-co-glycolic acid) (PLGA) and modified with rhTSH (I-PLGA-rhTSH), was a feasible avenue for the integration of I and rhTSH. Meanwhile, the encapsulation efficiency (EF) of I-PLGA-rhTSH nanoparticles was approximately 60%, and the radioactivity of a single nanoparticle was about 1.1×10-2 Bq. Meanwhile, the I-PLGA-rhTSH nanoparticles were selectively delivered into, gradually enriched and slowly downregulated in xenograft tumor after the administration of I-PLGA-rhTSH nanoparticles through tail vein in mouse tumor xenograft model. Thereafter, the tumor weight was significantly reduced after the administration of I-PLGA-rhTSH nanoparticles. Subsequently, the application of I-PLGA-rhTSH nanoparticles facilitated apoptosis and attenuated immobilization via inhibiting F-actin assembling of FTC-133 cells.
The present study develops a suitable approach integrating I and rhTSH, and this strategy is a feasible regimen enhancing the effect of radioiodine ablation for the treatment of thyroid cancer.
侵袭性甲状腺癌（ATC）通常因钠/碘同向转运体（NIS）下调而失去对碘-131（I）的放射性碘摄取能力。促甲状腺激素受体（TSHR）的表达比NIS更持久，重组人促甲状腺激素（rhTSH）的给药可促进NIS的从头合成。因此，探索将I与rhTSH相结合的方法可能是一种将I选择性递送至甲状腺癌以增强放射性碘消融效果的可行治疗策略。
使用I、聚乳酸-羟基乙酸共聚物（PLGA）和rhTSH合成I-PLGA-rhTSH纳米颗粒。通过光学显微镜、扫描电子显微镜（SEM）、放射自显影和免疫荧光（IF）染色来确定I-PLGA-rhTSH纳米颗粒的特性。用Mastersizer 3000测量I-PLGA-rhTSH纳米颗粒的直径，并测定I在I-PLGA-rhTSH纳米颗粒中的包封率（EF）和单个纳米颗粒的放射性。然后，建立小鼠肿瘤异种移植模型，在体内研究I-PLGA-rhTSH纳米颗粒的生物分布及其对甲状腺癌细胞凋亡的影响。此后，使用细胞计数试剂盒-8和乳酸脱氢酶（LDH）释放试验研究I-PLGA-rhTSH纳米颗粒在细胞活力方面的作用。随后，通过免疫染色、博伊登侵袭试验和鬼笔环肽染色评估I-PLGA-rhTSH纳米颗粒降低细胞活力的潜在机制。
我们的结果表明，使用聚乳酸-羟基乙酸共聚物（PLGA）包裹I并经rhTSH修饰（I-PLGA-rhTSH）来制备纳米颗粒的方法，是将I与rhTSH相结合的可行途径。同时，I-PLGA-rhTSH纳米颗粒的包封率（EF）约为60%，单个纳米颗粒的放射性约为1.1×10-2 Bq。在小鼠肿瘤异种移植模型中通过尾静脉注射I-PLGA-rhTSH纳米颗粒后，I-PLGA-rhTSH纳米颗粒被选择性地递送至异种移植肿瘤中，逐渐富集并缓慢下调。此后，注射I-PLGA-rhTSH纳米颗粒后肿瘤重量显著减轻。随后，I-PLGA-rhTSH纳米颗粒的应用通过抑制FTC-133细胞的F-肌动蛋白组装促进了细胞凋亡并减弱了细胞固定。
本研究开发了一种将I与rhTSH相结合的合适方法，该策略是增强放射性碘消融治疗甲状腺癌效果的可行方案。
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