肝癌射频消融后残余肿瘤的坏死亲和性靶向放射治疗及其机制研究

Radiofraquency ablation (RFA) has become one of the widely used minimally invasive treatments for hepatic carcinoma recent years. However, high local recurrence, resulted from residual tumor cells after RFA, usually leads to poor prospective efficacy, especially for the tumors near vessels or dangerous organs. Necrosis targeting internal radiotherapy (NTIRT) is a new anticancer strategy which we propose on the basis of previous researches, aiming at killing residual tumor cells after RFA to decrease local recurrence. According to the NTIRT strategy, necrosis avid agents labeled by therapeutic radioactive nuclide may selectively deposit at coagulative necrosis induced by RFA, which will form resistant radioactive surroundings among and peri-lesions to kill residual tumor cells. Eventually, the entire tumor will be eradiated radically. To validate the hypothesis, rat hepatic Radiation-induced Fibrosarcoma-1 (R1) tumor will be used to establish the model of residual tumor around necrosis by partial RFA. Hypericin labeled by 131I as a necrosis avid agent will be administered intravenously 24h after RFA. Necrosis targeting capability of hypericin will be evaluated through in vivo and ex vivo methods including SPECT, fluorescence microscope and phosphor imager. To evaluate the therapeutic effect of NTIRT, Tumor volume and apoptosis index of residual tumor in different groups will be calculated at different time points through contrast magnetic resonance imaging (MRI), terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) and AnnexinV/PI Flow Cytometry. The mechanisms of the treatmemt will be explored by detection of expression of apoptosis related factors such as caspase-3, PARP, bcl-2, bax, fas and P53. The necrosis affinity mechanisms will be speculated by microradioautography, protein segregation, identification and bioinformatics analysis. The study may provide an entirely new remedy for residual tumor after RFA to decrease local recurrence and increase prospective efficacy. Also, the study may elucidate the mechanisms of NTIRT.

肝癌射频消融治疗后肿瘤残存与局部复发是影响其中远期疗效的重要因素,目前尚无有效的解决方案。坏死亲和性靶向放射治疗是本课题组在前期研究基础上提出的针对肝癌射频消融治疗后残余肿瘤细胞的一种全新的治疗策略。利用标记治疗性放射性核素的坏死亲和剂靶向性地沉积于射频消融后的凝固性坏死组织中，在其内部和周边形成持续性的放射性环境，杀灭病灶内部和边缘的残存肿瘤细胞，而达到根治性放射治疗的效果。本研究拟通过静脉注射标记131I的坏死亲和剂-金丝桃素，对大鼠R1肝癌射频消融后残余瘤模型进行治疗，通过SPECT成像等多种方法检测其对射频消融后凝固性坏死的靶向性，通过残余瘤体积变化、细胞凋亡率等评价疗效，检测凋亡相关因子的表达情况并推测其作用机制，通过相关蛋白质的分离、鉴定和分析探索金丝桃素对坏死组织的亲和性机制。本研究将为治疗肝癌射频消融后残余肿瘤、降低局部复发率提供新方法，为明确其作用机制提供理论和实验依据。

肝癌射频消融治疗后肿瘤残存与局部复发是影响其中远期疗效的重要因素,目前尚无有效的解决方案。坏死亲和性靶向放射治疗是本课题组在前期研究基础上提出的针对肝癌射频消融融治疗后残余肿瘤细胞的一种全新的治疗策略。利用标记治疗性放射性核素的坏死亲和剂靶向性地沉积于射频消融后的凝固性坏死组织中，在其内部和周边形成持续性的放射性环境，杀灭病灶内部和边缘的残存肿瘤细胞，而达到根治性放射治疗的效果。本研究通过静脉注射标记131I 的坏死亲和剂-金丝桃素，对大鼠肝癌射频消融后残余瘤模型进行治疗，通过MRI、SPECT、γ计数及荧光成像等多种方法检测其对射频消融后凝固性坏死的靶向性。实验结果证明，131I标记的金丝桃素对射频消融后的凝固性坏死具有良好的靶向性，且随着时间的推移，该靶向性进一步加强。131I标记的金丝桃素可以明显地抑制射频消融后残余瘤的生长，延长肿瘤的倍增时间。本研究证明了射频消融联合131I标记的金丝桃素具有潜在的协同抗肿瘤效应，该思路为治疗肝癌射频消融后残余肿瘤、降低局部复发率提供新方法，为明确其作用机制提供了理论和实验依据。