多功能核仁素靶向增殖抑制性诊疗体在三阴性乳腺癌中的实验研究

Triple negative breast cancer (TNBC) is notorious for its less sensitivity to ordinary treatments and high rate of tumor recurrence. As photothermal therapy (PTT) combined with photoacoustic imaging bring inspiration for its theranostic, it still remains to be solved that the residual tumor grows faster and becomes more invasive. In our previous research, two-dimensional photothermal agents exhibited great heating performance and the extent of heating area was enlarged, and yet tumor still reappeared after treatment. On the other hand, nucleolin-targeted aptamer AS1411 exhibits great ability to suppress the proliferation of tumor cells. Therefore, we propose an effective PTT in TNBC by combining two-dimensional photothermal agents with AS1411 to reinforce the impact of therapy as well as reduce DNA replication by binding to nucleolin and restraining connect to its ligand competitively for further antiproliferative effects. To further realize our proposal, we plan to fabricate a composite microbubbles (MBs)-based theranostic system, on which silicene (photothermal agent) and AS1411 is loaded. Furthermore, the antiproliferating mechanism of AS1411 on residual tumor growth and development after photothermal therapy will be elucidated based on the detailed performance study in MDA-MB-231 cell line and animal models. This project would provide great inspiration and promote the future clinical applications of PTT.

三阴性乳腺癌是一种对常规治疗手段不敏感且极易复发的难治性肿瘤，光声成像引导的光热疗法虽为其诊疗开辟新思路，但成像分辨率低、残余瘤生长加快、侵袭力增强等缺陷亟待解决。项目组前期研究发现，二维光热剂尚佳的光热性能增大了肿瘤消融范围，但仍存在复发；此外，核酸适配体AS1411可靶向肿瘤细胞高表达的核仁素且具有增殖抑制性。本研究提出：新型二维光热剂联合AS1411不仅强化消融效果，亦可通过竞争性抑制核仁素-配体复合物的形成，减少肿瘤细胞复制，进一步抑制其增殖，克服光热疗法后残余瘤易复发的难题。为验证这一设想，拟构建一种以气体微泡为基底，同时携带光热剂及AS1411的诊疗体；在MDA-MB-231细胞及裸鼠肿瘤模型中进行实验，利用声阻抗使其兼具增强造影功能；阐明AS1411对光热术后残余瘤生长的影响及机制，明确光热疗法联合适配体对术后消融范围及生长情况的影响，为实现光热疗法在临床中应用提供重要依据。

三阴性乳腺癌是一种对常规治疗手段不敏感且极易复发的难治性肿瘤，光声成像引导的光热疗法虽为其诊疗开辟新思路，但成像分辨率低、残余瘤生长加快、侵袭力增强等缺陷亟待解决。项目组前期研究发现，二维光热剂尚佳的光热性能增大了肿瘤消融范围，但仍存在复发；此外，核酸适配体AS1411可靶向肿瘤细胞高表达的核仁素且具有增殖抑制性。本研究提出：新型二维光热剂联合AS1411不仅强化消融效果，亦可通过竞争性抑制核仁素-配体复合物的形成，减少肿瘤细胞复制，进一步抑制其增殖，克服光热疗法后残余瘤易复发的难题。为验证这一设想，本课题构建了一种以二维纳米光热诊疗剂为基底，同时包裹有二氧化硅层且携带原卟啉及AS1411的诊疗体在乳腺癌模型中进行实验；阐明AS1411对光热及声动力术后残余瘤生长的影响及机制，明确光热疗法联合适配体对术后消融范围及生长情况的影响，为实现光热疗法在临床中应用提供依据。在课题进展过程中，考虑到原卟啉可用于超声动力学治疗，将原卟啉引入治疗体系中，可实现同时利用在光热条件刺激下响应释放从而实现在肿瘤区域内的级联治疗策略；在完成本课题的基础上，也针对三阴性乳腺癌肿瘤微环境氧气含量设计开展了相关课题，以期进一步提高三阴性乳腺癌治疗策略，解决其难治性问题；此外，申请人也进一步结合肿瘤原位微环境特点，调研其微环境对肿瘤免疫微环境的影响，结合超声治疗治疗深部肿瘤的特异性、肿瘤微环境特征及免疫抑制微环境三者设计了一种新型的基于超声治疗手段的免疫增效治疗。