多模态纳米探针--乳腺癌个体化诊疗的探索

With the development of diagnostic modalities on breast cancer, breast-conserving surgery (BCS) has become the standard method of treatment for early stage breast cancer. However, because there is a considerable debate regarding what margin of normal tissue surrounding the tumor constitutes a negative margin and staging of axillary lymph nodes, the rate of surgical excision and recurrence were still controversial. HER-2 has become an important prognostic and predictive factor, as well as a target for molecular imaging in many imaging technologies in recent years. While reports on the application of ultrasound contrast agents (UCAs) in ultrasound targeted HER-2 imaging were rare because the micron-sized diameter of UCAs are incapable of crossing the gap of vascular endothelium. In order to resolve the relevant clinical problems of BCS, we changed the size of UCAs by preparing a nano-sized UCA and accomplished HER-2 targeted ultrasound binding in previous study. Meanwhile, the current nano-sized UCA still need to be optimized infuture, such as the targeted binding ability, the signal to noise ratio (SNR) during imaging, and so on. Based on the research progress, we aim to enhance the target binding ability by conjugating a fluorescent contrast agent, which can be actively taken up and accumulated by cancer cells but not by normal cells, improve the SNR by combining the complementary features of both ultrasound and optimal imaging, and introduce the time-boxed photodynamic therapy properly. With this study, we hope to provide new strategies and research data for individualized diagnosis and therapy.

得益于乳腺癌诊断技术的进步，保乳治疗已经成为大多数早期乳腺癌患者的治疗标准。但是，由于缺乏对肿瘤浸润边缘和淋巴结状态的精确判断，导致直接影响手术疗效。HER-2分子作为重要的肿瘤标记物，已成为众多影像学分子成像技术的热门靶点。然而，由于成像介质（超声造影剂）存在粒径大、难以通过血管内皮的问题，以HER-2为靶点的超声分子成像研究鲜有报道。通过前期研究，我们以HER-2分子作为切入点，通过改变造影剂粒径大小，制备具有HER-2靶向性的纳米级超声造影剂，实现HER-2分子靶向成像，以解决保乳治疗中的现实问题。同时，我们也认识到现有的造影剂还存在靶向结合力及成像信噪比有待提高等不足。基于以上研究，我们拟通过增加具有肿瘤自主亲和性的荧光素提高寻靶能力，结合超声与光学成像的优势互补以提高成像信噪比，并适时引入可控性光动能治疗，优化及更好的利用纳米级超声造影剂，为最终的乳腺癌个体化诊疗提供思路。

得益于乳腺癌诊断技术的进步，保乳治疗已经成为大多数早期乳腺癌患者的治疗标准。但是，由于缺乏对肿瘤浸润边缘和淋巴结状态的精确判断，导致直接影响手术疗效。HER2分子作为重要的肿瘤标记物，直接影响患者治疗与预后，因此备受关注。前期研究中，我们以HER2分子作为切入点，通过改变造影剂粒径大小，制备具有HER2靶向性的纳米级超声造影剂Nbs-Affibody，实现HER2分子靶向成像，其体外靶向结合率可以达到36.7%。但是，Nbs-Affibody造影剂还存在靶向结合力不足，以及由于超声成像信噪比低造成的肿瘤边缘与淋巴结转移追踪能力弱的实际问题，在本研究中我们引入了IR783—近红外染料，利用IR783的肿瘤特异亲和性，制备具有双靶向（肿瘤靶向与HER2靶向）、双成像功能（超声成像与近红外成像）的多模态纳米微泡IR783-Nbs-Affibody，实现高效的HER2阳性乳腺癌靶向结合，同时兼具超声成像与近红外成像能力，实现更优的肿瘤边缘与转移灶的显示与追踪；我们同时引入光动能治疗原件HPPH，制备靶向治疗型纳米微泡IR783-Nbs-Affibody-HPPH，实现靶向成像后的后续靶向治疗。以上结果对于解决HER2阳性乳腺癌保乳治疗的诊断瓶颈提供了可行的参考方法，同时进行了靶向治疗的积极尝试。