T1/T2双模MRI纳米探针在乳腺癌靶向分子诊疗中的基础与应用研究

Breast cancer is the most common malignancy among women and severely threatens women’s health. Breast cancer diagnosis is of great difficult because of its complex biological behaviors. Diagnosis and treatment is even more difficult in a specific subtype named triple negative breast cancer (TNBC), which lacks prominent tumor markers including estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-). Hence, developing molecular theranostics that could specifically target TNBC is of great value and significance. Magnetic resonance imaging (MRI) plays important rule in facilitating breast cancer diagnosis, however, conventional MRI suffers low tumor detection specificity and sometimes lacks of enough tissue contrast. Currently, T1 or T2 signal enhancing contrasts are often utilized to obtain better MR images. But single enhancement of either T1 or T2 signal still could not fulfill the diagnostic requirements. Therefore, we aim to synthesize a Gd loaded Au-Pt-Iron oxide nanoparticle (named as DB-HNT) which could simultaneously enhance both T1 and T2 signal. We will also conjugate the DB-HNT with peptides which can bind with the previously identified TNBC marker CXCR4, to establish a dual signal enhanced molecular probe for breast cancer diagnosis. Moreover, we will incorporate miR-22, a small non-coding RNA which plays important roles in preventing cancer metastasis, into our CXCR4 targeted DB-HNT to develop a TNBC theranostic agent named as CM-DB-HNT. Overall, we expect that our research will provide a new method and technique for breast cancer diagnosis, localization as well as personalized treatment.

乳腺癌是女性最常见的恶性肿瘤，严重威胁女性生命健康。当前，乳腺癌异质性导致其肿瘤生物学行为复杂，尤其是无ER，PR，HER2受体的三阴性乳腺癌更因缺乏特异性受体而相对诊疗困难。因此研究新的三阴性乳腺癌靶向诊疗探针具有重要意义。MRI作为一种先进的影像诊断手段，在乳腺癌的诊断中起着重大作用，然而常规MRI对乳腺癌的成像缺乏特异性，且对某些类型的组织缺乏足够的对比度，常需注射对比剂实现更佳的成像效果，但目前单一T1或者T2成像对比剂仍然难以满足复杂的肿瘤诊断需求。基于此，本课题以新型T1/T2双增强金-铂-氧化铁纳米颗粒为平台，以前期工作中证明在三阴乳腺癌高表达的CXCR4为靶点，通过简易的化学方法制备以CXCR4靶向的T1/T2双增强的MRI纳米分子探针，并进一步负载miR-22作为治疗药物，评价其在乳腺癌中的诊断及治疗的基础和效果， 从而为乳腺癌的诊断、定位及个性化治疗等提供一个新的方法。

在本研究中，通过将哑铃状的Au-Fe2O3纳米与CXC趋化因子受体4（CXCR4）结合多肽连接来构建多肽功能化的Au-Fe2O3纳米颗粒（称为anti-CXCR4-Au-Fe2O3纳米探针）。哑铃状的Au-Fe2O3纳米粒子的金纳米粒子（直径3.3±0.3纳米）与巯基化的CXCR4结合环形多肽通过Au-S共价键结合，而Fe2O3纳米粒子（直径8.7±0.8纳米）用于T2加权磁共振成像（MRI）。Anti-CXCR4-Au-Fe2O3纳米探针具有良好的生物相容性，可以作为T2加权磁共振成像造影剂，并且具有肿瘤靶向功能。anti-CXCR4-Au-Fe2O3纳米探针与MCF-7和MDA-MB-231两种乳腺癌细胞表现出强烈的相互作用。在MDA-MB-231荷瘤小鼠模型中，62％的MRI信号负增强，表明anti-CXCR4-Au-Fe2O3纳米粒子能高效和特异性识别肿瘤。 在修饰miR-22 分子后，纳米探针对肿瘤生长有明显的抑制效果。发表论文5篇，其中SCI论文4篇，申请专利一项。