双功能铂纳米团簇药物体系的构建及其抗血液肿瘤机制的研究

Recently, the incidence of hematological malignancy, such as various leukemia, multiple myeloma, and malignant lymphoma, exhibits an increasing tendency, resulting in the irreversible health hazard. Platinum anti-tumor drugs are the most effective methods for the treatment of diverse tumors, however, number of drawbacks impede their anticancer efficiency including their systemic toxicities and poor specificity. In order to develop a novel anti-tumor drugs with little side-effect, this project is intended to study on the synthesis of bifunctional platinum nanoclusters (Pt NCs@NH2) with fluorescent and anti-tumor properties, the chemical binding model between Pt NCs and ligands, and the mechanism of fluorescence, which subsequently applied in the bio-imaging of hematological system cells. After modification with a targeted antibody onto Pt NCs, an anti-tumor drug system (anti-CD19-Pt NCs@NH2) which has the trend to target the B-cell lymphoblastic leukemia can be established and the Pt NCs-induced apoptosis mechanisms can be proposed. This bifunctional Pt NCs-based anti-tumor drug is superior to traditional one, which could image the suspension cells and avoid the introducing of other fluorescent dyes (like cy5.5, IRDye 800CW, and QDots, etc.). Simultaneously, it could achieve selective labelling of tumor cells and inhibition of cell proliferation, providing a new idea for the clinical tracing, diagnosis and treatment of hematological diseases, especially acute lymphoblastic leukemia.

近几十年来，血液系统恶性肿瘤包括各类白血病、多发性骨髓瘤以及恶性淋巴瘤等，发病率逐年增加，带来的危害日益加剧。铂类抗肿瘤药物是治疗肿瘤最有效的手段，但其具有一定的毒副作用和缺乏组织特异性的缺点。本项目以研发新型、低毒副作用抗肿瘤药物为目的，拟研究荧光—抗肿瘤双功能性铂纳米团簇（Pt NCs@NH2）的合成方法、团簇与配体稳定模型及荧光机理，并应用于血液系统悬浮细胞的光学成像中。重点构建靶向抗体修饰的抗肿瘤药物体系（anti-CD19-Pt NCs@NH2），靶向定位B淋巴细胞白血病细胞，提出诱导肿瘤细胞凋亡机制。优于传统铂类抗肿瘤药物，这种双功能性铂纳米团簇靶向药物体系，可避免引入其他荧光染料（如cy5.5、IRDye 800CW、量子点等），完成对血液系统细胞光学成像的同时，选择性标定肿瘤细胞并抑制细胞增殖，对血液系统疾病，尤其是急性淋巴细胞白血病的临床示踪、诊断和治疗提供新思路。

血液系统恶性肿瘤包括各类白血病、多发性骨髓瘤以及恶性淋巴瘤等，发病率逐年增加，带来的危害日益加剧。铂类抗肿瘤药物是治疗肿瘤最有效的手段，但其具有一定的毒副作用和缺乏组织特异性的缺点。本项目以开发新型、低毒副作用抗肿瘤药物为目的，研究荧光—抗肿瘤双功能性铂纳米团簇（Pt NCs@NH2）的合成方法、团簇与配体稳定模型及荧光机理，并应用于血液系统悬浮细胞的光学成像中；重点构建靶向抗体修饰的新型抗肿瘤药物体系（anti-CD19-Pt NCs@NH2），靶向定位B淋巴细胞白血病细胞，提出诱导肿瘤细胞凋亡机制。研究结果表明，大部分铂纳米团簇与配体的伯胺基通过弱共价键相结合，其荧光发射机理遵循配体-金属电子转移理论（LMCT）。荧光Pt NCs@NH2具有对血液系统悬浮细胞光学成像的功能，并展现出对血液系统肿瘤细胞更强的亲和力。基于表面可修饰性，靶向抗体修饰的新型抗肿瘤药物体系（anti-CD19-Pt NCs@NH2）能选择性进入CD19表达阳性的人外周血B淋巴细胞BV173，实现肿瘤细胞的靶向识别。铂纳米团簇材料在肿瘤细胞的内在化途径表明Pt NCs@NH2在K562细胞膜处聚集，采用小窝蛋白介导的内吞途径和巨细胞胞饮途径进入细胞，分散于细胞质中，随后在溶酶体、胞内体等酸性细胞器处聚集，相互作用生成带有腐蚀性的铂离子，离子通过增加PUMA和cleaved caspase 3蛋白的表达，激活p53活性，启动肿瘤细胞的凋亡通路，抑制肿瘤细胞的增殖、侵袭和迁移，诱导肿瘤细胞凋亡。活体动物试验证明Pt NCs@NH2药物能够在肿瘤部位聚集，发挥令人满意的抗肿瘤效果，而对于其他正常器官无明显毒副作用。相比于传统铂类抗肿瘤药物，这种新型荧光-抗肿瘤双功能铂纳米团簇材料，可避免引入其他荧光染料，完成对血液系统细胞光学成像的同时，选择性标定肿瘤细胞并抑制细胞增殖，对血液系统疾病，尤其是急性淋巴细胞白血病的临床示踪、诊断和治疗提供新思路。