血流环境中白细胞介导纳米药物载体与肿瘤细胞的靶向结合研究

Clinical data shows that about 90% death cases are due to tumor metastasis. The metastassis of tumor cells may lead to the formation of secondary tumor, Studies demostrated that inflammatory cells, such as leukocytes, lymphocytes and monocytes, have close connections to tumor and tumor metastassis. Cell mechanics studies have indicated that white blood cells could facilitate the metastasis of tumor cells in blood flow by targeted adhesion. However, whether the similar mechanism could be applied to anti-tumor nanoparticle carriers transportation to tumor focus is rarely known, which is of great interest and remains challenging. Based on previous studies we intend to take advantage of those white blood cells to facilitate nanoparticle drug carriers targeting tumor cells under blood flow in this proposal, 1) We will first explore the feasibility that white blood cells may act as "Trojan" to help nanoparticle drug carriers bind to tumor cells by in vitro experiment; 2) Furthermore, we will quantify the target molecules, flow conditions and efficiency in the process that white blood cells facilitate adhesion between nanoparticle carriers and tumor cells. We aim to provide promising experimental evidence for tumor-targeted nanoparticle carriers design and improve the efficiency of drug delivery.

临床数据表明因癌症死亡的病人90%归结于肿瘤转移。血液中肿瘤细胞的微转移是形成继发性肿瘤的先决条件，各种炎症细胞，如中性粒细胞、淋巴细胞和单核细胞等，都与肿瘤及其转移有着密不可分的联系。细胞力学研究已揭示了白细胞借助靶向结合在肿瘤细胞通过血液循环的转移中起介导作用。同样的机理能否用于将抗癌药物微纳米粒子有效输送到病灶部位与肿瘤细胞结合，成为抗癌药物靶向治疗的一个热点。本项目拟在前者研究成果的基础上，进行流动状态下白细胞介导微纳米药物粒子与肿瘤细胞的靶向结合研究：1）通过体外实验方法，探索白细胞介导纳米药物载体与肿瘤细胞靶向结合的可行性和效率；2）定量研究白细胞介导靶向微纳米粒子与肿瘤细胞结合的靶标、流动条件及效率。目标为微纳米靶向药物载体的设计，提高其输送并杀灭肿瘤细胞的效率提供实验依据。

临床数据表明因癌症死亡的病人90%归结于肿瘤转移。血液中肿瘤细胞的微转移是形成继发性肿瘤的先决条件，各种炎症细胞与肿瘤及其转移有着密不可分的联系。细胞力学研究已揭示了白细胞借助靶向结合在肿瘤细胞通过血液循环的转移中起介导作用。同样的机理能否用于将抗癌药物微纳米粒子有效输送到病灶部位与肿瘤细胞结合，成为抗癌药物靶向治疗的一个热点。我们的研究表明：1）在剪切流中白细胞浓度增加对肿瘤细胞在内皮细胞上的黏附起到促进作用。细胞浓度比为3：1时，肿瘤细胞在内皮细胞上的瞬时黏附和累积黏附均比细胞浓度比为1：1时有显著提升，且在高剪切率( 100、200 s -1 ) 下更为明显。在观察的5 分钟内，随着剪切率的增加，细胞浓度比增大对肿瘤细胞黏附产生影响的时间点有所提前。2）在剪切流中造影红细胞的存在对肿瘤细胞在内皮细胞上的黏附起到促进作用。造影红细胞促进了白细胞在内皮细胞上的黏附，增加了肿瘤细胞与黏附白细胞的碰撞频率，并最终促进了肿瘤细胞在内皮细胞上的黏附，且这一现象在高剪切率（200 s-1）更为明显；肿瘤细胞黏附效率在前3分钟内逐渐提高。3）内皮细胞单层不但改变流动腔内的局部速度场分布，也使得壁面剪切率升高。而黏附在纤维蛋白上的黑色素瘤细胞对局部水动力环境的影响要大于黏附着的白细胞；4）PMN能够介导靶向脂质体和肿瘤细胞的结合，但效率需要提高。