靶向PD-L1和PS磷脂的抗肿瘤金纳米材料的分子模拟设计和机制研究

Lung cancer is the malignant tumor with the highest incidence and mortality in China. It is of great significance to develop diversified drugs. Our previous work has shown that small-sized, hydrophilic nanoparticles may serve as a respiratory drug carrier, greatly reducing the side effects in delivering drugs to lung cancers. Besides, we found proteins' membrane orientation dynamics could be regulated by lipid dynamics. In this project, molecular simulations will be used to design a multi-functional anti-tumor gold nanomaterial. First, it can target PD-L1 and regulate its membrane orientation dynamics to block its binding to PD-1, which thus recovers the killing power of immune cells to cancer cells. Then, it can target PS lipids in cancer cell membranes, which promotes the killing of cancer cells when being locally heated to a very high temperature. Finally, it can be applied to the respiratory administration. For molecules targeting PD-L1, we will screen FDA-approved drugs and ZINC15 drug-like molecules. We expect to achieve the new use of old drugs from the former, and obtain high binding small molecules from the latter. We will further use molecular simulations to explore the effects of the surface modification of two small molecules targeting PD-L1 and cell membrane on nanoparticles' anti-tumor efficiency. This research will have important theoretical guiding significance for the development of nanomedicines targeting lung cancer.

肺癌是高居我国发病率和死亡率首位的恶性肿瘤，研发多样化的药物具有重大意义。我们前期工作表明：小尺寸、亲水的纳米颗粒有望作为呼吸药物载体，显著降低递送药物至肺癌部位的副作用；另外，磷脂动力学可以调控膜蛋白膜取向动力学。本项目将运用分子模拟技术设计一种多功能的抗肿瘤金纳米材料。首先，它能够靶向PD-L1并调控其膜取向动力学，进而阻断它与PD-1的结合，恢复免疫细胞对肿瘤细胞的杀伤作用；其次，它还能靶向肿瘤细胞膜中的PS磷脂，通过局部升温发挥促进杀伤肿瘤细胞的作用；最后，它有望呼吸给药。对于靶向PD-L1分子的筛选，我们将从FDA已批准的“老药”以及ZINC15类药小分子数据库中筛选，以期“老药新用”及确保获得高结合力的小分子。我们将进一步运用分子模拟研究靶向PD-L1和PS的两种小分子在纳米颗粒表面的修饰方式对其抗肿瘤作用效率的影响。该项研究将对靶向肺癌的纳米药物研发具有重要的理论指导意义。

近年来，随着纳米技术在生物医学领域应用的不断深入，调控免疫响应的纳米药物已得到广泛的关注。本项目中，我们主要聚焦于分子模拟设计靶向细胞膜、调控免疫响应的抗肿瘤金纳米材料。我们首先运用分子动力学模拟并辅以细胞生物学实验揭示了细胞膜脂筏结构域的动力学调控机制和生物学意义，以及不同结构域对PD-L1蛋白膜取向动力学的调控细节，为PD-L1蛋白胞外结构域的膜取向动力学的调控作为免疫调控的一种新途径奠定理论基础。随后，我们运用分子动力学模拟及自由能计算明确了金纳米颗粒的表面配体的理化性质与细胞膜靶向能力、PD-L1蛋白膜取向动力学调控能力的相关性。最后，我们借助分子对接和MM/PBSA自由能计算方法筛选获得了多个候选小分子，其可作为金纳米颗粒的修饰配体、以调控PD-L1蛋白的膜取向动力学及T细胞的免疫杀伤响应。此外，我们还在此基础上，进一步开发了机器学习算法，以实现快速预测对PD-L1蛋白具有抑制活性的小分子。相关的研究结果项目负责人以通讯作者在J. Am. Chem. Soc.、Nanoscale、Biomater. Sci.、J. Chem. Phys.、J. Chem. Inf. Model.等期刊上发表8篇论文、累计引用344次（Google Scholar），另有5篇论文在准备投稿中。其中，1篇论文被F1000Prime推荐一次，1篇论文被引用280余次、入选ESI高被引论文。此外，项目负责人还发表外文图书章节1章、作为客座编辑负责3本SCI期刊的3个专辑。