生物伪装化的近红外光响应载体系统用于多药耐药肿瘤治疗

How to overcome the multidrug resistance of tumor and realize the real-time monitoring of the therapeutic efficacy are big challenges in tumor therapy. In this proposal, a bio-camouflaged near-infrared light-responsive carrier system will be fabricated by loading 3 nm Ag2S quantum dots into cell-secreted microvesicles, which can be used for effective therapy of multidrug resistant tumor. The carrier system holds such advantages: (1) Cell-derived microvesicles with tumor targeting capability will firstly be prepared by taking advantage of the characteristic that microvesicles are formed by direct budding from the cell membrane and engineering the donor cell membrane with functionalized phospholipids via hydrophobic interaction. Then Ag2S quantum dots will be loaded into the vesicles to obtain bio-camouflaged carrier systems, which can escape the reticuloendothelial system uptake, prolong the blood circulation time and improve the tumor accumulation of the carrier systems; (2) The 3 nm Ag2S quantum dots will be site-specifically released on the tumor sites by utilizing the near-infrared photothermal effect of the Ag2S quantum dots since the vesicles can be broken down by the heat energy produced in the light-heat conversion process. The released quantum dots then can penetrate into the tumor tissues through free diffusion and thus more effectively kill multidrug resistant tumor cells by photothermal effect; (3) Real-time monitoring of the therapeutic efficacy can be performed by near-infrared fluorescence imaging with the Ag2S quantum dots. This research can provide a new method for the therapy of multidrug resistant tumor.

如何克服肿瘤多药耐药，并实时跟踪治疗效果是肿瘤治疗面临的巨大挑战。本项目拟将3 nm Ag2S量子点载入细胞分泌的微囊泡，构建生物伪装化的近红外光响应载体系统用于高效治疗多药耐药肿瘤。该载体系统具有以下特征：（1）用功能化磷脂分子通过疏水相互作用自然嵌合到细胞膜上，然后利用细胞通过出芽分泌微囊泡这一特性，获得具有肿瘤靶向功能的细胞源性微囊泡，再将Ag2S量子点载入囊泡实现生物伪装，从而躲避机体免疫细胞吞噬，延长血液循环时间，提高载体系统在肿瘤部位的富集量；（2）利用Ag2S量子点近红外光热转换产生的热量分解囊泡，在肿瘤部位定点释放3 nm Ag2S量子点，该量子点可通过自由扩散渗透到肿瘤组织内部，再通过光热作用更好地杀死耐药肿瘤细胞；（3）利用Ag2S量子点的近红外荧光成像功能实时跟踪光热治疗效果。本项目能为多药耐药肿瘤治疗提供一种新的方法。

纳米材料在肿瘤诊断与治疗方面表现出极大潜力。然而，由于体内免疫细胞对外源性物质的清除以及肿瘤组织致密的胞外基质和高间质液压阻碍，纳米颗粒往往难以高效靶向并深入渗透到肿瘤组织内部。本项目基于近红外量子点和胞外囊泡，构建了生物伪装的刺激响应型纳米平台，通过调节纳米材料的微观结构控制其性能，达到增强肿瘤成像及治疗的目的。我们调控Ag2S量子点晶体生长，获得可经肾清除的小粒径Ag2S量子点，该量子点兼具近红外荧光和近红外光热转换性能。继而通过电穿孔将Ag2S量子点隐藏在巨噬细胞分泌的囊泡中，构建出具有天然外壳的近红外光响应的纳米复合材料，实现了在肿瘤中高效富集、可控释放抗肿瘤纳米颗粒并通过近红外荧光成像实时监测抗肿瘤治疗过程。释放出的小粒径Ag2S量子点可穿透直径9 mm的肿瘤并通过光热作用有效地杀死肿瘤细胞，在治疗后还可通过肾脏迅速从体内排出，避免了纳米颗粒长期滞留引起的潜在毒性。在此基础上，我们还构建了肿瘤微环境刺激响应型纳米平台，研究了其在多药耐药肿瘤治疗中的应用潜力。本项目对纳米材料结构与性能关系的研究，为后续开发新型多功能纳米材料用于疾病诊断与治疗奠定了基础。项目执行期间，发表SCI论文8篇，其中影响因子大于10的3篇，申请发明专利1项，培养研究生3名。