仿生隐形红细胞膜包被磁性夹心二氧化硅纳米药物载体的长循环和肿瘤治疗研究

Designing long-term circulation nanocarriers in vivo is crucial for achieving efficient passive targeting to tumor, which is bottleneck problem of anti-drugs. To reduce the elimination of mononuclear phagocyte system and improve tumor targeting and ultimately enhance treatment, a novel biomimetic stealth nano-based drug delivery system will be constructed based on the magnetic rattle-type silica (MRS) nanocarriers coated with red blood cell membrane (RBCm), RBCm-MRS, possessing the advantage of long-term circulation in vivo. We plan to explore the molecular mechanism of long-term circulation RBCm-MRS in vivo through the self-recognition of CD47 protein in RBCm and the non-specific adsorption of plasma proteins. Furthermore, we will also evaluate the effectiveness and biocompatibility of the RBCm-MRS system by using the rodent model of human breast cancer. The RBCm-MRS system can combine extraordinary mechanical stability and high drug loading efficiency of MRS, and bio-inspired long circulation lifetime properties of the RBCm to escape the macrophage uptake, improve the tumor-targeted efficiency and eventually obtain an optimal therapeutic effect. Benefiting from the outstanding properties of long-term circulation, high drug loading and targeting to tumor and magnetic resonance imaging, this advanced drug delivery system can kill cancer cells completely. More importantly, we believe this project can not only provide new approaches and theories for theranostics and personalized cancer therapy but also will significantly promote the clinical application of nanocomposite-based drug delivery.

设计构筑具有长时间血液循环特性的纳米药物载体是实现高效被动靶向到肿瘤组织的关键，也是当前解决抗癌药物瓶颈问题最为有效的一种方法。本项目拟利用红细胞膜体内长循环的特点，首创构建以磁性夹心二氧化硅纳米颗粒为药物载体，表面包被红细胞膜的新型仿生隐形纳米药物体系。该体系兼具了磁性夹心二氧化硅药物载体的高稳定性、高载药量和磁共振（MR）影像的优势和红细胞膜的仿生伪装和长循环特性，可以降低单核巨噬细胞系统的清除，提高肿瘤靶向性，从而最终提高治疗效果。从CD47自我识别和调理素非特异性吸附角度探讨其长循环的分子机制，同时在人乳腺癌啮齿类动物模型上进一步评价该体系的安全性和有效性。该载药体系利用长循环、高药物负载、高效靶向输送药物结合MR影像的优势，达到彻底杀死癌细胞的目的，有望为实现癌症的诊疗一体化、个体化疗法开拓新方法和新理论，进一步推进复合纳米材料药物临床应用的进程。

本项目紧扣纳米药物载体在肿瘤治疗中所面临的血液循环时间短、靶向效果差的关键问题，首先制备了磁性夹心二氧化硅多功能纳米颗粒。然后利用红细胞膜长循环特性，通过包被技术，成功构建了一种具有高药物负载、隐形长循环、高效靶向和生物相容性好的磁性夹心二氧化硅纳米药物载体，证明了长循环能提高药物载体在癌症中的高靶向，证明了其在诊疗一体化中的潜在应用前景。为进一步证明红细胞膜长循环的普适性，我们还研究红细胞膜对金壳的包覆以及体外和体内长循环性能、肿瘤治疗的研究。研究结果表明，红细胞膜长循环的特性为解决无机纳米颗粒的体内循环时间短，肝脾摄取多，肿瘤靶向低等问题提供全新的思路。夹心二氧化硅的亚急性毒性表明，夹心二氧化硅的毒性表现出明显的尺寸依赖性，尺寸越小毒性越大。由于动物模型对纳米材料表现出不同的毒性反应，特别是处于哺乳期的母鼠和仔鼠。以氧化石墨烯（GO）为模型，研究发现哺乳期母鼠饮用含氧化石墨烯的水溶液，GO会引起母鼠的肠道绒毛脱落，高浓度的GO会延缓仔鼠生长。纳米材料毒性的研究为其作为药物载体提供了实验依据。除了开展上述研究，为提高肿瘤的治疗效果，我们以微波热疗为主要的治疗方式，针对不同的肿瘤模型制备了对应的微波增敏剂。针对中晚期肝癌的大肿瘤，制备了微波增敏栓塞微球，实现了微波增敏和栓塞的协同治疗效果。为了降低化疗药物的耐药和副作用，我们尝试了制备Mn-ZrMOF材料实现了微波动力和微波热疗的协同治疗效果。在本项目的支持下，本课题实现了多种功能性纳米颗粒的制备，并超额完成了新型纳米颗粒的设计、合成与新机制的探索，推动了纳米制剂以及纳米药物载体材料向临床的应用。