基于FLIM/PA复合成像精准监控的二维黑磷纳米片靶向肿瘤化疗和热疗机制研究

Cancer has been a major killer of human life. However, there are various drawbacks in traditional therapeutic methods during the process of diagnosis, monitoring, and treatment of cancer. Therefore, it is urgent to develop a cancer treatment with precise monitoring and targeted treatment properties, to achieve effective cancer treatment. However, to date, no suitable drug platforms or effective monitoring methods have been developed. In this project, polydopamine (PDA) modified two-dimension black phosphorus nanosheets (BPNSs) were synthesized as an enhanced photothermal therapy agent. The formed PDA-BPNSs were then modified with targeted agent RGD peptide and fluorescent dye rhodamine B (RB) through chemical bonding, and loaded with an anticancer drug doxorubicin (DOX) through π-π stacking interaction to build a hybridized nanodrug with targeted chemo-photothermal therapy and optical imaging properties. Fluorescence lifetime imaging microscopy (FLIM) was used to monitor DOX related to the process of chemotherapy in vitro and RB related to the process of photothermal therapy in vitro in real time. Hereafter, in vivo treatment process was monitored by photoacoustic (PA) imaging in detail. Therefore, this project will organically combine cancer therapy with cancer monitoring to realize theranostics in vitro and in vivo. What’s more, the project will lay great experimental and theoretical groundwork for precise targeted cancer treatment, which shows a great research meaning.

癌症是威胁人类生命健康的主要杀手，目前传统的治疗方法在癌症诊断、监控和治疗过程中仍存在一定的局限性。因此，需要开发一种精准监控与靶向治疗为一体的癌症治疗手段以期实现癌症的有效治疗。但现阶段仍缺乏合适的药物平台和有效的监控方法。本项目拟以聚多巴胺修饰的二维黑磷纳米片为增强型光热治疗的基础平台，利用聚多巴胺表面丰富的氨基化学键合RGD多肽和荧光染料罗丹明B（rhodamine B, RB）、π-π堆积作用负载化疗药物阿霉素DOX，构建具有靶向化疗/热疗和光学成像功能为一体的杂化纳米药物。利用荧光寿命成像FLIM动态监测DOX引导的体外化疗过程和RB引导的体外热疗过程；利用光声成像PA动态监测体内肿瘤治疗过程。通过将治疗和实时监控有机结合，实时监测体外到体内的肿瘤治疗过程，实现诊疗一体化，为癌症的精准靶向治疗奠定重要的实验和理论基础，具有重要的研究意义。

癌症是人类生命健康的重要杀手，癌症的早期诊断和精准治疗依然是科研工作者研究的重要和热点问题。本项目依据新型二维黑磷纳米材料，通过负载化疗药物MTX，修饰Tmab单抗实现对Her2阳性乳腺癌的靶向光热化疗。研究结果发现二维黑磷能有效负载MTX，并成功修饰Trastuzumab(Tmab)单抗。体外细胞毒性表明，制备的BP-PEG-MTX-Tmab纳米药物能有效杀伤肿瘤细胞，对Her2阳性细胞SKBR3细胞显示出更强的杀伤能力。通过在其表面修饰荧光素FITC发现，修饰了Tmab单抗后有效靶向SKBR3细胞，显示出明显的绿色荧光信号，相反，没有修饰Tmab的药物无法显示明显的绿色荧光信号。另外，体内荧光成像说明Tmab修饰的纳米药物有效靶向Her2阳性的肿瘤。基于二维黑磷的Tmab靶向的纳米药物能有效运输到肿瘤部位，并在激光照射下，快速升温至50摄氏度左右，可以有效杀伤肿瘤组织。体内抗肿瘤实验，再次说明Tmab修饰的纳米药物能有效抑制肿瘤生长。本项目对于癌症尤其是Her2阳性乳腺癌具有良好的治疗效果，对Her2阳性乳腺癌的精准治疗和诊断具有重要的研究价值。另外，我们还研究了其他光热试剂如金纳米棒和氧化铁锰纳米颗粒，研究了基于它们的光热免疫联合治疗，这对于癌症的创新疗法提供了新的思路。