间充质干细胞膜包覆枝状金/多聚儿茶素纳米复合材料应用于肿瘤靶向光热治疗的研究

Photothermal therapy on the basis of the conversion of near-infrared irradiation into heat energy by nanomaterials has become a promising cancer therapy because the advantage of noninvasive and slight side effects. In order to improve the effect of therapy and target at tumor site, it is vital to develop new multifunctional nanomaterials to realize the precise and efficient combination therapy. The current developed photothermal conversion agents are mainly focused on the first biological window (650-950 nm). While considering the biological tissue absorption and scattering of light, the light source in the second biological window (1000-1350 nm) exhibits a larger penetration depth and higher maximum permissible exposure to laser, which is more suitable for clinical applications. So this project aims to synthesis the new photothermal conversion agents in the second biological window through the galvanical replacement reaction between Ag seeds and HAuCl4 with the addition of catechin as reductant. This photothermal conversion agent is formed with branched Au NPs as core and polycatechin as shell. Then the anticancer drug doxorubicin can be conjugated with catechol on the polycatechin shell by schiff base reaction and unload via pH-triggered in tumor tissue. Finally taking the advantages of the stem cell inherent tumoritropic property, mesenchymal stem cells membranes are chosen as the nanocarriers to camouflage photothermal conversion agents to realize the multifunctional photothermal platforms for anticancer drugs pH-triggered release, resistance to the immune clearance and tumor targeting, which has a promising prospect in precise tumor therapy.

利用具有光热转化性质的纳米材料进行肿瘤热消融的光热治疗因非侵入性、副作用小等优点成为新型肿瘤治疗技术。为提高光热疗效，靶向识别肿瘤位点，亟待开发多功能复合纳米材料，实现精准、高效肿瘤联合治疗。目前光热材料主要应用于生物学第一窗口 (650-950 nm)，因为生物体组织对光源的吸收和散射作用，处于生物学第二窗口(1000-1350 nm)的光源具有更深的组织透过性和更高的生物体耐受能力,更加适合临床应用。因此本项目拟选用儿茶素类化合物作为金银电位差取代反应的辅助还原剂制备生物学第二窗口的枝状金/多聚儿茶素纳米光热材料，并以多聚儿茶素为载体，通过希夫碱反应偶联抗癌药物阿霉素，在肿瘤偏酸的微环境中实现阿霉素pH刺激释放。进一步利用间充质干细胞的肿瘤趋向性质，提取细胞膜作为载体包覆载药光热纳米材料，构建兼具药物控释、抗免疫清除和肿瘤靶向能力的新型光热复合材料，在肿瘤精准治疗中具有巨大应用前景。

目前肿瘤是威胁人类生命健康的重要疾病，传统的化疗、放疗存在靶向性差、副作用大的缺点，纳米技术的发展为肿瘤治疗提供了新思路。光热治疗是利用激光照射光热纳米材料产生的高热破坏肿瘤细胞，从而导致肿瘤细胞凋亡坏死的新型肿瘤治疗方法。其中在近红外第二区域的激光具有更深的辐照深度和更强的皮肤耐受度，更有利于临床应用。因此本项目主要研究内容为开发吸收峰在近红外第二区域的新型光热纳米材料，并负载抗肿瘤药物，然后利用具有靶向性质的干细胞膜作为光热纳米材料的运载体，高效递送至肿瘤组织，从而实现对肿瘤的高效精准治疗。. 本项目以儿茶素为还原剂，采用HAuCl4和Ag纳米粒子电位差刻蚀法，成功制备在近红外二区有强吸收的以多聚儿茶素为壳层，高枝状金银合金纳米粒子为核心的纳米粒子。并以多聚儿茶素为载体偶联阿霉素，进一步将具有肿瘤靶向性质的干细胞膜包覆于高枝状纳米粒子表面，通过流式细胞仪、激光共聚焦等结果证明，干细胞膜复合材料对黑色素瘤细胞具有更明显的亲和性，从而可以实现对黑色瘤细胞的精准治疗。. 此外，本项目也研究了其他细胞膜载体光热复合平台。以干细胞膜为靶向载体，运载聚多巴胺包被Fe3O4粒子及siRNA，实现光热联合基因靶向治疗前列腺癌的治疗效果，为干细胞膜复合材料高效治疗肿瘤提供了可靠的实验基础。另外本项目以对二苯酚为还原剂制备小尺寸金纳米棒，并以红细胞膜为载体，降低金纳米棒的细胞毒性，对肺癌细胞产生显著的光热抑制效果。综上，本项目研究的细胞膜包被光热纳米材料为实现和发展精准高效肿瘤治疗提供了重要理论依据和新思路。