介孔二氧化硅包覆金纳米棒的肿瘤靶向化疗-热疗-光动力联合治疗研究

Current clinical therapy investigation has shown that combined therapy techniques such as thermo-chemotherapy or thermo-photodynamic therapy could result in additionally enhanced anticancer efficacy. However, for traditional treatment techniques, the synergistic effects of combined therapy are difficult to realize in vivo because co-delivery of different agents or tools together to the target tissues is still challenging. Fortunately, the rapid development of nanotechnologies provides a new impetus for cancer therapy due to its unique physical properties. Recently, more and more interests have been attracted in the field of multifunctional targeting delivery nanosystem for the tumor treatment. Herin, we will design and develop the mesoporous silica-encapsulated gold nanorods（GNRs@mSiO2） as NIR-light-absorbing agents and a drug delivery system for in vivo chemo-photothermal-photodynamic treatment of tumor. DOX and ZnPcS4 can be easily loaded into GNRs@mSiO2 nanomaterials owing to the large surface area and high accessible pore volume. The as-prepared GNRs@mSiO2 can be used as effective thermal generators because of intrinsic optical properties of GNRs to convert NIR light into heat. Thus, chemo-photothermal-photodynamic treatment of tumor can be achieved by our GNRs@mSiO2. The ablation of tumor both in vitro and in vivo by the combined therapy is to be performed. And the therapy outcome will be compared with that of chemotherapy, photothermal or photodynamic treatment alone. The combined treatment might show a potentially synergistic effect, resulting in higher therapeutic efficacy. Since few literatures have been reported on estabishment of targeting delivey nanosystem and its combined therapy model, our study is of great significance and novelty.

临床研究表明，联合不同治疗手段如化疗-热疗、热疗-光动力等进行肿瘤治疗可以增强抗肿瘤疗效。但传统治疗技术较难将两种以上药物制剂或技术同时输送到肿瘤部位，因此很难取得较为理想的效果。当前，多功能纳米载体的构建及肿瘤联合治疗应用正成研究热点。本项目拟设计构建一种新型的基于介孔二氧化硅包覆金纳米棒，集肿瘤化疗-热疗-光动力治疗于一体的联合治疗靶向递释系统。该系统可利用介孔二氧化硅孔道高效负载化疗药物阿霉素和光敏剂四磺酸基酞菁锌；由于纳米粒中金纳米棒可吸收近红外光，具有很好光热转化能力，因此能够同时发挥化疗-热疗-光动力联合治疗优势，有望取得比单一治疗模式或化疗-热疗联合模式更好的抗肿瘤效果。该纳米靶向联合递释系统的多联合治疗模式研究，目前国内外未见报道，具有很高的创新意义和研究价值。

热疗-化疗-光动力联合治疗可以增强抗肿瘤疗效，主要由于热疗在杀死癌细胞的同时，有助于化疗和光动力药物进入肿瘤细胞和增加化疗与光动力药物的细胞毒性。但传统的联合治疗技术很难达到理想效果，受限于热疗制剂、化疗与光动力药物很难同时到达肿瘤部位，协同发挥作用。纳米技术的迅猛发展，尤其在肿瘤治疗方面展现出独特优势，使得联合治疗变得可能实现。本项目设计并构建了一种新型的基于介孔二氧化硅包覆金纳米棒（GNRs@mSiO2）的肿瘤热疗-化疗-光动力联合治疗靶向递释系统。GNRs@mSiO2纳米粒比表面积为327.42 m2/g，孔体积为0.64 cm3/g，平均孔道直径2.9 nm。由于合适的介孔孔道和巨大的比表面积，纳米粒可高负载化疗和光动力药物，且可吸收近红外激光并将其转换成大量的热能，发热效果与纳米粒的浓度、激光照射强度、激光照射时间相关。为了提高肿瘤靶向效率，经过PEG和RGD修饰后的纳米粒具有很好的生物相容性和很低的生物毒性，可避免单核巨噬系统的吞噬，并能主动靶向肿瘤细胞和组织。细胞和动物实验结果表明，载药纳米粒在低光热治疗时，热疗-化疗-光动力联合治疗的细胞毒性和药效，优于单纯的化疗、光动力和激光照射热疗。但增加激光照射强度和照射时间，升高光热温度后，单一热疗效果可完全杀死肿瘤细胞和组织，无需再同时实施化疗-光动力联合治疗。我们对纳米粒的毒性也进行了初步评价，结果显示，有CTAB残留于孔道内的GNRs@mSiO2，在高浓度时有一定的细胞毒性，经硝酸铵乙醇溶液离子交换去除CTAB后无明显的细胞毒性。单纯激光照射细胞，对细胞生存无影响。经过PEG和RGD修饰的纳米粒无明显的细胞毒性和不引起血液指标发生明显异常；不引起心、脾、肺、肾的巨噬细胞增多，主要脏器组织无明显病理反应。通过本项目的实施，表明纳米粒热疗不足时，通过联合化疗-光动力治疗，可增强肿瘤治疗效果，但纳米粒在激光照射下产生足够的热量和保持较长治疗时间时，单纯热疗即可杀灭肿瘤，为我们后续重点开展肿瘤热疗系列研究奠定基础。