宽波长纳米金载药系统的制备及其组装机制和光响应研究

At present, there are still some unsolved problems in the field of optically controlled drug delivery system, including time delay of drug release in vivo, no response for deep tissue, great difficulty to achieve on-demand drug release and batch perparation. In this project, liposome encapsulated Au nanoparticles with a wide wavelength region for surface plasmon resonance will be developed to improve vastly the abilities of photoresponse and instantaneous release in deep tissue. As the core scientific issues of this project, synthesis mechanisms of the drug delivery system and its response regularity to optical radiation will be explored in depth. Meanwhile, several factors are regarded as the extremely important things to regulate the properties of this novel drug delivery system, such as distribution of gold nanoparticles on the surface of liposomes, partical size and gap between gold nanoparticles. In order to measure photoresponse depth of nanogold shell liposomes with different surface plasmon resonance peaks, agarose-gel photo-controlled drug release detection technology will be applied, which can illistrate dose-effect relationship between light wavelength and response depth of drug delivery system and reveal the fundamental controlling rules of the system's drug release quantity under different optical radiation conditions. In addition, the synthesis rules of the nanogold coated liposomes for large-scale preparation will be explored. To our knowledge, by far, there is no related research report on response depth of drug delivery system with 800-1000 nm resonance peak to outside photoexcitation. Our results will supply pivotal basic data and theoretical foundation for drug delivery system's large-scale preparation and widespread application.

目前光控药物传递系统仍存在体内释药延迟、深部组织无响应、不能按需释药和批量合成困难等问题。本项目旨在通过控制合成宽波长的纳米金球壳载药系统，大幅度提高纳米金载药系统在深部组织的光响应性和瞬间释药能力。重点研究其中的核心科学问题- - 宽波长等离子共振峰纳米金载药系统的制备及其机制和深部组织光响应规律，通过调控纳米金粒子在脂质体表面的排布、纳米金粒径和间距等，制备出超薄纳米金球壳包覆的载药系统，实现在组织深部由纳米金控制的药物按需释放。采用琼脂糖凝胶光控释药检测技术研究不同波长纳米金载体对应的光响应深度，阐明光辐射条件对纳米金载药系统释药量的控制规律，以及光辐射波长与载药系统响应深度的量效关系，并探讨规模化制备该载药系统的合成规律。有关800-1000 nm波长的纳米金载药脂质体对应组织光控响应深度的研究未见文献报道，此研究结果将为药物传递系统的规模化合成和应用提供重要的基础数据和理论依据。

纳米金材料具有很强的光热转换性能，其光响应时间短，生物相容性高，将其与药物载体相结合，可以实现药物的靶向光响应性释放，提高药物对肿瘤的治疗效果。然而，纳米金的尺寸、形貌与其光热转换效率之间的关系，以及其在不同组织深度的光响应能力等问题，尚不明确。这些问题，严重制约着纳米金材料在抗肿瘤药物载体领域的应用。针对上述问题，本项目首先利用静电吸附或共价结合等方式，成功在纳米载药脂质体表面形成了金球壳结构，并通过调节制备参数，使其特征吸收峰位于800-1000 nm之间，展现出良好的光热转换性能。合成的纳米金载药系统具有快速的光响应性，在近红外光照射下，可以迅速地将光能转化为热能，促进药物的快速释放。在此基础上，以晶种生长法为基本原理，采用一次或多次还原的方式，成功制备了具有不同厚度、不同粒径的纳米金球壳结构，并探究了球壳结构与共振吸收波长和光热转换性能之间的关系。在此基础上，我们对纳米金载药系统的抗肿瘤效果进行了系统研究。由于光热治疗能够有效抑制并杀伤肿瘤细胞，因此纳米金载药系统在体外和体内实验中均表现出良好的抗肿瘤效果。这一研究结果也为今后的肿瘤治疗提供了新的思路。通过本项目的实施，已按计划完成了相应的全部研究内容。项目执行期间，共培养3名博士后出站，1名博士研究生毕业，11名硕士研究生毕业。此外，仍在课题组培养的有：4名博士研究生在读，11名硕士研究生在读。基于本项目的研究成果，已发表相关SCI研究论文30篇，其中1区和2区文章20篇，申请发明专利15项。