超小的核靶向硫化铜类诊疗一体化平台的构建及其在肿瘤治疗上的应用研究

Near infrared light (NIR) photothermal theranostics, which is the combination of NIR photothermal therapy and imaging diagnosis, is an emerging therapy that has great potential in cancer therapy. The advancement of theranostics is dependent on the development of NIR light theranostics agents. Although substantial NIR light theranostics agents have been designed and synthesized by the researcher in the world wide, many of these agents still show some limitations. Obstacles, such as nonspecific distribution due to the biological barriers, inadequate accumulation of agents in the cancer site and relatively poor therapeutic effects, remain formidable challenges. The project intends to develop ultra-small nuclear targeting copper sulfide theranotics agents. The theranostics agents have the following characteristics: (1) ultra-small diameter and polyethylene glycol modified surface. These characteristics can address the biological barriers and achieve long blood circulation time. (2) Cell membrane targeting. RGD loaded on the surface of theranostics agents is known to target the cell surface, which results in adequate accumulation of therapeutics agents at the cancer site. (3) Nuclear targeting. Nuclear localization signal peptide is known to associate with karyopherins in the cytoplasm, after which translocation to the nucleus occurs. A new therapy way from inside to outside (the destruction of nucleus firstly inside will subsequently affect the outside whole cell, thereby leading to apoptosis) will be developed to improve the therapeutic effects. The construction and application research of the ultra-small nuclear targeting copper sulfide theranostics agents will create a new way for cancer theranostics.

基于近红外光热治疗的诊疗一体化技术是一种新兴的具有广阔应用前景的癌症治疗方法。诊疗一体化的发展依赖于诊疗一体化试剂的开发，尽管国内外科学家们开发了一系列的近红外光热诊疗试剂，但仍然面临着很多问题。如有效克服层层生物壁垒，将诊疗试剂输送并富集到肿瘤部位，并提高治疗的有效性等。本项目拟开发具有以下特性的硫化铜类诊疗试剂：（1）超小粒径以及聚乙二醇修饰的表面，该特性能有效克服生物组织截留，延长体内循环时间；（2）细胞膜靶向性，表面负载的RGD肽能特异性的靶向在癌细胞表面，实现诊疗试剂在肿瘤病灶的有效富集；（3）细胞核靶向性，表面修饰的核定位信号肽能将诊疗试剂输送到细胞核，实施由内而外的新光热治疗模式，即通过破坏细胞核，进而导致细胞凋亡的策略，提高光热治疗的有效性。该超小的核靶向硫化铜类诊疗试剂的构建和应用研究为肿瘤的诊疗提供了新思路。

围绕肿瘤的精准诊疗，本项目开展了两部分工作：（1）将肿瘤微环境和近红外吸收材料联合起来，设计开发了用于肿瘤精准诊疗的硫化铜和聚苯胺类智能试剂。该类试剂只有在特定的肿瘤微环境触发条件下才能呈现出影像造影和治疗功能，即使该类材料被正常组织截留，也不会产生影像信号和治疗效果，极大的提高了该类材料对肿瘤造影的对比度和治疗的效果；（2）由于超小的纳米材料（<50 nm）能提高其血液内循环时间和提高生物安全性，本项目设计开发了Au棒、没食子酸-Fe的配位聚合物以及氧化钨等超小的纳米试剂，并探究了其在癌症诊疗上的应用。同时利用自组装、巨噬细胞担载等策略，设计了进一步提高该类材料诊断和治疗效果的方法。