基于上转换纳米粒的深层肿瘤光动力学治疗量效关系的基础研究

Featured with the merits of controllable in laser intensity, irradiation time and areas, photodynamic therapy(PDT) possess the capability of quantitative tumor therapy in designated time and specific pathological location. However, the tradition PDT is unable to perform the therapy in the site of deep tissue due to the limited penetration depth of the irradiation light on the living tissue. Upconversion nanoparticles (UCNP), with the ability of conversing the absorbed near-infrared light to visible light to trigger the surrounding photosensitizers, provide the possibility of deep tumor PDT. Unfortunately, upconversion nanoparticles-based PDT is in its initial stage, the dose-effect relationship and other properties serving as drug are unclear, which is the aim of this project. In this proposed work, we will firstly synthesize and optimize the conversional optical properties of our rare earth nanopartilces to math the traditional photosensitizers. Then, we will build an energy transfer PDT system by entrapping the UCNP and two matched photosensitizers into the high payload chitosan micells. The promising of the PDT system as feasible drug carrier will be evaluated. We will place our emphasis on the dose-effect relationship including the energy density of the light, irradiation time and periods, concentration of the UCNP-photosensitizer compound, depth of the tissue, production of reactive oxygen, to establish a mathematic model to guide the real PDT in deep tissue. Furthermore, we will investigate the combined efficacy of PDT with chemotherapy by uploading the anticancer drug into the NIR triggered chitosan micells based PDT system.

光动力治疗PDT以其光照强度、时间、范围等可控性可实现肿瘤病灶的定时定位定量治疗，但传统PDT由于其激发光的组织穿透能力弱而不能进行深层病灶的治疗；上转换纳米粒具有将较深组织穿透力的近红外光转变成可见光的能力，为深层肿瘤PDT提供了可能。但基于上转换机制的PDT研究刚刚起步，许多量效关系及成药前景尚不明确。本项目拟在实验室工作基础上,进一步合成并优化上转换纳米粒发光特性，通过智能壳聚糖胶束包裹上转换纳米粒及两种匹配的光敏剂而构建能量转移系统，评价其成药前景，重点考察各量效关系（激光能量、照射时间及频率、复合物浓度、组织深度、活性氧产量等）建立数学模型以指导深层PDT。同时，通过光可控壳聚糖胶束的崩解，优化上转换纳米粒、光敏剂及氧分子间能量转移特性使PDT活性氧最优。进一步，将抗肿瘤药物同时载入壳聚糖复合载体中，由近红外光触发光敏纳米胶束的定时释放，在时序上实现先光动力治疗后化疗的联合作用。

上转换纳米材料具有反斯托克斯位移大、发射光谱窄、光学和化学性质稳定性高等优势，因而它被广泛应用于深层光动力治疗研究。本项目旨在利用上转换纳米粒，进而对深层肿瘤进行光动力学治疗，并研究其量效关系，完成了以下几个方面的工作：1.构建了一系列基于上转换纳米粒的靶向诊疗系统，具有较高的单线态氧产率，分别在细菌引发的炎症反应以及恶性肿瘤中表现出良好的治疗效果，解决了炎症和恶性肿瘤的多药耐药性，主要包括c(RGDyK)-SOC-UCNPs-ZnPc，OC-UCNP-ZnPc，FA-PAAO-UCNPs-MC540-ZnPc；2.构建了多种上转换纳米探针检测肿瘤微环境的ROS等指标，包括PAAO-UCNPs-RhBs，PAAO-UCNPs-DCM-B2，PAAO-UCNPs-MC540-IR820等，为后续量效关系研究提供研究基础；3.利用上转换纳米探针进行深层活体水平的量效关系的研究，优化上转换纳米光动力学载药系统的浓度、激光能量密度，光照时间等与PDT活性氧产率相关的条件，以指导荷瘤鼠PDT研究；4.构建了一系列的靶向载药系统，包括对肿瘤高度特异性的具有双重靶向性修饰的纳米材料，基因治疗与化疗联合的载药系统，光热治疗与化疗联合的功能材料，肿瘤端粒酶响应性的特异性药物递送与释放体系，以及基于AMD3100修饰硫化银荧光量子点递送体系，为肿瘤的深层治疗研究提供研究基础。5.设计了一系列针对肿瘤特异性指标的荧光分子信标，包括miR-21分子信标，STAT5b分子信标，EML4-ALK分子信标，Akt-mTOR分子信标，MDR1分子信标，可在活细胞以及临床样本上对肿瘤特异性基因进行检测,推动分子信标向临床转化。