肿瘤特异靶向的长循环多功能纳米胶束用于肝癌的光声成像及光热/光动力协同治疗研究

Here, we intend to design a long circulation, multifunctional hepatocellular carcinoma (HCC) targeting nanomicelles, which are based on the slightly acidic environment of the tumor tissues and the specific surface biomarkers, for the targeting photoacoustic imaging and photothermal/photodynamic synergistic therapy of HCC. Under physiological conditions, the nanomicelle’s surface which possesses approximately equal positive and negative charges can protect them from being eliminated by the reticuloendothelial system, then prolong the blood circulation and further improve the tumor tissue targeting by passive accumulation via the enhanced permeability and retention (EPR) effect. Due to the slightly acidic feature of the tumor extracellular environment, the zwitterionic charges on the nanomicelle’s surface can switch to positive which can significantly enhance the cellular uptake due to the strengthened nanomicelle-cellular membrane interaction; furthermore, the specific targeting ligand on the micelle’s surface would further increase the specific uptake by hepatocellular carcinoma cancer cells via the ligand-receptor interactions. The photo sensitizer Ce6 and semiconducting polymer nanoparticles (Pdots) were packed inside the nanomicelles; since the Pdots have excellent photoacoustic contrast ability and photo-thermal conversion ability, the nanomicelles could be applied for the targeting photoacoustic imaging and photothermal therapy of HCC. Meanwhile, the encapsulated photo sensitizer Ce6 could be released and activated by destroying the nanomicelles via the high temperature that produced by the Pdots under infra-red laser irradiation, then it would further facilitate the photothermal/photodynamic synergistic therapy of HCC. This project would provide further valuable information for design novel HCC targeting theranostic agents.

本课题针对肿瘤微酸环境与肝癌表面的特异分子标志物，设计一种具有肝癌特异靶向能力的长循环、多功能纳米胶束，用以实现对肝癌的光声成像和光热/光动力协同治疗。在生理条件下，胶束表面的两性离子使纳米胶束呈电中性，可使其避免被网状内皮系统清除，延长血液循环时间，有利于通过高通透与滞留效应（EPR）提高药物在肿瘤部位的富集度。在肿瘤间质微酸环境中，胶束表面的两性电荷翻转为正电荷，易于被癌细胞摄取；同时，胶束表面的特异性靶向配体可进一步增加肝癌细胞对纳米胶束的选择性摄取。胶束内部包裹二氢卟吩e6（Ce6）和半导体聚合物量子点（Pdots）。半导体聚合物量子点具备光声造影和光热转换的功能，因此该纳米胶束可用于肝癌的光声成像和光热治疗；同时，半导体聚合物量子点产生的过高热，能够使纳米胶束达到玻璃化温度而产生相变熔化，进而释放出Ce6分子并激活Ce6分子的光敏化活性，实现对肝癌的光热/光动力协同治疗。

本项目针对肿瘤特异的微环境（如微酸性、高GSH、乏氧等）和肝癌表面的分子标志物（如CD44受体等），开发了一系列具备肝癌靶向能力的长循环、多功能诊疗一体化纳米探针，并实现了对肝癌动物模型的光声/荧光/核磁多模态成像和光热/光动力/化疗/免疫治疗多模态协同治疗，有望为临床上肝癌的早诊早治提供新思路。主要开展的工作如下：（1）开发了具备光声/磁共振双模态成像及光热/光动力双模态治疗功能的长循环纳米胶束，并在肝癌荷瘤小鼠模型中证明了该纳米胶束对于微小肿瘤病灶优异的成像能力和协同治疗能力。（2）针对肝癌细胞表面高表达的CD44受体，分别构建了肝癌细胞特异高表达的mRNA响应的荧光成像引导下的光动力/化疗双模态治疗纳米凝胶和在近红外二区具备高光热转化效率的半导体聚合物纳米胶束，并分别在肝癌细胞和肝癌荷瘤小鼠模型中证明了其良好的诊断与治疗效果。（3）针对肿瘤特异的微酸、高GSH、乏氧微环境，设计了一系列肿瘤微环境程序化响应的智能诊疗一体化纳米探针，有机整合了荧光成像/光声成像/磁共振成像与光热治疗/光动力治疗/化疗等多种功能，并在肝癌荷瘤小鼠模型中证明了其良好的诊疗一体化效果，同时这些智能协同策略均显著降低了肿瘤治疗后的复发转移率。