文献：Chemo-Photodynamic Therapy With Light-Triggered Disassembly of Theranostic Nanoplatform In Combination With Checkpoint Blockade For Immunotherapy of Hepatocellular Carcinoma

文献链接：https://pubmed.ncbi.nlm.nih.gov/34717654/

作者：Jianjun Xu，Qichang ZhengXiang Cheng，Shaobo Hu，Chen Zhang，Xing Zhou，Ping Sun，Weimin Wang，Zhe Su，Tianhao Zou，Zifang Song，Yun Xia，Xiaoqing Yi，Yang Gao

相关产品：PTX（紫杉醇）

PEG (5k)-TK-PLGA (2k)（聚乙二醇5k-酮缩硫醇-聚乳酸-羟基乙酸共聚物2k） 

NHS-PEG-TK-PLGA（活性酯-聚乙二醇-酮缩硫醇-聚乳酸 - 羟基乙酸共聚物）

原文摘要：

Background: Hepatocellular carcinoma (HCC) is a common malignant tumor with high rate of metastasis and recurrence. Although immune checkpoint blockade (ICB) has emerged as a promising type of immunotherapy in advanced HCC, treatment with ICB alone achieves an objective remission rate less than 20%. Thus, combination therapy strategies is needed to improve the treatment response rate and therapeutic effect.

Methods: A light-triggered disassembly of nanoplatform (TB/PTX@RTK) co-loaded an aggregation induced emission (AIE) photosensitizer (TB) and paclitaxel (PTX) was prepared for on-command drug release and synergistic chemo-photodynamic therapy (chemo-PDT). Nano-micells were characterized for drug loading content, hydrodynamic size, absorption and emission spectra, reactive oxygen species production, and PTX release from micells. The targeted fl uorescence imaging of TB/PTX@RTK micells and the synergistic antitumor effi cacy of TB/PTX@RTK micells-mediated chemo-PDT combined with antiPD-L1 were assessed both in vitro and in vivo.

Results: The TB/PTX@RTK micells could specifi cally accumulate at the tumor site through cRGDmediated active target and facilitate image-guided PDT for tumor ablation. Once irradiated by light, the AIEgens photosensitizer of TB could produce ROS for PDT, and the thioketal linker could be cleaved by ROS to precise release of PTX in tumor cells. Chemo-PDT could not only synergistically inhibit tumor growth, but also induce immunogenic cell death and elicit anti-tumor immune response. Meanwhile, chemo-PDT signifi cantly upregulated the expression of PD-L1 on tumor cell surface which could effi ciently synergize with anti-PD-L1 monoclonal antibodies to induce an abscopal effect, and establish long-term immunological memory to inhibit tumor relapse and metastasis.

Conclusion: Our results suggest that the combination of TB/PTX@RTK micell-mediated chemo-PDT therapy with anti-PD-L1 monoclonal antibodies can synergistically enhance systemic antitumor effects,and provide a novel insight into the development of new nanomedicine with precise controlled release and multimodal therapy to enhance the therapeutic effi cacy of HCC.   

紫杉醇是一种从红豆杉属植物的树皮中提取的天然抗cancer化合物。它属于紫杉烷类化合物，具有复杂的化学结构，其核心结构是紫杉烷环。主要是通过促进微管蛋白聚合，抑制微管解聚，从而使细胞有丝分裂停止在 G2/M 期，进而阻止cancer细胞的增殖。

PEG (5k)-TK-PLGA (2k)：PEG聚乙二醇是一种合成的聚合物，具有良好的水溶性、生物相容性和低poison性。TK是酮缩硫醇，一类含有硫原子的有机化合物。它是由酮与硫醇发生缩合反应而形成的。其结构特点是在碳-硫-碳（C - S - C）的骨架基础上，连接有来自酮的烃基。PLGA 是一种生物可降解的聚酯，由乳酸和羟基乙酸聚合而成。它的分子量在这里是 2000（2k）。这种聚合物具有良好的生物相容性和可降解性，可以逐渐降解为乳酸和羟基乙酸，它常用于化合物缓释系统和组织工程支架等领域。

NHS-PEG-TK-PLGA：NHS 是一种常用的化学活性基团，在有机合成和生物偶联反应中发挥重要作用。它能够与含有氨基（- NH2）的化合物发生酰胺化反应，形成稳定的酰胺键。PEG聚乙二醇具有良好的水溶性、生物相容性和柔性。它可以改善整个材料的亲水性，并且在生物体内能够减少蛋白质吸附和细胞黏附，延长材料的循环时间。酮缩硫醇（TK）是一类含有硫原子的有机化合物。它是由酮与硫醇发生缩合反应而形成的。PLGA是一种生物可降解的聚酯。它可以逐渐降解，释放出包裹的化合物或者生物活性物质。基于PTX、PEG (5k)-TK-PLGA (2k)、NHS-PEG-TK-PLGA的特性，光触发拆卸纳米平台TB/PTX@RTK的合成如下：

图：紫杉醇结构式

RTK、TB@RTK、PTX@RTK、TB/PTX@TK和TB/PTX@RTK的制备：

将PEG-TK-PLGA、RTK、TB和PTX溶解在THF/CHCl3的溶剂中，然后将超纯水（8.5 mL）缓慢加入该溶液中。然后，在超纯水中透析，制备具有活性tumour靶向性的TB/PTX@RTK胶束。同样，用该方法将PEG-TK-PLGA、TB和PTX混合制备TB/PTX@TK胶束。RTK、TB@RTK和PTX@RTK胶束的制备方法与TB/PTX@RTK胶束相似。

图：表征图像

结论：

该文献成功制出基于PTX、PEG (5k)-TK-PLGA (2k)、NHS-PEG-TK-PLGA合成的光触发拆卸纳米平台TB/PTX@RTK。研究结果表明，TB/PTX@RTK细胞介导的pdt与抗pd-l1单克隆抗体可以协同增强系统性抗tumour作用，纳米化合物的发展与准确控释和多模式heal提高HCC的效果。