文献：Low-intensity focused ultrasound targeted microbubble destruction reduces tumor blood supply and sensitizes anti-PD-L1 immunotherapy

文献链接：

https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2023.1173381/full

作者：Jie Li , Huamin Zeng , Yu You, Rongrong Wang , Tiantian Tan , Weiming Wang , Liyan Yin , Zhaowu Zeng , Yiying Zeng , Tian Xie

相关产品：DSPE-PEG2000（磷脂-聚乙二醇2000）

原文摘要：

Immune checkpoint blockade (ICB) typified by anti-PD-1/PD-L1 antibodies as a revolutionary treatment for solid malignancies has been limited to a subset of patients due to poor immunogenicity and inadequate T cell infiltration. Unfortunately, no effective strategies combined with ICB therapy are available to overcome low therapeutic efficiency and severe side effects. Ultrasound-targeted microbubble destruction (UTMD) is an effective and safe technique holding the promise to decrease tumor blood perfusion and activate anti-tumor immune response based on the cavitation effect. Herein, we demonstrated a novel combinatorial therapeutic modality combining low-intensity focused ultrasound-targeted microbubble destruction (LIFU-TMD) with PD-L1 blockade. LIFU-TMD caused the rupture of abnormal blood vessels to deplete tumor blood perfusion and induced the tumor microenvironment (TME) transformation to sensitize anti-PD-L1 immunotherapy, which markedly inhibited 4T1 breast cancer’s growth in mice. We discovered immunogenic cell death (ICD) in a portion of cells induced by the cavitation effect from LIFU-TMD, characterized by the increased expression of calreticulin (CRT) on the tumor cell surface. Additionally, flow cytometry revealed substantially higher levels of dendritic cells (DCs) and CD8+ T cells in draining lymph nodes and tumor tissue, as induced by pro-inflammatory molecules like IL-12 and TNF-α. These suggest that LIFU-TMD as a simple, effective, and safe treatment option provides a clinically translatable strategy for enhancing ICB therapy.  

DSPE-PEG2000:DSPE ：DSPE 即 1,2 - 二硬脂酰 - sn - 甘油 - 3 - 磷酸乙醇胺。它包含两条硬脂酸（C18 脂肪酸）链，这两条长的疏水链赋予了分子很强的疏水性，使其能够与脂质双层相互作用。在生理环境下，这些疏水链可以插入细胞膜或脂质体的磷脂双分子层中，起到稳定结构的作用。PEG2000 ：PEG 是聚乙二醇，分子量为 2000 的 PEG 链在这个结构中发挥了关键作用。它具有良好的亲水性，是一种高度水合的聚合物。PEG 链连接在 DSPE 上，像一条长长的 “手臂”，使得整个分子兼具亲水性和疏水性。这种两亲性结构有助于在水性环境中形成稳定的胶束或脂质体结构。基于DSPE-PEG2000的相关性能，微泡LIFU-TMD的介绍如下： 

图：DSPE-PEG结构式

合成如下：

将DPPC 和DSPE-PEG2000 溶解于甘油-磷酸盐缓冲盐水（PBS）悬浮液中，采用薄膜水化法制成脂膜溶液，储存于小瓶中。然后将全氟丙烷倒入小瓶中。最后，用牙科混合器振荡得到MBs。用光学显微镜（Olympus）观察MB的形态。采用动态光散射法（Malvern）测量了颗粒大小和zeta电位。

图：机制示意

结论：

该文献成功制备出基于DSPE-PEG2000合成的微泡LIFU-TMD，这是一种将低强度聚焦超声靶向微泡。各项实验表明 LIFU-TMD 可作为一种简单、有效和安全的heal选择，为增强 ICB heal提供了一种可转化的策略。