Identification of an ALK-2 inhibitor as an agonist for intercellular exchange and tumor delivery of nanomaterial.
Identification of an ALK-2 inhibitor as an agonist for intercellular exchange and tumor delivery of nanomaterial.
复制标题
鉴定 ALK-2 抑制剂作为纳米材料细胞间交换和肿瘤递送的激动剂。
DOI：
10.1002/adtp.202200173
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发表时间：
2023
影响因子：
4.6
通讯作者：
Pang,Hong-Bo
中科院分区：
文献类型：
--
作者：
Wu,Xian;Guo,Hong;Zhao,Jiaqi;Wei,Yushuang;Li,Yue-Xuan;Pang,Hong-Bo
实体组织中的低效外渗和渗透阻碍了纳米颗粒（NP）的临床效果。最近的研究表明，实体瘤中纳米颗粒的外渗和渗透主要是通过主动的跨细胞途径实现的。许多努力致力于阐明纳米颗粒的内吞作用和亚细胞运输。然而，它们如何从一个细胞退出并重新进入邻近细胞（称为细胞间交换）仍然知之甚少。先前的研究表明，很大一部分纳米颗粒在细胞外囊泡（EV）内转移。抑制 EV 生物发生可显着减少体内各种 NP 的肿瘤积累和血管渗透。在这里，通过该测定进行了手动化学筛选，确定 LDN-214117（激活素受体样激酶 2，ALK-2 的抑制剂）是 NP 细胞间交换的激动剂。 LDN-214117 通过骨形态发生蛋白-丝裂原激活蛋白激酶 (BMP-MAPK) 信号通路增加 EV 生物发生来调节细胞间交换。 LDN-214117治疗进一步增强了多种纳米颗粒在多种肿瘤模型中的肿瘤积累和血管渗透，从而提高了它们的抗肿瘤功效。总体而言，通过细胞间交换测定鉴定出一种新型化合物，可以调节 EV 介导的运输，从而提高纳米材料的递送和治疗效果。
Inefficient extravasation and penetration in solid tissues hinder the clinical outcome of nanoparticles (NPs). Recent studies have shown the extravasation and penetration of NPs in solid tumor are mostly achieved via an active transcellular route. Numerous efforts are devoted to elucidate the endocytosis and subcellular trafficking of NPs. However, how they exit from one cell and re‐enter into neighboring ones (termed intercellular exchange) remains poorly understood. The previous study showed that a significant portion of NPs are transferred inside extracellular vesicles (EVs). Inhibition of EV biogenesis significantly reduces tumor accumulation and vascular penetration of various NPs in vivo. Here, a manual chemical screen is performed with this assay, which identifies that LDN‐214117 (an inhibitor for activin receptor‐like kinase‐2, ALK‐2) as an agonist of NP intercellular exchange. LDN‐214117 is showed to regulate the intercellular exchange by increasing the EV biogenesis via bone morphogenetic protein–mitogen‐activated protein kinase (BMP–MAPK) signaling pathway. LDN‐214117 treatment further enhances tumor accumulation and vascular penetration of a variety of NPs in multiple tumor models, which improves their antitumor efficacy. Overall, the identification of a novel chemical compound with intercellular exchange assay is showcase to modulate EV‐mediated transport, thus boosting the delivery and therapeutic efficacy of nanomaterials.