Reinforcing vascular normalization therapy with a bi-directional nano-system to achieve therapeutic-friendly tumor microenvironment
Reinforcing vascular normalization therapy with a bi-directional nano-system to achieve therapeutic-friendly tumor microenvironment
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用双向纳米系统强化血管正常化治疗，以实现治疗友好的肿瘤微环境
DOI：
10.1016/j.jconrel.2021.10.016
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发表时间：
2021-10-30
影响因子：
10.8
通讯作者：
Yao, Jing
中科院分区：
文献类型：
--
作者：
Deng, Yudi;Jiang, Zhijie;Yao, Jing
有害的肿瘤微环境(TME)依赖于扭曲的肿瘤血管来进一步扩大肿瘤。血管正常化治疗通过血管修复部分改善TME，而这些治疗进入牢不可破的Mobius环，因为每次尝试都受到TME促血管生成因子的阻碍，导致血管正常化的持续时间和范围有限。在这里，我们开发了一种纳米系统，包括Flg和MAR/MPA纳米微球，用于调节肿瘤血管和TME。将血管内皮生长因子/血管内皮生长因子受体2抑制的低分子肝素和藤黄酸与F3肽修饰连接，构建成Flg纳米载体，直接调控血管内皮细胞，诱导血管归一化。同时，设计了包裹CCL5/CCR5阻断剂马拉韦罗的MAR/MPA纳米微片，以限制血管生成和TME恶化的细胞因子功能，有助于血管修复和TME重建。我们的结果表明，这种联合纳米系统协同诱导了持续9天的血管正常化窗口，并恢复了PANC-1肿瘤的血管通透性和氧气供应。此外，在黑色素瘤中，我们的纳米系统通过在重塑的TME中增加CD4(+)和CD8(+)T细胞的渗透而实现了免疫改善。这两个纳米药物在血管修复和TME改善方面相互帮助，成功地将恶性串扰逆转为积极串扰，实现了整体TME重塑并提高了治疗效率。
Detrimental tumor microenvironment (TME) relies on distorted tumor vasculature for further tumor expansion. Vascular normalization therapy partly improves TME through vessel repairing, while these therapies enter an unbreakable Mobius ring due to each attempt hindered by pro-angiogenic factors from TME, leading to limited duration and extent of vascular normalization. Here, we developed a nanosystem including FLG and MAR/MPA nanodrugs to regulate both tumor vasculature and TME. FLG nanodrugs were constructed by connecting VEGF/VEGFR2 inhibitory low molecular weight heparin and gambogic acid with F3 peptide decoration for directly regulating on vascular endothelial cells and inducing vascular normalization. Meanwhile, MAR/MPA nanodrugs encapsulating CCL5/CCR5 blocker maraviroc were designed to restrict cytokine functions of angiogenesis and TME deterioration, contributing to vasculature repairing and TME reconstruction. Our results demonstrated this combined nanosystem synergistically induced vascular normalization window lasting 9 days and restored vascular permeability and oxygen supply in Panc-1 tumor. Furthermore, in melanoma, our nanosystem achieved immune improvements with increased infiltration of CD4(+) and CD8(+)T cells in a remodeled TME. The two nanodrugs assisting each other in terms of both vascular repairing and TME improvements successfully reversed the vicious crosstalk to a positive one, achieving overall TME remodeling and promoting therapeutic efficiency.