■肠巨噬细胞的M1/M2极化在溃疡性结肠炎(UC)的发病机理中起着重要作用,可以调整缓解UC症状。
■一种pH敏感性脂质磷酸钙核壳纳米颗粒(NPs),与地塞米松(Dex)及其水溶性盐共负载,地塞米松磷酸钠(Dsp),构建了全面调节巨噬细胞在不同状态下朝向M2表型,以促进抗炎作用。
■将Dex和Dsp加载到LdCaPdNP的外脂质壳和内脂质磷酸钙(Cap)核心中,分别。然后,研究了NPs的形态和药物浓度的测定方法,其次是体外蛋白质吸附,稳定性,和发布测试。细胞实验评估了细胞毒性,细胞摄取,和NPs的巨噬细胞极化诱导能力。通过2,4,6-三硝基苯磺酸(TNBS)诱导的BALB/c小鼠溃疡性结肠炎模型评估了NPs的体内分布和抗炎作用。
■LdCaPdNP显示出约200nm的粒度并获得相当大的Dex和Dsp负载量。体外和体内研究表明,在酸性UC微环境中,LdCaPd的阳离子脂质壳经历质子化解离以首先释放Dex,用于创建有利于M2极化的微环境。然后,暴露的CaP核心进一步被M1巨噬细胞吞噬,释放Dsp,通过激活GC受体和NFκB抑制剂α(I-κBα)来抑制核因子κB(NF-κB)的激活和功能,从而限制促炎细胞因子的产生,分别,最终逆转M1极化以促进抗炎治疗。
■LdCaPdNP完成了Dex和Dsp向UC部位的顺序释放和在该部位的炎性M1巨噬细胞,促进巨噬细胞极化的调节,加速UC症状的缓解。
UNASSIGNED: The M1/M2 polarization of intestinal macrophages exerts an essential function in the pathogenesis of ulcerative colitis (UC), which can be adjusted to alleviate the UC symptoms.
UNASSIGNED: A kind of pH-sensitive lipid calcium phosphate core-shell nanoparticles (NPs), co-loading with dexamethasone (Dex) and its water-soluble salts, dexamethasone sodium phosphate (Dsp), was constructed to comprehensively regulate macrophages in different states towards the M2 phenotype to promote anti-inflammatory effects.
UNASSIGNED: Dex and Dsp were loaded in the outer lipid shell and inner lipid calcium phosphate (Cap) core of the LdCaPd NPs, respectively. Then, the morphology of NPs and methods for determining drug concentration were investigated, followed by in vitro protein adsorption, stability, and release tests. Cell experiments evaluated the cytotoxicity, cellular uptake, and macrophage polarization induction ability of NPs. The in vivo distribution and anti-inflammatory effect of NPs were evaluated through a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced BALB/c mice ulcerative colitis model.
UNASSIGNED: The LdCaPd NPs showed a particle size of about 200 nm and achieved considerable loading amounts of Dex and Dsp. The in vitro and in vivo studies revealed that in the acidic UC microenvironment, the cationic lipid shell of LdCaPd underwent protonated dissociation to release Dex first for creating a microenvironment conducive to M2 polarization. Then, the exposed CaP core was further engulfed by M1 macrophages to release Dsp to restrict the pro-inflammatory cytokines production by inhibiting the activation and function of the nuclear factor kappa-B (NF-κB) through activating the GC receptor and the NF kappa B inhibitor α (I-κBα), respectively, ultimately reversing the M1 polarization to promote the anti-inflammatory therapy.
UNASSIGNED: The LdCaPd NPs accomplished the sequential release of Dex and Dsp to the UC site and the inflammatory M1 macrophages at this site, promoting the regulation of macrophage polarization to accelerate the remission of UC symptoms.