以下文章来源于食品放大镜 ，作者文献解读
近日，中国科学院上海硅酸盐研究所施剑林院士、杨博文博士（共同通讯）在国际著名期刊Angewandte（Ⅰ区；IF 16.6）发表题为《A Nanomedicine-Enabled Ion-Exchange Strategy for EnhancingCurcumin-Based Rheumatoid Arthritis Therapy》的研究型文章。这项工作提供了一种通过离子交换策略增强姜黄素抗关节炎作用的新方法。
类风湿性关节炎（RA）是一种自身免疫性炎症疾病，全球患病率约为1%。其特征是炎症细胞浸润滑膜，随后滑膜增生，最终导致骨和关节软骨的破坏。RA的发病机制尚不清楚，但大量研究表明其机制与氧化应激导致活性氧（ROS）过量产生有关，这不仅诱导关节细胞氧化损伤，而且激活巨噬细胞向促炎M1表型极化，释放各种炎症因子，包括白细胞介素-6 (IL-6)、白细胞介素-1β (IL-1β)和肿瘤坏死因子-α (TNF-α)，加重炎症反应。因此，清除过量的ROS对于抑制RA的进展非常重要。
姜黄素（Curcumin, Cur）是从草本植物的根中提取的天然多酚二酮类化合物，是一种典型的通过电子转移或供氢清除活性氧的抗氧化剂。Cur的药理活性和生物相容性自古以来就被广泛探索，其在抗氧化治疗类风湿性关节炎中的应用已初步探讨。但由于Cur的疏水性和生理环境难溶性，导致其生物利用度差，抗氧化性能有限，制约了其进一步应用。由于其在化学结构中具有高度共轭的β-二酮基团，因此，Cur可以与Mn2+、Fe2+、Cu2+、Zn2+、Fe3+等多种金属离子螯合形成金属-Cur配合物，这进一步改变Cur的化学性质。有趣的是，螯合Zn2+后，Cur的溶解度大大提高，而螯合Cu2+后，Cur的抗氧化性能显著增强。更重要的是，由于Cur对不同金属离子的亲和力不同，会发生离子交换反应。比如，Cu-Cur具有比Zn-Cur更高的稳定常数，Cu2+可以取代Zn-Cur配合物中的Zn2+形成Cu-Cur。如果这种离子交换反应能够在RA区域特异性地发生，使Zn-Cur在原位合成具有高抗氧化性且具有理想水溶性的Cu-Cur，则可以同时克服Cur在RA治疗中疏水和抗氧化活性不理想的固有缺点，从而大大提高治疗效果。
目前迫切需要一种专门在RA区触发离子交换反应的技术。介孔二氧化硅纳米颗粒（MSNs）由于其独特的介孔结构、高生物相容性和易于功能化而被广泛用于药物递送系统。值得注意的是，MSN的组成是可调的，其-Si-O-Si-骨架可以与金属离子工程形成-Si-O-M- (M = Fe, Mn)杂化骨架，其间形成中空结构。这样的纳米系统使得金属离子在外壳和水溶性药物在中空腔内的共载成为可能，有利于两种活性剂的释放及其进一步的反应。
该文采用聚乙二醇（PEG）修饰硅酸铜纳米颗粒负载Zn-Cur，在RA区特异性触发离子交换反应。硅酸铜纳米载体在关节炎部位的酸性微环境中降解释放Cu2+和Zn-Cur，随后Cu2+取代Zn-Cur中的Zn2+生成具有所需抗氧化性能的Cu-Cur，能够有效清除ROS。在细胞水平上，纳米药物（CSP@Zn-Cur）可以减轻M1巨噬细胞的氧化应激，促进其向抗炎M2表型转化，从而进一步逆转其对骨间充质干细胞（BMSCs）活力的抑制作用。此外，纳米载体降解后释放的硅酸盐和离子交换反应后释放的Zn2+可以协同促进BMSCs生物矿化，有利于骨再生。小鼠体内模型进一步证明纳米药物不仅可以缓解关节肿胀，降低炎症因子表达，还可以促进骨组织修复，显著提高RA的治疗效果。
Scheme 1.Schematic illustration for the synthesis (a), composition (b) and therapeutic mechanism of CSP@Zn-Cur nanomedicine for RA treatment (c).
Figure 1.Characterizations of copper silicate nanoparticle and CSP@Zn-Cur nanomedicine.(a) SEM image of copper silicate nanoparticles. Scale bar: 200 nm. (b) TEM and SAED images (inset) of copper silicate nanoparticles. Scale bars: 200 nm and 5 nm-1(inset). (c) N2adsorption-desorption isotherm and pore size distribution curve (inset) of copper silicate nanoparticles. (d) High-angle annular dark-field image and element mappings of copper silicate nanoparticles. Scale bar: 200 nm. (e) XPS spectrumof Cuin copper silicate nanoparticles. (f) Solid-state 29Si NMR patterns of SiO2and copper silicate nanoparticles. (g) UV-Vis absorptionspectra of CSP, Zn-Cur, and CSP@Zn-Cur.
Figure 2.Degradation of CSP@Zn-Cur nanomedicine and in situ formation of Cu-Cur.(a) Chemical mechanism of nanocarrier degradation in acidic environment. (b) Scheme of Cu-Cur formation after nanomedicine degradation through an ion-exchange reaction. (c) TEM images of CSP@Zn-Cur nanomedicine degraded in mild acidic PBS solutions (pH = 6.5) for 4, 12 and 48 h, respectively. Scale bar: 200 nm. (d) TEM images of CSP@Zn-Cur nanomedicine degraded in neutral PBS solutions (pH = 7.4) for 48 h. Scale bar: 200 nm. (e-g) Accumulated release profiles of Si (e), Cu (f), and Zn (g) elements during the degradation of nanomedicine in PBS solutions with pH =6.5 and 7.4, respectively. Data are expressed as means ± SD (N= 3)(h) UV-Vis absorption spectrum in different time points ofnanomedicine degradation.
Figure 3.Antioxidation performance and mechanism of nanomedicine.(a) ESR spectra of the XO + X reaction system after different treatments. (b) O2•-inhibition rate of Cur, Zn-Cur, and Cu-Cur. Data are expressed as means ± SD (N= 6). (c) Inhibition rates of O2•-by CSP@Zn-Cur nanomedicine at different time points of degradation. Data are expressed as means ± SD (N= 6). (d) ESR spectra of Fenton reaction system after different treatments. (e) MB degradation efficiencies under different conditions. Data are expressed as means ± SD (N= 6). (f) UV-Vis absorption spectra of MB in a Fenton reaction system after treated with degradation solution of CSP@Zn-Cur nanomedicine for different time durations. (g) CV curves evaluating the electrochemical behaviorsof Cur, Zn-Cur, and Cu-Cur in anacidicPBSsolution (pH = 6.5). (h) Schematics for the chemical mechanisms of O2•-(i) and •OH (ii) scavengingby Cu-Cur.
Figure 4. Cellular antioxidative and anti-inflammatory effects of CSP@Zn-Cur nanomedicine.(a) Cellular mechanism of nanomedicine for ROS scavenging and anti-inflammation. (b) Flow cytometric analysis for investigating the uptake of FITC-labeled CSP@Zn-Cur nanomedicine by M1 macrophages after co-incubation for 0, 2, 4, and 6 h. (c) Cell viability of M1 macrophages after the treatment with CSP@Zn-Cur nanomedicine for 24 and 48 h. Data are expressed as means ± SD (N= 6). (d) CLSM images and (e) flow cytometric analysis for evaluating ROS concentration in macrophages after different treatments. Scale bar: 50 μm. (f) CLSM images of macrophages stained with phalloidin after different treatments. Scale bars: 25 μm. (g) Relative expressions of various cytokines in macrophages after different treatments. Data are expressed as means ± SD (N= 4).Statistical significances were calculated via Student’s ttest. n.s., not significant, *P< 0.05, **P<0.01, ***P< 0.001.
Figure 5.Cytoprotective and pro-biomineralization effects of CSP@Zn-Cur nanomedicines.(a) Schematic diagram of a transwell system to study theanti-inflammatory effects of nanomedicines on the activity of mBMSCs. (b) Cell viability of mBMSCs after different treatments for 12, 24, 48, and 72 h, respectively. Data are expressed as means ± SD (N= 6). (c) CLSM images of live/death staining of mBMSCs after different treatments. Scale bars: 100 μm. (d) Flow cytometric analysis of mBMSCs after different treatments for 72 h. (e) Schematic illustration of different pro-biomineralization mechanisms of silicate released from degraded nanocarrier, and Zn2+released from ion exchange reaction. The two pathways synergistically promote biomineralization. (f) TEM image and enlarged TEM image (inset) of nanomedicine degraded in acidic SBF solution (pH = 6.5) for 12 h. Scale bars: 20 nm. (g) Alizarin red staining of mBMSCs after different treatments. Scalebar: 0.75 cm.
Figure 6.Evaluation on the efficacy of CSP@Zn-Cur nanomedicine in treating RA.(a) Joint swelling curves of mice after different treatments. Data are expressed as means ± SD (N= 6). (b) Relative expression of various cytokines in joints after different treatments. Data are expressed as means ± SD (N= 4). (c) Micro-CT scanning and 3D reconstructed images of ankle joints of mice in different groups. (d-i) Bone parameters including (d) BV/TV, (e) Tb.Th, (f) Tb.N, (g) Tb.Sp, (h) SMI, and (i) Tb.BMD, of ankle joints of mice in different experimental groups. Data are expressed as means ± SD (N= 3).Statistical significances were calculated viaStudent’s ttest. n.s., not significant, *P< 0.05, **P< 0.01, ***P< 0.001.
原文链接
https://onlinelibrary.wiley.com/doi/10.1002/ange.202310061
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