Department of Biomedical Engineering, Binghamton University (SUNY), Binghamton, NY, USA.
Department of Electrical and Biomedical Engineering, University of Vermont, Burlington, VT, USA.
Int J Nanomedicine. 2023 Jan 24;18:473-487. doi: 10.2147/IJN.S392567. eCollection 2023.
Inflammatory diseases are the leading cause of death in the world, accounting for 3 out of 5 deaths. Despite the abundance of diagnostic tools for detection, most screening and diagnostic methods are indirect and insufficient as they are unable to reliably discriminate between high-risk or low-risk stages of inflammatory diseases. Previously, we showed that the selective activation of interpolymer complexed superparamagnetic iron oxide nanoparticles (IPC-SPIOs) under oxidative conditions can be detected by a change in T magnetic resonance (MR) contrast. In this work, IPC-SPIOs were further modified by incorporating mannose as a targeting biomolecule to enhance nanoparticle delivery to M2 macrophages at inflammatory sites.
Uncoated SPIOs were synthesized via coprecipitation from a mixture of FeCl and FeCl, PEGylated by adsorbing PEG 300 kDa (40 mg/mL in water) to SPIOs (3 mg/mL in water) over 24 hours, and complexed by mixing 0.25 mg/mL aqueous poly(gallol) with 2 mg/mL PEG-SPIOs and adding 1 M of phosphate buffer in a 9:9:2 ratio. Mannose-PEG attachment was accomplished conducting a second complexation of mannose-PEG to IPC-SPIOs. M2 macrophages were treated with 150, 100, and 75 µg/mL of IPC-SPIOs and mannose-IPC-SPIOs to investigate activation of T MRI signals.
Surface modification resulted in a slight reduction in ROS scavenging capacity; however, nanoparticle uptake by M2 macrophages increased by over 50%. The higher uptake did not cause a reduction in cellular viability. In fact, mannose-IPC-SPIOs induced significant T MR contrast in M2 macrophages compared to IPC-SPIOs and nanoparticles exposed to M1 macrophages. M2 macrophages activated over 30% of mannose-IPC-SPIOs after 6 hours of exposure compared to M1 macrophages and untargeted M2 macrophages. These findings demonstrated that mannose-IPC-SPIOs specifically targeted M2 macrophages and scavenged cellular ROS to activate T MR signal, which can be used to detect inflammation.
炎症性疾病是世界上导致死亡的主要原因，占总死亡人数的五分之三。尽管有大量的诊断工具用于检测，但大多数筛查和诊断方法都是间接的，并且不够充分，因为它们无法可靠地区分炎症性疾病的高风险或低风险阶段。之前，我们已经证明，在氧化条件下，聚合体复合超顺磁性氧化铁纳米粒子（IPC-SPIOs）的选择性激活可以通过 T 磁共振（MR）对比的变化来检测。在这项工作中，我们进一步通过将甘露糖作为靶向生物分子来修饰 IPC-SPIOs，以增强纳米颗粒在炎症部位向 M2 巨噬细胞的递呈。
通过共沉淀法从 FeCl 和 FeCl 的混合物中合成未涂层的 SPIOs，通过将 PEG 300 kDa（40 mg/mL 于水中）吸附到 SPIOs（3 mg/mL 于水中）上 24 小时来对 SPIOs 进行 PEG 化，并通过将 0.25 mg/mL 水合聚（没食子酸）与 2 mg/mL PEG-SPIOs 混合并以 9:9:2 的比例加入 1 M 的磷酸盐缓冲液来进行复合物的混合。甘露糖-PEG 的附着是通过对 IPC-SPIOs 进行第二次甘露糖-PEG 复合物化来完成的。用 150、100 和 75 µg/mL 的 IPC-SPIOs 和甘露糖-IPC-SPIOs 处理 M2 巨噬细胞，以研究 T MRI 信号的激活情况。
表面修饰导致 ROS 清除能力略有下降，但 M2 巨噬细胞对纳米颗粒的摄取增加了 50%以上。更高的摄取量并没有降低细胞活力。事实上，与 M1 巨噬细胞和暴露于 M1 巨噬细胞的纳米颗粒相比，甘露糖-IPC-SPIOs 在 M2 巨噬细胞中诱导了显著的 T MRI 对比。与 M1 巨噬细胞和未靶向的 M2 巨噬细胞相比，M2 巨噬细胞在暴露于甘露糖-IPC-SPIOs 6 小时后激活了超过 30%的甘露糖-IPC-SPIOs。这些发现表明，甘露糖-IPC-SPIOs 特异性靶向 M2 巨噬细胞并清除细胞内的 ROS 以激活 T MRI 信号，可用于检测炎症。
