Wallace H. Coulter School of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA.
Wallace H. Coulter School of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30332, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA; Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA.
Biomaterials. 2021 Jan;265:120411. doi: 10.1016/j.biomaterials.2020.120411. Epub 2020 Sep 18.
Lymph nodes (LNs) are immune organs housing high concentrations of lymphocytes, making them critical targets for therapeutic immunomodulation in a wide variety of diseases. While there is great interest in targeted drug delivery to LNs, many nanoscale drug delivery carriers have limited access to parenchymal resident immune cells compared to small molecules, limiting their efficacy. Nitric oxide (NO) is a potent regulator of vascular and lymphatic transport and a promising candidate for modulating nanocarrier access to LNs, but its lymphatic accumulation is limited by its low molecular weight and high reactivity. In this work, we employ S-nitrosated nanoparticles (SNO-NP), a lymphatic-targeted delivery system for controlled NO release, to investigate the effect of NO application on molecule accumulation and distribution within the LN. We evaluated the LN accumulation, spatial distribution, and cellular distribution of a panel of fluorescent tracers after intradermal administration alongside SNO-NP or a small molecule NO donor. While SNO-NP did not alter total tracer accumulation in draining lymph nodes (dLNs) or affect active cellular transport of large molecules from the injection site, its application enhanced the penetration of nanoscale 30 nm dextrans into the LN and their subsequent uptake by LN-resident lymphocytes, while nontargeted NO delivery did not. These results further extended to a peptide-conjugated NP drug delivery system, which showed enhanced uptake by B cells and dendritic cells when administered alongside SNO-NP. Together, these results highlight the utility of LN-targeted NO application for the enhancement of nanocarrier access to therapeutically relevant LN-resident immune cells, making NO a potentially useful tool for improving LN drug delivery and immune responses.
淋巴结 (LNs) 是免疫器官，其中集中了大量淋巴细胞，使其成为多种疾病中治疗性免疫调节的关键靶点。虽然人们对靶向递送到 LNs 的药物很感兴趣，但与小分子相比，许多纳米级药物递送载体对实质驻留免疫细胞的进入能力有限，限制了其疗效。一氧化氮 (NO) 是血管和淋巴转运的有效调节剂，是调节纳米载体进入 LNs 的有前途的候选物，但由于其分子量低和反应性高，其淋巴积累受到限制。在这项工作中，我们使用 S-亚硝酰化纳米颗粒 (SNO-NP)，一种用于控制 NO 释放的淋巴靶向递药系统，研究 NO 应用对 LN 内分子积累和分布的影响。我们评估了在皮内给药的同时给予 SNO-NP 或小分子 NO 供体后，一组荧光示踪剂在 LN 中的积累、空间分布和细胞分布。虽然 SNO-NP 没有改变引流淋巴结 (dLNs) 中总示踪剂的积累，也没有影响大分子从注射部位的主动细胞转运，但它的应用增强了纳米级 30nm 葡聚糖进入 LN 的渗透及其随后被 LN 驻留淋巴细胞摄取，而非靶向 NO 递送则没有。这些结果进一步扩展到肽缀合的 NP 药物递送系统，当与 SNO-NP 一起给药时，该系统显示出对 B 细胞和树突状细胞摄取的增强。总之，这些结果突出了 LN 靶向 NO 应用增强纳米载体进入治疗相关 LN 驻留免疫细胞的效用，使 NO 成为改善 LN 药物递送和免疫反应的潜在有用工具。
