Doctoral Program in Medical Sciences, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile.
Int J Nanomedicine. 2024 Oct 24;19:10725-10743. doi: 10.2147/IJN.S477159. eCollection 2024.
The meningeal lymphatic vessels have been described as a pathway that transports cerebrospinal fluid and interstitial fluid in a unidirectional manner towards the deep cervical lymph nodes. However, these vessels exhibit anatomical and molecular characteristics typical of initial lymphatic vessels, with the absence of surrounding smooth muscle and few or absent valves. Given its structure, this network could theoretically allow for bidirectional motion. Nevertheless, it has not been assessed as a potential route for nanoparticles to travel from peripheral tissues to the brain.
We employed superparamagnetic iron oxide nanoparticles (SPIONs), exosomes loaded with SPIONs, gold nanorods, and Chinese ink nanoparticles. SPIONs were prepared via chemical coprecipitation, while exosomes were isolated from the B16F10 melanoma cell line through the Exo-Spin column protocol and loaded with SPIONs through electroporation. Gold nanorods were functionalized with polyethylene glycol. We utilized C57BL/6 mice for and in vivo procedures. To evaluate the retrograde directional flow, we injected each nanoparticle solution in the deep cervical lymph node. The head and neck were fixed for magnetic resonance imaging and histological analysis.
Here we show that extracellular vesicles derived from the B16F10 melanoma cell line, along with superparamagnetic iron oxide nanoparticles, gold nanorods, and Chinese ink nanoparticles can reach the meningeal lymphatic vessels and the brain of C57BL/6 mice after administration within the deep cervical lymph nodes and in vivo, exclusively through lymphatic structures.
The functional anatomy of dural lymphatics has been found to be conserved between mice and humans, suggesting that our findings may have significant implications for advancing targeted drug delivery systems using nanoparticles. Understanding the retrograde transport of nanoparticles through the meningeal lymphatic network could lead to novel therapeutic approaches in nanomedicine, offering new insights into fluid dynamics in both physiological and neuropathological contexts. Further research into this pathway may unlock new strategies for treating neurological diseases or enhancing drug delivery to the brain.
脑膜淋巴管已被描述为一种单向运输脑脊液和间质液到深部颈淋巴结的途径。然而，这些血管具有初始淋巴管的解剖和分子特征，缺乏周围平滑肌，且瓣膜较少或缺失。鉴于其结构，该网络理论上可以允许双向运动。然而，尚未评估其作为纳米颗粒从外周组织到大脑的潜在途径。
我们使用了超顺磁性氧化铁纳米颗粒（SPIONs）、负载 SPIONs 的外泌体、金纳米棒和中国墨纳米颗粒。SPIONs 通过化学共沉淀制备，而外泌体则通过 Exo-Spin 柱方案从 B16F10 黑色素瘤细胞系中分离，并通过电穿孔负载 SPIONs。金纳米棒通过聚乙二醇功能化。我们使用 C57BL/6 小鼠进行体内和体内实验。为了评估逆行方向的流动，我们将每种纳米颗粒溶液注入深部颈淋巴结。头部和颈部固定进行磁共振成像和组织学分析。
在这里，我们展示了源自 B16F10 黑色素瘤细胞系的细胞外囊泡，以及超顺磁性氧化铁纳米颗粒、金纳米棒和中国墨纳米颗粒，在注射到深部颈淋巴结后，可以通过淋巴结构到达 C57BL/6 小鼠的脑膜淋巴管和大脑，仅通过淋巴结构。
脑膜淋巴管的功能解剖在小鼠和人类之间被发现是保守的，这表明我们的发现可能对使用纳米颗粒的靶向药物输送系统的发展具有重要意义。了解纳米颗粒通过脑膜淋巴管网的逆行运输，可以为神经医学中的新治疗方法提供新的见解，为生理和神经病理学背景下的流体动力学提供新的认识。对该途径的进一步研究可能为治疗神经疾病或增强药物向大脑的输送提供新的策略。
