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Héctor M Ramos-Zaldívar,1 Iva Polakovicova2,3 ,† Edison Salas-Huenuleo,4 Claudia P Yefi,5 David Silva-Ancahuail,2,6 Pedro Jara-Guajardo,2,6 Juan Esteban Oyarzún,7,8 Álvaro Neira-Troncoso,3,9 Patricia V Burgos,9 Viviana A Cavieres,9 Eloísa Arias-Muñoz,9 Carlos Martínez,10 Ana L Riveros,2,6 Alejandro H Corvalán,2,3 Marcelo J Kogan,2,6 Marcelo E Andia7,8 1Doctoral Program in Medical Sciences, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; 2Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile; 3Department of Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; 4Advanced Integrated Technologies SpA, (AINTECH), Santiago, Chile; 5Escuela de Medicina Veterinaria, Facultad de Ciencias de la Naturaleza, Universidad San Sebastián, Santiago, Chile; 6Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Laboratorio de Nanobiotecnología, Universidad de Chile, Santiago, Chile; 7Millennium Institute for Intelligent Healthcare Engineering, Santiago, Chile; 8Biomedical Imaging Center, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; 9Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile; 10Experimental Surgery and Simulation Center, Department of Digestive Surgery, Clinic Hospital, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile†Iva Polakovicova passed away on October 12, 2020Correspondence: Héctor M Ramos-Zaldívar, Email hmramos@uc.clIntroduction: 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.Methods: 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 post-mortem 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.Results: 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 post-mortem and in vivo, exclusively through lymphatic structures.Discussion: 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.Keywords: extracellular vesicles, SPIONs, gold nanorods, Chinese ink, meningeal lymphatic vessels, nanomedicine |
