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This work was funded by the Spanish Ministry of Economy and Competitive-ness (MINECO) through the project NEUR-ON-A-CHIP (RTI2018-097038-B-C21 and RTI2018-097038-B-C22) and by the grant PDC2022-133918-C21 funded by MCIN/AEI/10.13039/501100011033 and by European Union Next Genera-tion EU/PRTR.This work was supported by Networking Biomedical Research Center (CIBER), Spain. CIBER is an initiative funded by the VI National R & D & i Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions,and the Instituto de Salud Carlos III (RD16/0006/0012), with the support of the European Regional Development Fund.This work was funded by the CERCA Programme and by the Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generali-tat de Catalunya (2023 SGR 015452). SPF acknowledges support from the program for predoctoral contracts for the training of doctors of the State Training Subprogram for the Promotion of Talent and its Employability in R + D + I (PRE2019-088286) by the Spanish Ministry of Science and Innovation (MICINN). ALC thanks MICINN for FPU fellowship FPU17/06161. MK acknowl-edge to Fondap 15130011 and Fondecyt 1211482.

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BBB-on-a-chip with integrated micro-TEER for permeability evaluation of multi-functionalized gold nanorods against Alzheimer's disease

Publicado en:Journal Of Nanobiotechnology. 21 (1): 115- - 2023-03-29 21(1), DOI: 10.1186/s12951-023-01798-2

Autores: Palma-Florez, S; López-Canosa, A; Moralez-Zavala, F; Castaño, O; Kogan, MJ; Samitier, J; Lagunas, A; Mir, M

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The lack of predictive models that mimic the blood-brain barrier (BBB) hinders the development of effective drugs for neurodegenerative diseases. Animal models behave differently from humans, are expensive and have ethical constraints. Organ-on-a-chip (OoC) platforms offer several advantages to resembling physiological and pathological conditions in a versatile, reproducible, and animal-free manner. In addition, OoC give us the possibility to incorporate sensors to determine cell culture features such as trans-endothelial electrical resistance (TEER). Here, we developed a BBB-on-a-chip (BBB-oC) platform with a TEER measurement system in close distance to the barrier used for the first time for the evaluation of the permeability performance of targeted gold nanorods for theranostics of Alzheimer's disease. GNR-PEG-Ang2/D1 is a therapeutic nanosystem previously developed by us consisting of gold nanorods (GNR) functionalized with polyethylene glycol (PEG), angiopep-2 peptide (Ang2) to overcome the BBB and the D1 peptide as beta amyloid fibrillation inhibitor, finally obtaining GNR-PEG-Ang2/D1 which showed to be useful for disaggregation of the amyloid in in vitro and in vivo models. In this work, we evaluated its cytotoxicity, permeability, and some indications of its impact on the brain endothelium by employing an animal-free device based on neurovascular human cells.In this work, we fabricated a BBB-oC with human astrocytes, pericytes and endothelial cells and a TEER measuring system (TEER-BBB-oC) integrated at a micrometric distance of the endothelial barrier. The characterization displayed a neurovascular network and the expression of tight junctions in the endothelium. We produced GNR-PEG-Ang2/D1 and determined its non-cytotoxic range (0.05-0.4 nM) for plated cells included in the BBB-oC and confirmed its harmless effect at the highest concentration (0.4 nM) in the microfluidic device. The permeability assays revealed that GNR-PEG-Ang2/D1 cross the BBB and this entry is facilitated by Ang2 peptide. Parallel to the permeability analysis of GNR-PEG-Ang2/D1, an interesting behavior of the TJs expression was observed after its administration probably related to the ligands on the nanoparticle surface.BBB-oC with a novel TEER integrated setup which allow a correct read-out and cell imaging monitoring was proven as a functional and throughput platform to evaluate the brain permeability performance of nanotherapeutics in a physiological environment with human cells, putting forward a viable alternative to animal experimentation.© 2023. The Author(s).

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