Purpose The therapeutic drug-loaded nanoparticles (NPs, 20–100 nm) have been widely used to treat brain disorders. To improve systemic brain delivery efficacy of these NPs, it is necessary to quantify their transport parameters across the blood–brain barrier (BBB) and understand the underlying transport mechanism. Methods Permeability of an in vitro BBB, bEnd3 (mouse brain microvascular endothelial cells) monolayer, to three neutral NPs with the representative diameters was measured using an automated fluorometer system. To elucidate the transport mechanism of the neutral NPs across the in vitro BBB, and that of positively charged NPs whose BBB permeability was measured in a previous study, we developed a novel transcellular model, which incorporates the charge of the in vitro BBB, the mechanical property of the cell membrane, the ion concentrations of the surrounding salt solution and the size and charge of the NPs. Results Our model indicates that the negative charge of the surface glycocalyx and basement membrane of the BBB plays a pivotal role in the transcelluar transport of NPs with diameter 20-100 nm across the BBB. The electrostatic force between the negative charge at the in vitro BBB and the positive charge at NPs greatly enhances NP permeability. The predictions from our transcellular model fit very well with the measured BBB permeability for both neutral and charged NPs. Conclusion Our model can be used to predict the optimal size and charge of the NPs and the optimal charge of the BBB for an optimal systemic drug delivery strategy to the brain.

The breadth of brain disorders and functions reported responsive to transcranial direct current stimulation (tDCS) suggests a generalizable mechanism of action. Prior efforts characterized its cellular targets including neuron, glia and endothelial cells. We propose tDCS also modulates the substance transport in brain tissue. High resolution multiphoton microscopy imaged the spread across rat brain tissue of fluorescently-labeled solutes injected through the carotid artery after tDCS. The effective solute diffusion coefficient of brain tissue (Deff) was determined from the spatio-temporal solute concentration profiles using an unsteady diffusion transport model. 5–10 min post 20 min–1 mA tDCS, Deff increased by ~ 10% for a small solute, sodium fluorescein, and ~ 120% for larger solutes, BSA and Dex-70k. All increases in Deff returned to the control level 25–30 min post tDCS. A mathematical model for Deff in the extracelluar space (ECS) further predicts that this dose of tDCS increases Deff by transiently enhancing the brain ECS gap spacing by ~ 1.5-fold and accordingly reducing the extracellular matrix density. The cascades leading ECS modulation and its impact on excitability, synaptic function, plasticity, and brain clearance require further study. Modulation of solute diffusivity and ECS could explain diverse outcomes of tDCS and suggest novel therapeutic strategies.

Introduction Transcranial direct current stimulation (tDCS) is a non‐invasive electrical stimulation investigated to treat a broad range of brain disorders and to enhance memory and cognition in healthy individuals. Our prior study has shown that tDCS with proper dosage can achieve non‐invasive and temporary increase in the blood‐brain barrier (BBB) permeability (P). To further investigate whether tDCS also increases the material transport in brain tissue, we employed high resolution multiphoton microscopy to collect the spreading images of fluorescently‐labeled solutes in the rat brain tissue after tDCS treatment. The effective solute diffusion coefficient in the brain tissue (Deff ) was determined by using our previously developed method. Deff is a quantitative indicator for solute transport in a medium. Methods After 20 min 1 mA tDCS treatment, sodium fluorescein (MW 376), or FITC‐dextran 70k in 1% BSA mammalian Ringer was injected into the rat (SD, 250–300g) cerebral circulation via the ipsilateral carotid artery by a syringe pump at a constant rate of ~3 ml/min. Simultaneously, the 3‐D images of a post‐capillary vessel and its surrounding area in the rat brain tissue 100–200 mm below the pia mater were collected by laser scanning multiphoton microscopy with 820 nm excitation wavelength. The cerebral microvessel permeability (P) and the effective solute diffusion coefficient in the brain tissue Deff were determined from the rate of dye spreading images. Specifically, Deff was estimated by curve fitting the spatio‐temporal solute concentration (fluorescence intensity) distribution by using an unsteady diffusion transport model. Results and Discussion It was found that in 5–10 min post 20 min–1mA tDCS, Deff/Dfree increases from 0.45 to 0.50 for sodium fluorescein (n=5) and from 0.11 to 0.25 for dextran 70k (n=6), all the increased Deff returned to the control level in 25–30 min post tDCS. tDCS indeed transiently makes the brain tissue less restrictive to solute transport, especially for larger solutes. Conclusions tDCS not only transiently increases the BBB permeability but also enhances the solute transport in brain tissue. Support or Funding Information Supported by NIH RO1 NS101362‐01