Master's Theses

Date of Award

2011

Document Type

Thesis

Department

Biomedical Engineering

Keywords

Transcellular, Bloood Brain Barrier, Charged Nanoparticles

Abstract

"The blood-brain barrier (BBB) is a dynamic interface between the blood circulation and the central nervous system (CNS). While it serves as a selective barrier to water and solutes to prevent the blood-borne toxins from entering into the brain tissue, it hinders the drug delivery to the CNS for the treatment of brain diseases. Recently therapeutic antibodies and a variety of drug-loaded nanoparticles (NPs) have been widely used to treat CNS disorders such as brain tumors, Alzheimer's disease and Parkinson's disease. To improve brain delivery efficacy of antibodies and NPs, it is necessary to quantify their transport parameters across the BBB and understand the underlying transport mechanisms. In this study, we used an in vitro BBB model of a cultured cell monolayer from an immortalized mouse cerebral microvascular endothelial cell line, bEnd3. Permeabilities of the monolayer to antibody IgG (MW~160kD, Stokes diameter ~10 nm), and to three neutral NPs with the representative diameter of 22nm, 48nm and 100nm were measured using an automated fluorometer system. The measured permeability to IgG was 22.2 (±0.56 SE, n=12) × 10-8 cm/s and those to NPs of diameter 22nm, 48nm and 100nm were 2.58 (±0.65SE, n=8) ×10-8cm/s, 2.27 (±0.85SE, n=6) ×10-8cm/s, and 2.23 (±0.89SE, n=11) × 10-8cm/s, respectively. By applying a previously-developed paracellular transport model for the in vitro BBB, we predicted the permeability to IgG for a range of IgG diffusion coefficient in the fiber-like glycocalyx at the surface of the cell monolayer, Dfiber, from 0.001 to 0.01of its free diffusion coefficient Dfree. Our predictions suggest that IgG is mostly likely across the in vitro BBB through a paracellular pathway. In 3 addition, to explain the in vitro BBB permeability to much larger NPs without charge, which was measured in this study and that to NPs with charge, which was measured in Yuan et al (2010), we developed a new transcellular transport model, which incorporates the charge at the surface glycocalyx of the bEnd3 monolayer, the mechanical property of the cell membrane, the ion concentrations of the surrounding salt solution, the size and charge of the NPs. Our model indicates that the negative charge of the surface glycocalyx plays a pivotal role in transcelluar transport of NPs of diameters ranging from 20 to100nm, regardless of charged or neutral NPs. The electrostatic attraction between the negative charge at the surface glycocalyx of the cell monolayer and the positive charge at NPs further increase the permeability of positively charged NPs greatly. Our model can be used to find the optimal size and charge of the NPs and the optimal surface charge of the BBB for an optimal drug delivery to the brain."

 
 

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