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Assessing the transport of receptor-mediated drug delivery devices across biological barriers
Dissertation   Open access

Assessing the transport of receptor-mediated drug delivery devices across biological barriers

Erik C. Brewer
Doctor of Philosophy (Ph.D.), Drexel University
Feb 2014
DOI:
https://doi.org/10.17918/etd-4364
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Abstract

Drug delivery devices Blood-Brain Barrier Chemical Engineering
Administering therapeutics through the oral route or to the central nervous system presents significant challenges for large-molecule drugs, primarily due to the diffusive barriers and efflux mechanisms present in the cellular lining of the gastrointestinal (GI) tract and blood brain barrier (BBB). Receptor-mediated endocytosis (RME) has been extensively studied as a method for augmenting the transport of therapeutic devices across these barriers. These devices range from simple ligand-therapeutic conjugates to complex ligand-nanoparticle systems. Customarily, characterizing the uptake of these carriers relies on their comparisons to the native therapeutic, which provides no understanding of ligand or cellular performance. Therefore, the focus of this research is to investigate the transport potential of the RME pathway itself, so that ligands can act as suitable benchmarks for success. To better understand the pharmacokinetics of the RME pathway, a model for barrier transport was designed based on the endocytosis cycle of transferrin, a ligand often used in RME drug-delivery research. This model established the correlation between apical receptor concentration and maximum transport capability. Experimental studies confirmed this relationship, demonstrating an upper transport limit independent of the applied dose. This contrasts with the dose-proportional pathways native therapeutics rely on for transport. Thus, the direct comparison of these two transport mechanisms can produce misleading results that change with arbitrarily chosen doses. Furthermore, transport potential was hindered by repeated use of the RME-cycle. Commonly, nanoparticles are incorporated to amplify the payload capacity of RME-devices despite the burden they pose to the cell. The response of size and the size distribution of nanoparticle-ligand formulations on the cell were tested and contrasted to their increasing payloads. These results demonstrate that size has a major influence on nanoparticle transport, and future studies should base the success of this technology not on the performance of the therapeutic itself, but on the capabilities of the cell. Using receptor-binding studies, we were able to demonstrate how these capabilities can be predicted and potentially adopted for high-throughput screening methods.

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