Abstract
Drug delivery to the brain is hampered by the presence of the blood-brain barrier, which excludes most molecules from freely diffusing into the brain, and tightly regulates the active transport mechanisms that ensure sufficient delivery of nutrients to the brain parenchyma. Harnessing the possibility of delivering neuroactive drugs by way of receptors already present on the brain endothelium has been of interest for many years. The transferrin receptor is of special interest since its expression is limited to the endothelium of the brain as opposed to peripheral endothelium. Here, we investigate the possibility of delivering immunoliposomes and their encapsulated cargo to the brain via targeting of the transferrin receptor. We find that transferrin receptor-targeting increases the association between the immunoliposomes and primary endothelial cells in vitro, but that this does not correlate with increased cargo transcytosis. Furthermore, we show that the transferrin receptor-targeted immunoliposomes accumulate along the microvessels of the brains of rats, but find no evidence for transcytosis of the immunoliposome. Conversely, the increased accumulation correlated both with increased cargo uptake in the brain endothelium and subsequent cargo transport into the brain. These findings suggest that transferrin receptor-targeting is a relevant strategy of increasing drug exposure to the brain.
Highlights
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To study the interaction between transferrin receptor-targeted (OX26) immunoliposomes and brain capillary endothelial cells (BCECs) in vitro, we employed a primary rat in vitro model of the blood-brain barrier (BBB), which consisted of a co-culture between BCECs and astrocytes (Fig. 1A)
The positive staining for the transferrin receptors was found to be associated with the luminal membrane as well as in the cell cytoplasm, which are the known locations of the transferrin receptors in BCECs in vivo (Fig. 1C, upper panel)
Summary
Users may download and print one copy of any publication from the public portal for the purpose of private study or research. Due to the BBB, drug delivery to the brain sustains a major challenge for effective treatment of brain diseases despite development of numerous drug compounds and nanomedicines that putatively fit this purpose[3] Many of these approaches base their brain accumulation strategies on targeting of the transferrin receptor[4]. We have taken a parallel approach by investigating either fluorescently labelled or oxaliplatin-loaded transferrin receptor-targeted immunoliposomes for their association to, and transport across, the BBB in vitro and in vivo. We study the potential of transferrin receptor-targeting to increase the transport of a liposome-encapsulated cargo (oxaliplatin) into the brain parenchyma after intravenous injection into young rats, and provide quantitative data for brain uptake after capillary depletion in combination with circulation time profiling and biodistribution analysis
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