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May 30, 2013
 |  BC Innovations  |  Tools & Techniques

Optimizing transferrin-mediated transcytosis

Researchers at the California Institute of Technology have shown how modulating the transferrin content on gold nanoparticles can optimize their delivery into the brain via the transferrin receptor.1 The group now needs to determine whether its strategy will translate to drug-nanoparticle conjugates amenable for use in the CNS.

The normal function of the transferrin receptor is to engage with transferrin to bring the iron-binding protein into cells that express the receptor. In the endothelial cells that line the vasculature of the brain, the receptor helps shuttle transferrin from one side of the blood brain barrier (BBB) to the other-a process called receptor-mediated transcytosis.2

Prior efforts to exploit the transferrin receptor's mechanism to improve the delivery of therapeutic agents into the brain involved conjugating the agents to transferrin receptor-binding mAbs or transferrin-conjugated nanoparticles.3-5 However, few such conjugates were successful.

A key breakthrough came in 2011 when researchers at Roche's Genentech Inc. unit realized that antibodies with high affinity for the transferrin receptor were being trapped in the endothelium because they remained bound to the receptor.6-8

This led the Genentech group to develop lower-affinity mAbs that would be released from the receptor after crossing the BBB and accumulate in the brain at higher concentrations than high-affinity mAbs.

The Caltech group has now found that a similar principle applies to transferrin-conjugated nanoparticles.

The researchers synthesized a series of gold nanoparticles of different diameters and surface transferrin content. In mice, nanoparticles with diameters of 40-80 nm and moderate transferrin content bound to the transferrin receptor, penetrated the BBB and accumulated in the brain parenchyma.

In contrast, nanoparticles with low...

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