Abstract
The ability to target therapeutic agents to specific tissues is an important element in the development of new disease treatments. The transferrin receptor (TfR) is one potential target for drug delivery, as it expressed on many dividing cells and on brain endothelium, the key cellular component of the blood-brain barrier. The aim of this study was to compare a set of new and previously-described polypeptides for their ability to bind to brain endothelium, and investigate their potential for targeting therapeutic agents to the CNS. Six polypeptides were ranked for their rate of endocytosis by the human brain endothelial cell line hCMEC/D3 and the murine line bEnd.3. One linear polypeptide and two cyclic polypeptides showed high rates of uptake. These peptides were investigated to determine whether serum components, including transferrin itself affected uptake by the endothelium. One of the cyclic peptides was strongly inhibited by transferrin and the other cyclic peptide weakly inhibited. As proof of principle the linear peptide was attached to 2nm glucose coated gold-nanoparticles, and the rate of uptake of the nanoparticles measured in a hydrogel model of the blood-brain barrier. Attachment of the TfR-targeting polypeptide significantly increased the rates of endocytosis by brain endothelium and increased movement of nanoparticles across the cells.
Highlights
The targeting of therapeutic agents to specific cells or tissues is central to the development of treatments for many diseases
The aim of this study was to compare the properties of a number of different peptides that bind to the transferrin receptor (TfR), including a linear peptide [21] and three recently-described cyclic peptides isolated from a phage-display library by binding to murine and human TfR [22]
A set of peptides known to bind to the TfR and peptides that selectively bind brain endothelium were synthesised with a fluorescent tag (Fitc) on either the N- or C-terminal amino acids (Table 1)
Summary
The targeting of therapeutic agents to specific cells or tissues is central to the development of treatments for many diseases. Increasing the proportion of a drug that reaches the target-tissue reduces potential off-target effects and the dose required to produce a therapeutic effect. This latter point is important as expensive biological agents are increasingly being developed for clinical use. The main approach to targeting has been to identify receptors that. Https://www.midatechpharma.com The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript Transferrin-receptor binding polypeptides nanoparticle carriers.’ Midatech pharma plc. https://www.midatechpharma.com The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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