Details

Autor(en) / Beteiligte

• Johnsen, Kasper Bendix
• Bak, Martin
• Melander, Fredrik
• Thomsen, Maj Schneider
• Burkhart, Annette
• Kempen, Paul Joseph
• Andresen, Thomas Lars
• Moos, Torben

Titel

Modulating the antibody density changes the uptake and transport at the blood-brain barrier of both transferrin receptor-targeted gold nanoparticles and liposomal cargo

Ist Teil von

• Journal of controlled release, 2019-02, Vol.295, p.237-249

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• Transport of the majority of therapeutic molecules to the brain is precluded by the presence of the blood-brain barrier (BBB) rendering efficient treatment of many neurological disorders impossible. This BBB, nonetheless, may be circumvented by targeting receptors and transport proteins expressed on the luminal surface of the brain capillary endothelial cells (BCECs). The transferrin receptor (TfR) has remained a popular target since its original description for this purpose, although clinical progression of TfR-targeted drug constructs or nanomedicines remains unsuccessful. One proposed issue pertaining to the use of TfR-targeting in nanomedicines is the efficient tuning of the ligand density on the nanoparticle surface. We studied the impact of TfR antibody density on the uptake and transport of nanoparticles into the brain, taking a parallel approach to investigate the impact on both antibody-functionalized gold nanoparticles (AuNPs) and cargo-loaded liposomes. We report that among three different low-range mean ligand densities (0.15, 0.3, and 0.6 ∗ 103 antibodies/μm2), the highest density yielded the highest ability towards both targeting of the BCECs and subsequent transport across the BBB in vivo, and in vitro using primary cultures of the murine BBB. We also find that TfR-targeting on liposomes in the mouse may induce severe adverse effects after intravenous administration. [Display omitted] •Ligand density impacts brain transport of TfR-targeted nanoparticles.•Very low antibody densities do not improve brain transport of AuNPs and liposomes.•TfR-targeting may increase off-target accumulation in the spleen.•Liposome-associated anti-TfR antibodies induce adverse effects after administration.