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Theranostics 2018; 8(12):3416-3436. doi:10.7150/thno.25228 This issue Cite

Research Paper

Antibody affinity and valency impact brain uptake of transferrin receptor-targeted gold nanoparticles

Kasper Bendix Johnsen^1,2, Martin Bak², Paul Joseph Kempen², Fredrik Melander², Annette Burkhart¹, Maj Schneider Thomsen¹, Morten Schallburg Nielsen³, Torben Moos^1✉, Thomas Lars Andresen^2✉

1. Laboratory for Neurobiology, Biomedicine, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
2. Center for Nanomedicine and Theranostics, Department of Micro- and Nanotechnology, Technical University of Denmark, Denmark.
3. Department of Biomedicine, Aarhus University, Denmark.

✉ Corresponding authors: Thomas Lars Andresen, PhD, Center for Nanomedicine and Theranostics, DTU Nanotech, Technical University of Denmark, Ørsteds Plads, Building 345B, Room 050, 2800 Kongens Lyngby, Denmark. E-mail: tlandtu.dk; Phone number: 0045 2537 4486 and Torben Moos, MD, PhD, DMSc, Laboratory for Neurobiology, Biomedicine, Department of Health Science and Technology, Aalborg University, Fredrik Bajers Vej 3B, 1.216, 9220 Aalborg Ø, Denmark. E-mail: tmoosaau.dk; Phone number: 0045 9940 2420 More

Abstract

Rationale: The ability to treat invalidating neurological diseases is impeded by the presence of the blood-brain barrier (BBB), which inhibits the transport of most blood-borne substances into the brain parenchyma. Targeting the transferrin receptor (TfR) on the surface of brain capillaries has been a popular strategy to give a preferential accumulation of drugs or nanomedicines, but several aspects of this targeting strategy remain elusive. Here we report that TfR-targeted gold nanoparticles (AuNPs) can accumulate in brain capillaries and further transport across the BBB to enter the brain parenchyma.

Methods: We characterized our targeting strategy both in vitro using primary models of the BBB and in vivo using quantitative measurements of gold accumulation by inductively-coupled plasma-mass spectrometry together with morphological assessments using light microscopy after silver enhancement and transmission electron microscopy with energy-dispersive X-ray spectroscopy.

Results: We find that the uptake capacity is significantly modulated by the affinity and valency of the AuNP-conjugated antibodies. Specifically, antibodies with high and low affinities mediate a low and intermediate uptake of AuNPs into the brain, respectively, whereas a monovalent (bi-specific) antibody improves the uptake capacity remarkably.

Conclusion: Our findings indicate that monovalent ligands may be beneficial for obtaining transcytosis of TfR-targeted nanomedicines across the BBB, which is relevant for future design of nanomedicines for brain drug delivery.

Keywords: Brain drug delivery, gold nanoparticle, transferrin receptor, targeting, affinity

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