Liposome nanoparticles functionalized with TfR ligands represent a promising drug delivery approach tested currently in preclinical trials in brain cancer, stroke, and Parkinson’s, Alzheimer’s, and Huntington’s disease, but the levels of nanoparticle transport into the brain need to improve to meet dosage requirements and reach clinical significance 12, 13.
In comparison, nanoparticle drug carriers are versatile delivery vehicles that can encapsulate large payloads of xenobiotics with a wide range of biophysical characteristics, offering diverse and unique therapeutic opportunities 9, 10, 11. Neuroprotective compounds show enhanced brain delivery when coupled to TfR ligands, e.g., antibody fragments 14, 15, but require chemical conjugation to the targeting moiety. The flagship ferrying receptor on BECs used for that purpose is the transferrin receptor (TfR) 8, 12, 13. Consequently, the BBB precludes more than 99% of neuroprotective compounds from reaching the brain, rendering central nervous system (CNS) disorders resistant to most conventional therapies 3, 7, 8.ĭrug delivery systems that aim to adapt receptor-mediated transcytosis (RMT) to shuttle therapeutic cargo across the BBB are currently at the forefront of modern therapeutic approaches against brain diseases 9, 10, 11.
Macromolecules, e.g., proteins, can enter the brain by vesicular transport, i.e., transcytosis, but this route is highly selective and actively suppressed by recently identified homeostatic mechanisms 5, 6. Most of them, however, including therapeutics, show negligible brain uptake due to rapid outward transport by efflux pumps to the bloodstream 3, 4. Diffusion of molecules across BECs is possible but restricted to low-molecular-weight hydrophobic compounds. The paracellular entry of molecules from the blood to the brain is barred by junctional complexes between adjoining brain endothelial cells (BEC) 2. The blood-brain barrier (BBB) is impermeable to most blood-borne substances, protecting the fragile brain environment from potentially harmful insults 1. Thus, post-capillary venules are the point-of-least resistance at the BBB, and compared to capillaries, provide a more feasible route for nanoparticle drug carriers into the brain. The vascular location of nanoparticle brain entry corresponds to the presence of perivascular space, which facilitates nanoparticle movement after transcytosis. The nanoparticles move unobstructed within endothelium, but transcytosis-mediated brain entry occurs mainly at post-capillary venules, and is negligible in capillaries.
We show that transferrin receptor-targeted liposome nanoparticles are sequestered by the endothelium at capillaries and venules, but not at arterioles. Here, using two-photon microscopy in mice, we characterize the receptor-mediated transcytosis of nanoparticles at all steps of delivery to the brain in vivo.
However, nanoparticle drug carriers explored for this purpose show negligible brain uptake, and the lack of basic understanding of nanoparticle-BBB interactions underlies many translational failures. Effective treatments of neurodegenerative diseases require drugs to be actively transported across the blood-brain barrier (BBB).
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