Drug Delivery Strategies to Overcome the Blood-Brain Barrier (BBB)
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Drug Delivery Strategies to Overcome the Blood-Brain Barrier (BBB). / Helms, Hans Christian Cederberg; Kristensen, Mie; Saaby, Lasse; Fricker, Gert; Brodin, Birger.
Handbook of Experimental Pharmacology. Bind 273 Springer, 2020. s. 151-183.Publikation: Bidrag til bog/antologi/rapport › Bidrag til bog/antologi › Formidling
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TY - CHAP
T1 - Drug Delivery Strategies to Overcome the Blood-Brain Barrier (BBB)
AU - Helms, Hans Christian Cederberg
AU - Kristensen, Mie
AU - Saaby, Lasse
AU - Fricker, Gert
AU - Brodin, Birger
PY - 2020
Y1 - 2020
N2 - The brain capillary endothelium serves both as an exchange site for gases and solutes between blood and brain and as a protective fence against neurotoxic compounds from the blood. While this “blood–brain barrier” (BBB) function protects the fragile environment in the brain, it also poses a tremendous challenge for the delivery of drug compounds to the brain parenchyma. Paracellular brain uptake of drug compounds is limited by the physical tightness of the endothelium, which is tightly sealed with junction complexes. Transcellular uptake of lipophilic drug compounds is limited by the activity of active efflux pumps in the luminal membrane. As a result, the majority of registered CNS drug compounds are small lipophilic compounds which are not efflux transporter substrates. Small molecule CNS drug development therefore focuses on identifying compounds with CNS target affinity and modifies these in order to optimize lipophilicity and decrease efflux pump interactions. Since efflux pump activity is limiting drug uptake, it has been investigated whether coadministration of drug compounds with efflux pump inhibitors could increase drug uptake. While the concept works to some extent, a lot of challenges have been encountered in terms of obtaining efficient inhibition while avoiding adverse effects.Some CNS drug compounds enter the brain via nutrient transport proteins, an example is the levodopa, a prodrug of Dopamine, which crosses the BBB via the large neutral amino acid transporter LAT1. While carrier-mediated transport of drug compounds may seem attractive, the development of drugs targeting transporters is very challenging, since the compounds should have a good fit to the binding site, while still maintaining their CNS target affinity.Receptor-mediated transport of drug compounds, especially biotherapeutics, conjugated to a receptor-binding ligand has shown some promise, although the amounts transported are rather low. This also holds true for drug-conjugation to cell-penetrating peptides. Due to the low uptake of biotherapeutics, barrier-breaching approaches such as mannitol injections and focused ultrasound have been employed with some success to patient groups with no other treatment options.
AB - The brain capillary endothelium serves both as an exchange site for gases and solutes between blood and brain and as a protective fence against neurotoxic compounds from the blood. While this “blood–brain barrier” (BBB) function protects the fragile environment in the brain, it also poses a tremendous challenge for the delivery of drug compounds to the brain parenchyma. Paracellular brain uptake of drug compounds is limited by the physical tightness of the endothelium, which is tightly sealed with junction complexes. Transcellular uptake of lipophilic drug compounds is limited by the activity of active efflux pumps in the luminal membrane. As a result, the majority of registered CNS drug compounds are small lipophilic compounds which are not efflux transporter substrates. Small molecule CNS drug development therefore focuses on identifying compounds with CNS target affinity and modifies these in order to optimize lipophilicity and decrease efflux pump interactions. Since efflux pump activity is limiting drug uptake, it has been investigated whether coadministration of drug compounds with efflux pump inhibitors could increase drug uptake. While the concept works to some extent, a lot of challenges have been encountered in terms of obtaining efficient inhibition while avoiding adverse effects.Some CNS drug compounds enter the brain via nutrient transport proteins, an example is the levodopa, a prodrug of Dopamine, which crosses the BBB via the large neutral amino acid transporter LAT1. While carrier-mediated transport of drug compounds may seem attractive, the development of drugs targeting transporters is very challenging, since the compounds should have a good fit to the binding site, while still maintaining their CNS target affinity.Receptor-mediated transport of drug compounds, especially biotherapeutics, conjugated to a receptor-binding ligand has shown some promise, although the amounts transported are rather low. This also holds true for drug-conjugation to cell-penetrating peptides. Due to the low uptake of biotherapeutics, barrier-breaching approaches such as mannitol injections and focused ultrasound have been employed with some success to patient groups with no other treatment options.
U2 - 10.1007/164_2020_403
DO - 10.1007/164_2020_403
M3 - Book chapter
SN - 978-3-030-99653-6
VL - 273
SP - 151
EP - 183
BT - Handbook of Experimental Pharmacology
PB - Springer
ER -
ID: 253689747