Targeting the Cerebrovascular Large Neutral Amino Acid Transporter (LAT1) Isoform Using a Novel Disulfide-Based Brain Drug Delivery System
Open Access
- 1 January 2007
- journal article
- research article
- Published by Informa UK Limited in Drug Delivery
- Vol. 14 (1), 25-31
- https://doi.org/10.1080/10717540600559510
Abstract
We describe a novel strategy to achieve high affinity recognition for the specific, cerebrovascular large neutral amino acid transporter (LAT1) isoform by covalent coupling of small molecules to the amino acid, L-cysteine (L-Cys). L-Cys (as the carrier) was covalently attached via a disulfide bond to either 6-mercaptopurine or 2-methyl-1-propanethiol (IBM) to form the brain-targeted drug delivery systems (BTDS). BTDS were designed for high affinity recognition by LAT1 at the cerebrovasculature. Using an in situ rat brain perfusion technique, competition between BTDS and the radiotracer [14C]L-Leu demonstrated significant inhibition of [14C]L-Leu brain uptake. BTDS possess affinity for cerebrovascular LAT1 in many distinct brain compartments, and the recognition of BTDS by LAT1 is influenced by hydrophobicity of the side-chain in BTDS. Thus, the BTDS strategy may be utilized for rapid shuttling of various neuropharmaceuticals into brain.Keywords
This publication has 24 references indexed in Scilit:
- Modulating Blood-Brain Barrier Interactions of Amino Acid-Based Anticancer AgentsDrug Delivery, 2000
- Carrier-Mediated Delivery of Metabotropic Glutamate Receptor Ligands to the Central Nervous System: Structural Tolerance and Potential of the l-system Amino Acid Transporter at the Blood-Brain BarrierJournal of Cerebral Blood Flow & Metabolism, 2000
- New approaches to drug delivery through the blood-brain barrierTrends in Biotechnology, 1994
- High levels of P-glycoprotein detected in isolated brain capillariesBiochimica et Biophysica Acta (BBA) - Biomembranes, 1993
- Drug metabolizing enzymes in the brain and cerebral microvesselsBrain Research Reviews, 1991
- Kinetics of Neutral Amino Acid Transport Across the Blood‐Brain BarrierJournal of Neurochemistry, 1987
- The “On–Off” Phenomenon in Parkinson’s DiseaseNew England Journal of Medicine, 1984
- Diet and Uptake of Aldomet by the Brain: Competition with Natural Large Neutral Amino AcidsScience, 1977
- S-Alkylthioisothioureas. ICHEMICAL & PHARMACEUTICAL BULLETIN, 1970
- JUNCTIONS BETWEEN INTIMATELY APPOSED CELL MEMBRANES IN THE VERTEBRATE BRAINThe Journal of cell biology, 1969