Journal
DRUG DELIVERY
Volume 14, Issue 1, Pages 25-31Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/10717540600559510
Keywords
amino acids; BBB targeting; brain targeted drug delivery; BTDS; cerebrovasculature; disulfides; LAT1; LAT2; neuropharmaceuticals
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Funding
- NCI NIH HHS [CA74377] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R15CA074377] Funding Source: NIH RePORTER
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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 [C-14] L-Leu demonstrated significant inhibition of [C-14] 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.
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