期刊
DRUG DELIVERY
卷 14, 期 1, 页码 25-31出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/10717540600559510
关键词
amino acids; BBB targeting; brain targeted drug delivery; BTDS; cerebrovasculature; disulfides; LAT1; LAT2; neuropharmaceuticals
资金
- NCI NIH HHS [CA74377] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R15CA074377] Funding Source: NIH RePORTER
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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