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Boramino acid as a marker for amino acid transporters.

Liu Z, Chen H, Chen K, Shao Y, Kiesewetter DO, Niu G, Chen X - Sci Adv (2015)

Bottom Line: Abnormal expression of AATs is often associated with cancer, addiction, and multiple mental diseases.The structure of a BAA is identical to that of the corresponding natural AA, except for an exotic replacement of the carboxylate with -BF3 (-).Cellular studies demonstrate strong AAT-mediated cell uptake, and animal studies show high tumor-specific accumulation, suggesting that BAAs hold great promise for the development of new imaging probes and smart AAT-targeting drugs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health (NIH), Bethesda, MD 20892, USA.

ABSTRACT
Amino acid transporters (AATs) are a series of integral channels for uphill cellular uptake of nutrients and neurotransmitters. Abnormal expression of AATs is often associated with cancer, addiction, and multiple mental diseases. Although methods to evaluate in vivo expression of AATs would be highly useful, efforts to develop them have been hampered by a lack of appropriate tracers. We describe a new class of AA mimics-boramino acids (BAAs)-that can serve as general imaging probes for AATs. The structure of a BAA is identical to that of the corresponding natural AA, except for an exotic replacement of the carboxylate with -BF3 (-). Cellular studies demonstrate strong AAT-mediated cell uptake, and animal studies show high tumor-specific accumulation, suggesting that BAAs hold great promise for the development of new imaging probes and smart AAT-targeting drugs.

No MeSH data available.


Related in: MedlinePlus

Cell uptake of BAAs is time-dependent with high channel specificity.(A) Schematic depiction of system A, system L, and system P transporters. (B) U87MG tumor cell uptake of 18F-BAAs. %AD, percentage of added dose. (C) Competitive inhibition of U87MG cell uptake of 18F-labeled Leu-BF3, Phe-BF3, Ala-BF3, and Pro-BF3. Cells are incubated in sodium-free phosphate-buffered saline (PBS) buffer or co-incubated with other AAs at 25 mM for 60 min. As shown, the entry of 18F-BAAs is channel-specific and can be inhibited efficiently by the corresponding natural AAs.
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Figure 3: Cell uptake of BAAs is time-dependent with high channel specificity.(A) Schematic depiction of system A, system L, and system P transporters. (B) U87MG tumor cell uptake of 18F-BAAs. %AD, percentage of added dose. (C) Competitive inhibition of U87MG cell uptake of 18F-labeled Leu-BF3, Phe-BF3, Ala-BF3, and Pro-BF3. Cells are incubated in sodium-free phosphate-buffered saline (PBS) buffer or co-incubated with other AAs at 25 mM for 60 min. As shown, the entry of 18F-BAAs is channel-specific and can be inhibited efficiently by the corresponding natural AAs.

Mentions: Under the guidance of computational prediction, we performed a systematic biological evaluation to explicate the AAT dependency of BAA transportation. As shown in Fig. 3B, 18F-BAAs accumulated in cells in a time-dependent manner, and different 18F-BAAs had distinctively different uptakes that were related to their side chains. To study the specificity of BAA transportation, we performed a competitive inhibition assay using U87MG cells in the presence of natural AAs and transporter inhibitors. After 60 min of incubation, the entries of Leu-BF3, Phe-BF3, Ala-BF3, and Pro-BF3 were substantially and selectively inhibited by natural Leu, Phe, Ala, and Pro, respectively (Fig. 3C). Moreover, the cellular uptake of Leu-BF3 and Phe-BF3 was efficiently reduced by 2-amino-2-norbornanecarboxylic acid (BCH), which is a classical inhibitor for system L transporters. The transportation of Ala-BF3 and Pro-BF3 was blocked under a sodium-free environment, which was as expected because the transportation of systems A and P is Na+-dependent. These results clearly demonstrate that cellular uptake of 18F-BAAs relies on specific channels and shares the same transporter systems used by the corresponding natural AAs.


Boramino acid as a marker for amino acid transporters.

Liu Z, Chen H, Chen K, Shao Y, Kiesewetter DO, Niu G, Chen X - Sci Adv (2015)

Cell uptake of BAAs is time-dependent with high channel specificity.(A) Schematic depiction of system A, system L, and system P transporters. (B) U87MG tumor cell uptake of 18F-BAAs. %AD, percentage of added dose. (C) Competitive inhibition of U87MG cell uptake of 18F-labeled Leu-BF3, Phe-BF3, Ala-BF3, and Pro-BF3. Cells are incubated in sodium-free phosphate-buffered saline (PBS) buffer or co-incubated with other AAs at 25 mM for 60 min. As shown, the entry of 18F-BAAs is channel-specific and can be inhibited efficiently by the corresponding natural AAs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4643766&req=5

Figure 3: Cell uptake of BAAs is time-dependent with high channel specificity.(A) Schematic depiction of system A, system L, and system P transporters. (B) U87MG tumor cell uptake of 18F-BAAs. %AD, percentage of added dose. (C) Competitive inhibition of U87MG cell uptake of 18F-labeled Leu-BF3, Phe-BF3, Ala-BF3, and Pro-BF3. Cells are incubated in sodium-free phosphate-buffered saline (PBS) buffer or co-incubated with other AAs at 25 mM for 60 min. As shown, the entry of 18F-BAAs is channel-specific and can be inhibited efficiently by the corresponding natural AAs.
Mentions: Under the guidance of computational prediction, we performed a systematic biological evaluation to explicate the AAT dependency of BAA transportation. As shown in Fig. 3B, 18F-BAAs accumulated in cells in a time-dependent manner, and different 18F-BAAs had distinctively different uptakes that were related to their side chains. To study the specificity of BAA transportation, we performed a competitive inhibition assay using U87MG cells in the presence of natural AAs and transporter inhibitors. After 60 min of incubation, the entries of Leu-BF3, Phe-BF3, Ala-BF3, and Pro-BF3 were substantially and selectively inhibited by natural Leu, Phe, Ala, and Pro, respectively (Fig. 3C). Moreover, the cellular uptake of Leu-BF3 and Phe-BF3 was efficiently reduced by 2-amino-2-norbornanecarboxylic acid (BCH), which is a classical inhibitor for system L transporters. The transportation of Ala-BF3 and Pro-BF3 was blocked under a sodium-free environment, which was as expected because the transportation of systems A and P is Na+-dependent. These results clearly demonstrate that cellular uptake of 18F-BAAs relies on specific channels and shares the same transporter systems used by the corresponding natural AAs.

Bottom Line: Abnormal expression of AATs is often associated with cancer, addiction, and multiple mental diseases.The structure of a BAA is identical to that of the corresponding natural AA, except for an exotic replacement of the carboxylate with -BF3 (-).Cellular studies demonstrate strong AAT-mediated cell uptake, and animal studies show high tumor-specific accumulation, suggesting that BAAs hold great promise for the development of new imaging probes and smart AAT-targeting drugs.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health (NIH), Bethesda, MD 20892, USA.

ABSTRACT
Amino acid transporters (AATs) are a series of integral channels for uphill cellular uptake of nutrients and neurotransmitters. Abnormal expression of AATs is often associated with cancer, addiction, and multiple mental diseases. Although methods to evaluate in vivo expression of AATs would be highly useful, efforts to develop them have been hampered by a lack of appropriate tracers. We describe a new class of AA mimics-boramino acids (BAAs)-that can serve as general imaging probes for AATs. The structure of a BAA is identical to that of the corresponding natural AA, except for an exotic replacement of the carboxylate with -BF3 (-). Cellular studies demonstrate strong AAT-mediated cell uptake, and animal studies show high tumor-specific accumulation, suggesting that BAAs hold great promise for the development of new imaging probes and smart AAT-targeting drugs.

No MeSH data available.


Related in: MedlinePlus