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Optical control of calcium affinity in a spiroamido-rhodamine based calcium chelator.

ABSTRACT: An optically controlled Ca(2+)-chelator 1 was developed to mimic natural calcium oscillations. Compound 1, a spiroamido-rhodamine derivative of 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), underwent cycles of reversible transitions between a colorless closed state and a fluorescent open form. The closed-state exhibited a high affinity for Ca(2+) (K(d): 509 nM) with excellent selectivity over Mg(2+) (K(d): 19 mM). The open isomer had a 350-fold lower Ca(2+) affinity (K(d): 181 ?M), while the Mg(2+) affinity was not significantly affected (K(d): 14 mM).

SUBMITTER: Wu L

PROVIDER: S-EPMC3147027 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Optical control of calcium affinity in a spiroamido-rhodamine based calcium chelator.

Wu Liangxing L Dai Yingrui Y Marriott Gerard G

Organic letters 20110321 8

An optically controlled Ca(2+)-chelator 1 was developed to mimic natural calcium oscillations. Compound 1, a spiroamido-rhodamine derivative of 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), underwent cycles of reversible transitions between a colorless closed state and a fluorescent open form. The closed-state exhibited a high affinity for Ca(2+) (K(d): 509 nM) with excellent selectivity over Mg(2+) (K(d): 19 mM). The open isomer had a 350-fold lower Ca(2+) affinity (K(d): 18 ...[more]

PMID: 21417245

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Project description:In this study, we evaluated Cu(L1) in two xenografted tumor-bearing (U87MG and MDA-MB-435) animal models to prove the concept that Cu(II)-labeled rhodamine derivatives, Cu(L) (L = L1 - L4) are useful as selective fluorescent probes for tumor imaging. We found that both multidrug resistance (MDR) negative U87MG gliomas and MDR-positive MDA-MB-435 breast tumors could be visualized. Because of tissue attenuation, accurate quantification of tumor uptake was difficult by optical methods. Therefore, (64)Cu(L) (L = L1 - L4) were evaluated to compare their biodistribution properties. It was found that all four (64)Cu radiotracers had a high glioma uptake ((64)Cu(L1): 5.71± 1.43 %ID/g; (64)Cu(L2): 5.98 ± 2.75 %ID/g; (64)Cu(L3): 4.28 ± 1.45 %ID/g; and (64)Cu(L4): 6.25 ± 3.42 %ID/g) with (64)Cu(L1) showing the highest tumor/background ratios. In athymic nude mice bearing MDA-MB-435 breast cancer xenografts, (64)Cu(L4) showed almost identical normal organ uptake to that in the glioma-bearing animals, but its breast tumor uptake (1.26 ± 0.10% ID/g) was significantly lower (p < 0.001) than that in the glioma (6.25 ± 3.42% ID/g) because of MDR Pgps (P-glycoproteins) and MRPs (multidrug resistance-associated proteins) overexpressed in the xenografted MDA-MB-435 breast tumors. Results from cellular staining assays showed that both Cu(L2) and Cu(L4) were able to localize in mitochondria of U87MG cells, and their tumor selectivity was caused by the elevated negative mitochondrial potential in U87MG glioma cells as compared to that in human fibroblast cells. On the basis of these results, it was concluded that Cu(L) (L = L1 - L4) are useful as selective fluorescent probes for cellular staining assays and optical tumor imaging while (64)Cu(L) (L = L1 - L4) have the potential as PET radiotracers for tumor imaging. This study represents a good example of dual modality imaging (PET and optical) using two agents, (64)Cu(L) and Cu(L), with identical chemical composition. Future research will focus on developing new fluorescent probes with longer wavelength and reduced liver uptake.

Dataset Information

Optical control of calcium affinity in a spiroamido-rhodamine based calcium chelator.

Publications

Optical control of calcium affinity in a spiroamido-rhodamine based calcium chelator.

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