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Azo-Based Iridium(III) Complexes as Multicolor Phosphorescent Probes to Detect Hypoxia in 3D Multicellular Tumor Spheroids.

Sun L, Li G, Chen X, Chen Y, Jin C, Ji L, Chao H - Sci Rep (2015)

Bottom Line: Hypoxia is an important characteristic of malignant solid tumors and is considered as a possible causative factor for serious resistance to chemo- and radiotherapy.All of the iridium(III) complexes incorporate an azo group as an azo-reductase reactive moiety to detect hypoxia.Reduction of non-phosphorescent probes Ir1-Ir8 by reductases under hypoxic conditions resulted in the generation of highly phosphorescent corresponding amines for detection of hypoxic regions.

View Article: PubMed Central - PubMed

Affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, 510275, China.

ABSTRACT
Hypoxia is an important characteristic of malignant solid tumors and is considered as a possible causative factor for serious resistance to chemo- and radiotherapy. The exploration of novel fluorescent probes capable of detecting hypoxia in solid tumors will aid tumor diagnosis and treatment. In this study, we reported the design and synthesis of a series of "off-on" phosphorescence probes for hypoxia detection in adherent and three-dimensional multicellular spheroid models. All of the iridium(III) complexes incorporate an azo group as an azo-reductase reactive moiety to detect hypoxia. Reduction of non-phosphorescent probes Ir1-Ir8 by reductases under hypoxic conditions resulted in the generation of highly phosphorescent corresponding amines for detection of hypoxic regions. Moreover, these probes can penetrate into 3D multicellular spheroids over 100 μm and image the hypoxic regions. Most importantly, these probes display a high selectivity for the detection of hypoxia in 2D cells and 3D multicellular spheroids.

No MeSH data available.


Related in: MedlinePlus

(a) Emission spectra of probes incubated with rat liver microsomes and 50 μM NADPH at 37 °C for 30 min. (b) Photos of probes Ir1-Ir8 after incubation with rat liver microsomes and NADPH were captured under a handle UV lamp (365  nm).
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f4: (a) Emission spectra of probes incubated with rat liver microsomes and 50 μM NADPH at 37 °C for 30 min. (b) Photos of probes Ir1-Ir8 after incubation with rat liver microsomes and NADPH were captured under a handle UV lamp (365  nm).

Mentions: Next, we tested the capability of these probes to detect hypoxia in biological systems using rat liver microsomes, which contain various reductases. Dissolved oxygen was removed from a PBS solution of probes by argon bubbling, and then fresh microsomes from rat liver were added. When NADPH as a cofactor for the reductases was added into this mixture, the phosphorescence intensity increased sharply to maximum within 30 s and then remained constant (Fig. 3b and S26), suggesting that these probes were reduced rapidly by reductases in liver microsomes. More importantly, this enhancement in phosphorescence intensity was only observed under hypoxic conditions. When reduced under hypoxia, these probes exhibited enhancements in phosphorescence intensity of 17.5-fold for Ir1, 16.9-fold for Ir2, 39.0-fold for Ir3, 38.4-fold for Ir4, 11.4-fold for Ir5, 13.5-fold for Ir6, 58.8-fold for Ir7, and 54.2-fold for Ir8, respectively. After reduction under hypoxia, the maximum emission intensity ranged from 510 nm for Ir1 and Ir5 to 640 nm for Ir4 and Ir8, displaying a green to red emissive solution, which could be observed by the naked eye (Fig. 4). Interestingly, the phosphorescent response to hypoxia could also be obtained in a mixed solution containing a high concentration of ions or bio-related reducing agents (Fig. 3a), indicating that these probes could also function in a complex biological background. Additionally, the phosphorescence intensities of these reduction products were only slightly affected by pH when the pH values were varied from 3.0 to 10.0. (Figure S27) Thus, the azo-based Ir(III) complexes Ir1-Ir8 could be selective turn-on phosphorescent probes for hypoxia with a multi-emissive color.


Azo-Based Iridium(III) Complexes as Multicolor Phosphorescent Probes to Detect Hypoxia in 3D Multicellular Tumor Spheroids.

Sun L, Li G, Chen X, Chen Y, Jin C, Ji L, Chao H - Sci Rep (2015)

(a) Emission spectra of probes incubated with rat liver microsomes and 50 μM NADPH at 37 °C for 30 min. (b) Photos of probes Ir1-Ir8 after incubation with rat liver microsomes and NADPH were captured under a handle UV lamp (365  nm).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4589790&req=5

f4: (a) Emission spectra of probes incubated with rat liver microsomes and 50 μM NADPH at 37 °C for 30 min. (b) Photos of probes Ir1-Ir8 after incubation with rat liver microsomes and NADPH were captured under a handle UV lamp (365  nm).
Mentions: Next, we tested the capability of these probes to detect hypoxia in biological systems using rat liver microsomes, which contain various reductases. Dissolved oxygen was removed from a PBS solution of probes by argon bubbling, and then fresh microsomes from rat liver were added. When NADPH as a cofactor for the reductases was added into this mixture, the phosphorescence intensity increased sharply to maximum within 30 s and then remained constant (Fig. 3b and S26), suggesting that these probes were reduced rapidly by reductases in liver microsomes. More importantly, this enhancement in phosphorescence intensity was only observed under hypoxic conditions. When reduced under hypoxia, these probes exhibited enhancements in phosphorescence intensity of 17.5-fold for Ir1, 16.9-fold for Ir2, 39.0-fold for Ir3, 38.4-fold for Ir4, 11.4-fold for Ir5, 13.5-fold for Ir6, 58.8-fold for Ir7, and 54.2-fold for Ir8, respectively. After reduction under hypoxia, the maximum emission intensity ranged from 510 nm for Ir1 and Ir5 to 640 nm for Ir4 and Ir8, displaying a green to red emissive solution, which could be observed by the naked eye (Fig. 4). Interestingly, the phosphorescent response to hypoxia could also be obtained in a mixed solution containing a high concentration of ions or bio-related reducing agents (Fig. 3a), indicating that these probes could also function in a complex biological background. Additionally, the phosphorescence intensities of these reduction products were only slightly affected by pH when the pH values were varied from 3.0 to 10.0. (Figure S27) Thus, the azo-based Ir(III) complexes Ir1-Ir8 could be selective turn-on phosphorescent probes for hypoxia with a multi-emissive color.

Bottom Line: Hypoxia is an important characteristic of malignant solid tumors and is considered as a possible causative factor for serious resistance to chemo- and radiotherapy.All of the iridium(III) complexes incorporate an azo group as an azo-reductase reactive moiety to detect hypoxia.Reduction of non-phosphorescent probes Ir1-Ir8 by reductases under hypoxic conditions resulted in the generation of highly phosphorescent corresponding amines for detection of hypoxic regions.

View Article: PubMed Central - PubMed

Affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, 510275, China.

ABSTRACT
Hypoxia is an important characteristic of malignant solid tumors and is considered as a possible causative factor for serious resistance to chemo- and radiotherapy. The exploration of novel fluorescent probes capable of detecting hypoxia in solid tumors will aid tumor diagnosis and treatment. In this study, we reported the design and synthesis of a series of "off-on" phosphorescence probes for hypoxia detection in adherent and three-dimensional multicellular spheroid models. All of the iridium(III) complexes incorporate an azo group as an azo-reductase reactive moiety to detect hypoxia. Reduction of non-phosphorescent probes Ir1-Ir8 by reductases under hypoxic conditions resulted in the generation of highly phosphorescent corresponding amines for detection of hypoxic regions. Moreover, these probes can penetrate into 3D multicellular spheroids over 100 μm and image the hypoxic regions. Most importantly, these probes display a high selectivity for the detection of hypoxia in 2D cells and 3D multicellular spheroids.

No MeSH data available.


Related in: MedlinePlus