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Discovery of a size-record breaking green-emissive fluorophore: small, smaller, HINA.

ABSTRACT: Astonishingly, 3-hydroxyisonicotinealdehyde (HINA) is despite its small size a green-emitting push-pull fluorophore in water (QY of 15%) and shows ratiometric emission response to biological relevant pH differences (pK _a2 ∼ 7.1). Moreover, HINA is the first small-molecule fluorophore reported that possesses three distinctly emissive protonation states. This fluorophore can be used in combination with metal complexes for fluorescent-based cysteine detection in aqueous media, and is readily taken up by cells. The theoretical description of HINA's photophysics remains challenging, even when computing Franck-Condon profiles via coupled-cluster calculations, making HINA an interesting model for future method development.

SUBMITTER: Kang R

PROVIDER: S-EPMC8179180 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Discovery of a size-record breaking green-emissive fluorophore: small, smaller, HINA.

Kang Rui R Talamini Laura L D'Este Elisa E Estevão Bianca Martins BM De Cola Luisa L Klopper Wim W Biedermann Frank F

Chemical science 20201125 4

Astonishingly, 3-hydroxyisonicotinealdehyde (HINA) is despite its small size a green-emitting push-pull fluorophore in water (QY of 15%) and shows ratiometric emission response to biological relevant pH differences (p<i>K</i> <sub>a2</sub> ∼ 7.1). Moreover, HINA is the first small-molecule fluorophore reported that possesses three distinctly emissive protonation states. This fluorophore can be used in combination with metal complexes for fluorescent-based cysteine detection in aqueous media, and ...[more]

PMID: 34163902

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Project description:Cryptococcal meningoencephalitis (CME) is deadly. CME is responsible for 19% of deaths in AIDS patients, and its global mortality is greater than 60%. The recommended CME therapy requires amphotericin B (AmB), a fungicidal drug targeting fungal ergosterol. AmB also binds to the host's cholesterol and is highly toxic. Liposomal AmB (AmB-LLs), relative to deoxycholate-solubilized AmB, has lower toxicity and longer tissue retention, but it requires high doses for treatment and its efficacy in treating CME remains unsatisfactory. To improve the effectiveness of AmB-LLs, we previously developed DectiSomes-targeted AmB-LLs decorated with host dectins that recognize fungal polysaccharides. DectiSomes, relative to untargeted AmB-LLs, modestly improve efficacy against systemic cryptococcosis, in contrast to the drastic improvement observed in candidiasis or aspergillosis models. We speculated that limited tissue penetration of the regular-sized DectiSomes might have contributed to the modest improvement in treating systemic cryptococcosis. Here, we discovered that DectiSomes of a smaller size (~50 nm), compared with DectiSomes of the regular size (~100 nm) or untargeted AmB-LLs of either size, had a much better capability in reducing cryptococcal burden of various organs including the brain and in prolonging the survival of mice with systemic cryptococcosis. The performance of small DectiSomes was far superior to all other groups at two different doses of AmB tested. Furthermore, no kidney toxicity was observed in any of the treatment regimens tested. Taken together, our findings indicate that small DectiSomes can be a powerful antifungal delivery platform to drastically improve therapies against the deadly CME.ImportanceSystemic cryptococcosis is fatal even with antifungal interventions. The most effective drug against this disease is amphotericin B (AmB). However, AmB is highly toxic as it binds to fungal ergosterol and also mammalian cholesterol. Liposomal AmB was introduced to the clinic in 1990s because it showed reduced toxicity and longer retention in various organs. However, the dose of AmB required for treatment using liposomal formulation is high and the outcome is far from satisfactory. In our previous work, we generated DectiSomes, dectin-decorated liposomes loaded with AmB that more effectively deliver the drug to the pathogen and enhance antifungal efficacy. However, the improvement in treating systemic cryptococcosis, compared with candidiasis and aspergillosis, is modest. Here, we generated DectiSomes that are half their regular size to improve tissue penetration. We discovered that small DectiSomes are superior in reducing fungal burden in various organs including the brain and in prolonging animal survival.

Project description:PurposeLittle is known about risk factors for sustaining a posterior cruciate ligament (PCL) rupture. Identifying risk factors is the first step in preventing a PCL rupture from occurring. The morphology of the knee in patients who ruptured their PCL may differ from that of control patients. The hypothesis was that the intercondylar notch dimensions, 3-D volumes of the intercondylar notch and, the 3-D volumes of both the ACL and the PCL were correlated to the presence of a PCL rupture.MethodsThe magnetic resonance imaging (MRI) scans of 30 patients with a proven PCL rupture were compared to 30 matched control patients with proven intact ACL and PCL. Control patients were selected from patients with knee trauma during sports but without cruciate ligament injury. Patients have been matched for age, height, weight, BMI, and sex. The volumes of the intercondylar notch and both the ACL and PCL were measured on 3D reconstructions. Second, the bicondylar width, the notch width, and the notch width index were measured of all subjects. The relationship between our measurements and the presence of a PCL rupture was analysed.ResultsThe results show a significant difference in the volumes of the intercondylar notch and the ACL between patients with a ruptured PCL and control patients. Patients with a PCL rupture have smaller intercondylar notch volumes and smaller ACL volumes. There were no significant differences in the bicondylar width, notch width, and notch width index. In the control patients, a significant correlation between the volume of the PCL and the volume of the ACL was found (0.673, p < 0.001).ConclusionPatients with a PCL rupture have smaller intercondylar volumes and smaller ACL volumes when compared to control patients. Second, patients with smaller ACL volumes have smaller PCL volumes. This study shows, for the first time, that there are significant size and volume differences in the shape of the knee between patients with a PCL rupture and control patients.Level of evidenceIV.

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Discovery of a size-record breaking green-emissive fluorophore: small, smaller, HINA.

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Discovery of a size-record breaking green-emissive fluorophore: small, smaller, HINA.

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