A nitroreductase responsive probe for early diagnosis of pulmonary fibrosis disease
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ABSTRACT:
SUBMITTER: Peng S
PROVIDER: S-EPMC11345524 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
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Project description:Nitroreductase (NTR) may be more active under the environment of hypoxic conditions, which are the distinctive features of the multiphase solid tumor. It is of great significance to effectively detect and monitor NTR in the living cells for the diagnosis of hypoxia in a tumor. Here, we synthesized a novel turn-on fluorescent probe NTR-NO2 based on a fused four-ring quinoxaline skeleton for NTR detection. The highly efficient probe can be easily synthesized. The probe NTR-NO2 showed satisfactory sensitivity and selectivity to NTR. Upon incubation with NTR, NTR-NO2 could successively undergo a nitro reduction reaction and then generate NTR-NH2 along with significant fluorescence enhancement (30 folds). Moreover, the fluorescent dye NTR-NH2 exhibits a large Stokes shift (Δλ = 111 nm) due to the intramolecular charge transfer (ICT) process. As a result, NTR-NO2 displayed a wide linear range (0-4.5 μg mL-1) and low detection limit (LOD = 58 ng mL-1) after responding to NTR. In addition, this probe was adopted for the detection of endogenous NTR within hypoxic HeLa cells.
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Project description:Tumor hypoxia has great importance in tumor progression and resistance to antitumor therapies. To precisely monitor tumor hypoxia, a controllable hypoxia imaging method is meaningful but still lacking. Herein, we develop a dual-controlled tumor hypoxia probe (TNB) by introducing a nitrophenol group and methyltetrazine group to the boron-dipyrromethene (BODIPY) dye. The fluorescence-quenching group nitrophenol is reduced to aminophenol by upregulated nitroreductase in hypoxic tumors, and the photocage methyltetrazine is cleaved by light irradiation. Hence the fluorescence of TNB is dual-controlled by hypoxia and photoactivation. We first evaluated TNB's potential for controllable hypoxia imaging in solution and tumor cells. The fluorescence of TNB under nitroreductase incubation and photoactivation increased more than 60 fold over that which was untreated or only treated with nitroreductase. Furthermore, results validate that TNB possesses photo-controllable activation features in tumor sections. We believe that the probe design based on enzyme and photoactivation responsiveness provides potential for spatiotemporal detection of other biomarkers.
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Project description:Identification of early, asymptomatic interstitial lung disease (ILD) in populations at risk of developing idiopathic pulmonary fibrosis (IPF) may improve the understanding of the natural history of IPF.To determine clinical, radiographic, physiologic, and pathologic features of asymptomatic ILD in family members of patients with familial IPF.One hundred sixty-four subjects from 18 kindreds affected with familial IPF were evaluated for ILD. Bronchoalveolar lavage fluid cells were analyzed using flow cytometry. Lung biopsies were performed in six subjects with asymptomatic ILD.High-resolution computed tomography abnormalities suggesting ILD were identified in 31 (22%) of 143 asymptomatic subjects. Subjects with asymptomatic ILD were significantly younger than subjects with known familial IPF (P < 0.001) and significantly older than related subjects without lung disease (P < 0.001). A history of smoking was identified in 45% of subjects with asymptomatic ILD and in 67% of subjects with familial IPF; these percentages were significantly higher than that of related subjects without lung disease (23%) (P = 0.02 and P < 0.001, respectively). Percentages of activated CD4(+) lymphocytes were significantly higher in bronchoalveolar lavage fluid cells from subjects with asymptomatic ILD compared with related subjects without lung disease (P < 0.001). Lung biopsies performed in subjects with asymptomatic ILD revealed diverse histologic subtypes.Asymptomatic ILD in individuals at risk of developing familial IPF can be identified using high-resolution computed tomography scan of the chest, especially in those with a history of smoking. Lung biopsies from individuals in this cohort with early asymptomatic lung disease demonstrate various histologic subtypes of ILD.
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Project description:Early diagnosis is critical for providing a timely window for effective therapy in pulmonary fibrosis (PF); however, achieving this remains a significant challenge. The distinct honeycombing patterns observed in computed tomography (CT) for the primary diagnosis of PF are typically only visible in patients with moderate to severe disease, often leading to missed opportunities for early intervention. In this study, we developed a nanoprobe designed to accumulate at fibroblastic foci and loaded with the CT sensitizer iodide to enable effective early diagnosis of PF. An antibody fragment (Fab') targeting the platelet-derived growth factor receptor-α, which specifically binds to (myo)fibroblasts, was conjugated to the nanoprobe surface to enhance targeting of fibroblastic foci. Additionally, collagenase was employed to facilitate nanoprobe penetration by degrading the local collagen fibers within these foci. This approach led to significant accumulation of the CT sensitizer iodide in fibrotic lung tissues, resulting in enhanced CT imaging for the detection of fibroblastic foci and enabling early diagnosis of PF. Moreover, a dual-drug combination of oltipraz and rosiglitazone was co-loaded into the nanoparticles for the treatment of early-diagnosed PF. Remarkable therapeutic efficacy was observed in model mice with early PF using these nanoparticles. Our findings present a promising strategy for the early diagnosis of PF, potentially offering a valuable time window for effective treatment of this life-threatening disease.
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Project description:AbstractIdiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by progressive lung fibrogenesis and histological features of usual interstitial pneumonia. IPF has a poor prognosis and presents a spectrum of disease courses ranging from slow evolving disease to rapid deterioration; thus, a differential diagnosis remains challenging. Several biomarkers have been identified to achieve a differential diagnosis; however, comprehensive reviews are lacking. This review summarizes over 100 biomarkers which can be divided into six categories according to their functions: differentially expressed biomarkers in the IPF compared to healthy controls; biomarkers distinguishing IPF from other types of interstitial lung disease; biomarkers differentiating acute exacerbation of IPF from stable disease; biomarkers predicting disease progression; biomarkers related to disease severity; and biomarkers related to treatment. Specimen used for the diagnosis of IPF included serum, bronchoalveolar lavage fluid, lung tissue, and sputum. IPF-specific biomarkers are of great clinical value for the differential diagnosis of IPF. Currently, the physiological measurements used to evaluate the occurrence of acute exacerbation, disease progression, and disease severity have limitations. Combining physiological measurements with biomarkers may increase the accuracy and sensitivity of diagnosis and disease evaluation of IPF. Most biomarkers described in this review are not routinely used in clinical practice. Future large-scale multicenter studies are required to design and validate suitable biomarker panels that have diagnostic utility for IPF.
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Project description:In idiopathic pulmonary fibrosis (IPF), some facts or concepts based on substantial evidence, whilst implicit for learned subspecialists, have previously been neglected and/or not explicitly formulated or made accessible to a wider audience. IPF is strongly associated with cigarette smoking and is predominantly a disease of ageing. However, its cause(s) remain elusive and, thus, it is one of the most challenging diseases for the development of novel effective and safe therapies. With the approval of pirfenidone for patients with mild-to-moderate IPF, an earlier diagnosis of IPF is a prerequisite for earlier treatment and, potentially, improvement of the long-term clinical outcome of this progressive and ultimately fatal disease. An earlier diagnosis may be achieved in IPF by promoting thin-slice chest high-resolution computed tomography screening of interstitial lung disease as a "by-product" of large-scale lung cancer screening strategies in smokers, but other techniques, which have been neglected in the past, are now available. Lung auscultation and early identification of "velcro" crackles has been proposed as a key component of early diagnosis of IPF. An ongoing study is exploring correlations between lung sounds on auscultation obtained using electronic stethoscopes and high-resolution computed tomography patterns.
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Project description:Bacterial nitroreductases (NTRs) have been widely utilized in the development of novel antibiotics, degradation of pollutants, and gene-directed enzyme prodrug therapy (GDEPT) of cancer that reached clinical trials. In case of GDEPT, since NTR is not naturally present in mammalian cells, the prodrug is activated selectively in NTR-transformed cancer cells, allowing high efficiency treatment of tumors. Currently, no bioluminescent probes exist for sensitive, non-invasive imaging of NTR expression. We therefore developed a "NTR caged luciferin" (NCL) probe that is selectively reduced by NTR, producing light proportional to the NTR activity. Here we report successful application of this probe for imaging of NTR in vitro, in bacteria and cancer cells, as well as in vivo in mouse models of bacterial infection and NTR-expressing tumor xenografts. This novel tool should significantly accelerate the development of cancer therapy approaches based on GDEPT and other fields where NTR expression is important.
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Project description:Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease without a clear recognizable cause. IPF has been at the forefront of new diagnostic algorithms and treatment developments that led to a shift in patients' care in the past decade, indeed influencing the management of fibrotic interstitial lung diseases other than IPF itself. Clinical presentation, pathophysiology, and diagnostic criteria are briefly addressed in this review article. Additionally, evidence regarding the use of antifibrotics beyond the settings of clinical trials, impact of comorbidities, and therapeutic approaches other than pharmacological treatments are discussed in further detail.
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Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disorder with an estimated median survival time of 3-5 years after diagnosis. This condition occurs primarily in elderly subjects, and epidemiological studies suggest that the main risk factors, ageing and exposure to cigarette smoke, are associated with both pulmonary and extrapulmonary comorbidities (defined as the occurrence of two or more disorders in a single individual). Ageing and senescence, through interactions with environmental factors, may contribute to the pathogenesis of IPF by various mechanisms, causing lung epithelium damage and increasing the resistance of myofibroblasts to apoptosis, eventually resulting in extracellular matrix accumulation and pulmonary fibrosis. As a paradigm, syndromes featuring short telomeres represent archetypal premature ageing syndromes and are often associated with pulmonary fibrosis. The pathophysiological features induced by ageing and senescence in patients with IPF may translate to pulmonary and extrapulmonary features, including emphysema, pulmonary hypertension, lung cancer, coronary artery disease, gastro-oesophageal reflux, diabetes mellitus and many other chronic diseases, which may lead to substantial negative consequences in terms of various outcome parameters in IPF. Therefore, the careful diagnosis and treatment of comorbidities may represent an outstanding chance to improve quality of life and survival, and it is necessary to contemplate all possible management options for IPF, including early identification and treatment of comorbidities.
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