Chemical nature and structure of organic coating of quantum dots is crucial for their application in imaging diagnostics

Rumiana Bakalova1, Zhivko Zhelev1, Daisuke Kokuryo1, Lubomir Spasov2, Ichio Aoki1, Tsuneo Saga11Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; 2Medical Faculty, Sofia University, Sofia, BulgariaBackground: One of the most attractive properties of quantum dots is their potential to extend the opportunities for fluorescent and multimodal imaging in vivo. The aim of the present study was to clarify whether the composition and structure of organic coating of nanoparticles are crucial for their application in vivo.Methods: We compared quantum dots coated with non-crosslinked amino-functionalized polyamidoamine (PAMAM) dendrimers, quantum dots encapsulated in crosslinked carboxyl-functionalized PAMAM dendrimers, and silica-shelled amino-functionalized quantum dots. A multimodal fluorescent and paramagnetic quantum dot probe was also developed and analyzed. The probes were applied intravenously in anesthetized animals for visualization of brain vasculature using two-photon excited fluorescent microscopy and visualization of tumors using fluorescent IVIS® imaging (Caliper Life Sciences, Hopkinton, MA) and magnetic resonance imaging.Results: Quantum dots coated with non-crosslinked dendrimers were cytotoxic. They induced side effects in vivo, including vasodilatation with a decrease in mean arterial blood pressure and heart rate. The quantum dots penetrated the vessels, which caused the quality of fluorescent imaging to deteriorate. Quantum dots encapsulated in crosslinked dendrimers had low cytotoxicity and were biocompatible. In concentrations <0.3 nmol quantum dots/kg bodyweight, these nanoparticles did not affect blood pressure and heart rate, and did not induce vasodilatation or vasoconstriction. PEGylation (PEG [polyethylene glycol]) was an indispensable step in development of a quantum dot probe for in vivo imaging, based on silica-shelled quantum dots. The non-PEGylated silica-shelled quantum dots possessed low colloidal stability in high-salt physiological fluids, accompanied by rapid aggregation in vivo. The conjugation of silica-shelled quantum dots with PEG1100 increased their stability and half-life in the circulation without significant enhancement of their size. In concentrations <2.5 nmol/kg bodyweight, these quantum dots did not affect the main physiological variables. It was possible to visualize capillaries, which makes this quantum dot probe appropriate for investigation of mediators of vasoconstriction, vasodilatation, and brain circulation in intact animals in vivo. The multimodal silica-shelled quantum dots allowed visualization of tumor tissue in an early stage of its development, using magnetic resonance imaging.Conclusion: The present study shows that the type and structure of organic/bioorganic shells of quantum dots determine their biocompatibility and are crucial for their application in imaging in vivo, due to the effects of the shell on the following properties: colloidal stability, solubility in physiological fluids, influence of the basic physiological parameters, and cytotoxicity.Keywords: quantum dot, organic shell, biocompatibility, in vivo imaging, two-photon excited fluorescent microscopy, magnetic resonance imagin

Nitroxyl Radical as a Theranostic Contrast Agent in Magnetic Resonance Redox Imaging

Significance: In vivo assessment of paramagnetic and diamagnetic conversions of nitroxyl radicals based on cyclic redox mechanism can be an index of tissue redox status. The redox mechanism of nitroxyl radicals, which enables their use as a normal tissue-selective radioprotector, is seen as being attractive on planning radiation therapy. Recent Advances: In vivo redox imaging using nitroxyl radicals as redox-sensitive contrast agents has been developed to assess tissue redox status. Chemical and biological behaviors depending on chemical structures of nitroxyl radical compounds have been understood in detail. Polymer types of nitroxyl radical contrast agents and/or nitroxyl radical-labeled drugs were designed for approaching theranostics. Critical Issues: Nitroxyl radicals as magnetic resonance imaging (MRI) contrast agents have several advantages compared with those used in electron paramagnetic resonance (EPR) imaging, while support by EPR spectroscopy is important to understand information from MRI. Redox-sensitive paramagnetic contrast agents having a medicinal benefit, that is, nitroxyl-labeled drug, have been developed and proposed. Future Directions: A development of suitable nitroxyl contrast agent for translational theranostic applications with high reaction specificity and low normal tissue toxicity is under progress. Nitroxyl radicals as redox-sensitive magnetic resonance contrast agents can be a useful tool to detect an abnormal tissue redox status such as disordered oxidative stress

A directly comparative two-gate case–control diagnostic accuracy study of the pure tone screen and HearCheck screener tests for identifying hearing impairment in school children

Objectives: This study directly compared the accuracy of two audiometry-based tests for screening school children for hearing impairment: the currently used test, pure tone screen and a device newly applied to children, HearCheck Screener. Design: Two-gate case–control diagnostic test accuracy study. Setting and participants: Hearing impaired children (‘intended cases’) aged 4–6 years were recruited between February 2013 and August 2014 from collaborating audiology services. Children with no previously identified impairment (‘intended controls’) were recruited from Foundation and Year 1 of schools between February 2013 and June 2014 in central England. The reference standard was pure tone audiometry. Tests were administered at Nottingham Hearing Biomedical Research Unit or, for some intended cases only, in the participant’s home. Main outcome measures: Sensitivity and specificity of the pure tone screen and HearCheck tests based on pure tone audiometry result as reference standard. Results: 315 children (630 ears) were recruited; 75 from audiology services and 240 from schools. Full test and reference standard data were obtained for 600 ears; 155 ears were classified as truly impaired and 445 as truly hearing based on the pure tone audiometry assessment. Sensitivity was estimated to be 94.2% (95% CI 89.0% to 97.0%) for pure tone screen and 89.0% (95% CI 82.9% to 93.1%) for HearCheck (difference=5.2% favouring pure tone screen; 95% CI 0.2% to 10.1%; p=0.02). Estimates for specificity were 82.2% (95% CI 77.7% to 86.0%) for pure tone screen and 86.5% (95% CI 82.5% to 89.8%) for HearCheck (difference=4.3% favouring HearCheck; 95% CI0.4% to 8.2%; p=0.02). Conclusion: Pure tone screen was better than HearCheck with respect to sensitivity but inferior with respect to specificity. As avoiding missed cases is arguably of greater importance for school entry screening, pure tone screen is probably preferable in this context

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]