We previously reported the synthesis of gadolinium-based nanoparticles (NPs) denoted AGuIX (activation and guiding of irradiation by X-ray) NPs and demonstrated their potential as an MRI contrast ...agent and their efficacy as radiosensitizing particles during X-ray cancer treatment. Here we focus on the elimination kinetics of AGuIX NPs from the subcellular to whole-organ scale using original and complementary methods such as laser-induced breakdown spectroscopy (LIBS), intravital two-photon microscopy, inductively coupled plasma optical emission spectrometry (ICP-OES), transmission electron microscopy (TEM), and electrospray ionization mass spectrometry (ESI-MS). This combination of techniques allows the exact mechanism of AGuIX NPs elimination to be elucidated, including their retention in proximal tubules and their excretion as degraded or native NPs. Finally, we demonstrated that systemic AGuIX NP administration induced moderate and transient effects on renal function. These results provide useful and promising preclinical information concerning the safety of theranostic AGuIX NPs.
•Positive nanoparticle/cell membrane interactions are privileged.•It is supposedly due to favorable electrostatic interactions.•But in biological media, a protein corona forms and adds a level of ...complexity.
It is acknowledged that physico-chemical features of nanoparticles have a major impact on their uptake, and especially their surface charge. A widespread observation is that positively charged nanoparticles are more uptaken by cells than neutral or negatively charged nanoparticles. The reason commonly evoked is the favorable electrostatic interactions with negatively charged cell membrane. However, this explanation seems simplistic as it does not take into account a fundamental element: the nanoparticle protein corona. This adds a new level of complexity in the interactions with biological systems that cannot be any more limited to electrostatic binding.
Abstract Background Recent findings show that cell-free miRNAs are stable in biological fluid. Urine provides an alternative to blood serum or plasma as a potential source of tumor biomarkers. ...MiR-210 is proven to be overexpressed in patients with a clear cell renal cell carcinoma (ccRCC). The purpose of this pilot study was to examine the urinary cell-free miR-210 as a potential tool of liquid biopsy for ccRCC. Methods Overall, 75 patients with a ccRCC and 45 control subjects without a cancer were included in this study. Urine samples were centrifuged twice and the cell-free urine supernanants were stored in −80°C until use. A total of 350 µl cell-free urine was used for the extraction of total RNA. The expression levels of these miRNAs were performed by using quantitative RT-PCR. Results The level of urinary cell-free miR-210 was significantly higher in patients with ccRCC than in control subjects ( P <0.001). The urinary cell-free miR-210 yielded the areas under the receiver operating characteristics curve of 0.76 in discriminating the patients with ccRCC from the control subjects with a sensitivity of 57.8% and a specificity of 80.0%. Moreover, the expression level of urinary cell-free miRNA-210 was significantly decreased in the patients a week after surgery ( P <0.001). Conclusion Urinary cell-free miR-210 may be used as a potential tool of liquid biopsy for ccRCC diagnosis. Further studies are needed to confirm our results.
There is limited research on cell‐free RNA (cf‐RNA) in the urine of cancer patients. The present study was performed to detect the cf‐RNA in the urine of patients with clear cell renal cell carcinoma ...(ccRCC). Ninety‐five urine samples from ccRCC patients and 50 urine samples from control subjects were analyzed. The cf‐RNA integrity index was calculated by using quantitative real‐time RT‐PCR assays of the small‐sized fragment (106 bp) and the big‐sized fragment (416 bp) in GAPDH mRNA. The initial analysis showed that cf‐RNA was stable and detectable in the urine. The mean cf‐RNA integrity index was significantly lower in the urine of ccRCC patients (mean: 0.07, 95%CI: 0.05–0.10) when compared with the urine from control subjects (mean: 0.25, 95%CI: 0.16–0.33) (p < 0.001). The value of the area under the receiver‐operating characteristic curve by using the cf‐RNA integrity index for the diagnosis of ccRCC was 0.858 with a sensitivity of 68.0% and a specificity of 92.6%. Moreover, the small‐sized VEGF mRNA fragment (98 bp) was detected in 31 of 50 urine samples of patients with ccRCC and in only 2 of 50 urine samples of control subjects (p < 0.001) while the detection of the big‐sized (420 bp) VEGF mRNA fragment was an infrequent event. Our findings suggest that the small‐sized cf‐RNA in urine was more abundant in cancer patients. The tumor‐related gene VEGF mRNA fragment was detectable in the urine of cancer patients. Our finding may provide a new molecular assay for the diagnosis of renal cell carcinoma.
What's new?
The detection of cell‐free RNA (cf‐RNA) in biological fluids raises possibilities for the development of new diagnostic assays for cancer. Such an assay may be applicable particularly for clear cell renal cell carcinoma (ccRCC). In this study, the urinary cf‐RNA integrity index in ccRCC patients was found to be significantly reduced compared to control subjects. However, small‐sized cf‐RNA fragments, including small fragments (98 bp) of VEGF mRNA, were present at increased levels in the urine of cancer patients. Additional investigation is needed to confirm the findings and to define the clinical utility of cf‐RNA detection for ccRCC.
To relate exposure to adverse health effects, it is necessary to know where particles in the submicron range deposit in the respiratory tract. The possibly higher vulnerability of children requires ...specific inhalation studies. However, radio-aerosol deposition experiments involving children are rare because of ethical restrictions related to radiation exposure. Thus, an in vivo study was conducted using three baboons as a child respiratory tract model to assess regional deposition patterns (thoracic region vs. extrathoracic region) of radioactive polydisperse aerosols (d16-d84, equal to 0.15 µm-0.5 µm, 0.25 µm-1 µm, or 1 µm-9 µm). Results clearly demonstrated that aerosol deposition within the thoracic region and the extrathoraic region varied substantially according to particle size. High deposition in the extrathoracic region was observed for the 1 µm-9 µm aerosol (72% ± 17%). The 0.15 µm-0.5 µm aerosol was associated almost exclusively with thoracic region deposition (84% ± 4%). Airborne particles in the range of 0.25 µm-1 µm showed an intermediate deposition pattern, with 49% ± 8% in the extrathoracic region and 51% ± 8% in the thoracic region. Finally, comparison of baboon and human inhalation experiments for the 1 µm-9 µm aerosol showed similar regional deposition, leading to the conclusion that regional deposition is species-independent for this airborne particle sizes.
Abstract On the cusp of massive commercialization of nanotechnology-enhanced products and services, the physical and chemical analysis of nanoparticles in human specimens merits immediate attention ...from the research community as a prerequisite for a confident clinical interpretation of their occurrence in the human organism. In this review, we describe the caveats in current practices of extracting and isolating nanoparticles from clinical samples and show that they do not help truly define the clinical significance of detected exogenous nano-sized objects. Finally, we suggest a systematic way of tackling these demanding scientific tasks. More specifically, a precise and true qualitative evaluation of nanoparticles in human biological samples is still hindered by various technical reasons. Such a procedure is more refined when the nature of the pollutants is known, like in the case of nano-sized wear debris originating from biomedical prostheses. Nevertheless, nearly all available analytical methods provide unknown quantitative accuracy and qualitative precision due to the challenging physical and chemical nature of nanoparticles. Without trustworthy information to describe the nanoparticulate load of clinical samples, it is impossible to accurately assess its pathological impact on isolated cases or allow for relevant epidemiological surveys on large populations. Therefore, we suggest that the many and various specimens stored in hospitals be used for the refinement of methods of exhaustive quantitative and qualitative characterization of prominent nanoparticles in complex human milieu.
ABSTRACT
Purpose
Improvement of clinical outcome in patients with sinuses disorders involves targeting delivery of nebulized drug into the maxillary sinuses. We investigated the impact of ...nebulization conditions (with and without 100 Hz acoustic airflow), particle size (9.9 μm, 2.8 μm, 550 nm and 230 nm) and breathing pattern (nasal
vs
. no nasal breathing) on enhancement of aerosol delivery into the sinuses using a realistic nasal replica developed by our team.
Methods
After segmentation of the airways by means of high-resolution computed tomography scans, a well-characterized nasal replica was created using a rapid prototyping technology. A total of 168 intrasinus aerosol depositions were performed with changes of aerosol particle size and breathing patterns under different nebulization conditions using gentamicin as a marker.
Results
The results demonstrate that the fraction of aerosol deposited in the maxillary sinuses is enhanced by use of submicrometric aerosols, e.g. 8.155 ± 1.476 mg/L of gentamicin in the left maxillary sinus for the 2.8 μm particles
vs
. 2.056 ± 0.0474 for the 550 nm particles. Utilization of 100-Hz acoustic airflow nebulization also produced a 2- to 3-fold increase in drug deposition in the maxillary sinuses (e.g. 8.155 ± 1.476
vs
. 3.990 ± 1.690 for the 2.8 μm particles).
Conclusions
Our study clearly shows that optimum deposition was achieved using submicrometric particles and 100-Hz acoustic airflow nebulization with no nasal breathing. It is hoped that our new respiratory nasal replica will greatly facilitate the development of more effective delivery systems in the future.
Anatomical models to study aerosol delivery impose huge limitations and extrapolation to humans remains controversial. This study aimed to develop and validate an ex vivo human-like respiratory tract ...model easy to use and relevant to compare to in vivo human data. A human plastinated head is connected to an ex vivo porcine pulmonary tract ventilated artificially by passive expansion. A physiological study measures "pleural" depressions, tidal volumes, and minute ventilation for the respiratory rates chosen (10, 15, and 20 per minute) with three inspiratory/expiratory ratios (1/1, 1/2, and 1/3). Scintigraphy with
Krypton assesses the homogeneity of the ventilation. Forty different experiments were set for validation, with 36 (90%) ventilating successfully. At a respiratory rate of 15/minute with inspiratory/expiratory ratio of 1/2, the tidal volume average was 824 mL (standard deviation, 207 mL). The scintigraphy performed on 16 ex vivo models (44.4%), showed homogenous ventilation with great similarity to human physiological studies. Ratio of the peripheral to central count rates were equally correlated with human data published in the literature. This new model, combining research feasibility and human physiology likeness, provides a realistic approach to human inhalation and therefore can be an interesting tool in aerosol regional deposition studies.
Liquid deposit mimicking surface aerosolization in the airway is a promising strategy for targeting bronchopulmonary tumors with reduced doses of nanoparticle (NPs). In mimicking and studying such ...delivery approaches, the use of human in vitro 3D culture models can bridge the gap between 2D cell culture and small animal investigations. Here, we exposed airway epithelia to liquid-apical gadolinium-based AGuIX.sup.R NPs in order to determine their safety profile. We used a multiparametric methodology to investigate the NP's distribution over time in both healthy and tumor-bearing 3D models. AGuIX.sup.R NPs were able to target tumor cells in the absence of specific surface functionalization, without evidence of toxicity. Finally, we validated the therapeutic potential of this hybrid theranostic AGuIX.sup.R NPs upon radiation exposure in this model. In conclusion, 3D cell cultures can efficiently mimic the normal and tumor-bearing airway epitheliums, providing an ethical and accessible model for the investigation of nebulized NPs.
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