Xray enabled detection and eradication of circulating tumor cells with nanoparticles

a b s t r a c t The early detection and eradication of circulating tumor cells (CTCs) play an important role in cancer metastasis management. This paper describes a new nanoparticle-enabled technique for integrated enrichment, detection and killing of CTCs by using magnetic nanoparticles and bismuth nanoparticles, X-ray fluorescence spectrometry, and X-ray radiation. The nanoparticles are modified with tumor targeting agents and conjugated with tumor cells through folate receptors over-expressed on cancer cells. A permanent micro-magnet is used to collect CTCs suspended inside a flowing medium that contains phosphate buffered saline (PBS) or whole blood. The characteristic X-ray emissions from collected bismuth nanoparticles, upon excitation with collimated X-rays, are used to detect CTCs. Results show that the method is capable of selectively detecting CTCs at concentrations ranging from 100-100,000 cells/mL in the buffer solution, with a detection limit of $ 100 CTCs/mL. Moreover, the dose of primary X-rays can be enhanced to kill the localized CTCs by radiation induced DNA damage, with minimal invasiveness, thus making in vivo personalized CTC management possible

Experimental Study on Catalytic Combustion of Methane in a Microcombustor with Metal Foam Monolithic Catalyst

Utilizing catalysts in microcombustors is probably an excellent practical solution to stabilize fuel combustion because of the relatively fast reaction speed. In the present work, the monolithic catalyst Pd/A2O3/Fe-Ni with metal foam as matrix was used inside a 5 mm in diameter microcombustor. Then the effects of inlet velocity and equivalent ratio on catalytic combustion characteristics of methane were studied experimentally. The results showed that the methane and air mixture with the stoichiometric ratio Φ = 1.0 could be ignited at v = 0.2⁻0.6 m/s. The velocity of premixed mixture had a great influence on the catalytic combustion of methane. The larger the inlet velocity, the higher the temperature and the brighter the flame were. The experiment results also showed that the equivalence ratio had a large essential impact on the catalytic combustion, especially for the lean mixture of methane and air. It seemed the addition of the porous matrix with catalysts could significantly extend the limits of stable combustion. In the detection of exhaust gas, CO selectivity increased and CO2 selectivity decreased with the equivalence ratio. When Φ was between 0.94 and 1.0 m/s, a little amount of hydrogen was produced due to the lack of oxygen. The measured conversion of methane to CO and CO2 was very high, usually greater than 99%, which indicated the excellent performance of the catalyst

Targeted Nanoparticles For Enhanced X-Ray Radiation Killing Of Multidrug-Resistant Bacteria

This paper describes a nanoparticle enhanced X-ray irradiation based strategy that can be used to kill multidrug resistant (MDR) bacteria. In the proof-of-concept experiment using MDR Pseudomonas aeruginosa (P. aeruginosa) as an example, polyclonal antibody modified bismuth nanoparticles are introduced into bacterial culture to specifically target P. aeruginosa. After washing off uncombined bismuth nanoparticles, the bacteria are irradiated with X-rays, using a setup that mimics a deeply buried wound in humans. Results show that up to 90% of MDR P. aeruginosa are killed in the presence of 200 μg ml-1 bismuth nanoparticles, whereas only ∼6% are killed in the absence of bismuth nanoparticles when exposed to 40 kVp X-rays for 10 min. The 200 μg ml-1 bismuth nanoparticles enhance localized X-ray dose by 35 times higher than the control with no nanoparticles. In addition, no significant harmful effects on human cells (HeLa and MG-63 cells) have been observed with 200 μg ml-1 bismuth nanoparticles and 10 min 40 kVp X-ray irradiation exposures, rendering the potential for future clinical use. Since X-rays can easily penetrate human tissues, this bactericidal strategy has the potential to be used in effectively killing deeply buried MDR bacteria in vivo. © The Royal Society of Chemistry

Visible Light Mediated Killing Of Multidrug-Resistant Bacteria Using Photoacids

Increasing acidity is a promising method for bacterial inactivation by inhibiting the synthesis of intracellular proteins at low pH. However, conventional ways of pH control are not reversible, which can cause continuous changes in cellular and biological behaviours and are harmful to the host. Utilizing a photoacid that can reversibly alter pH over two units, we demonstrated a strong bacterial inhibition assisted by visible light. The pH value of the solution reverts back to the original level immediately after the irradiation is stopped. If a photoacid is combined with colistin, the minimum inhibitory concentration (MIC) of colistin on multidrug-resistant (MDR) Pseudomonas aeruginosa can be improved ∼32 times (from 8 to 0.25 μg mL-1), which significantly decreases the toxicity of colistin in clinics. Evidenced by the extremely low toxicity of the photoacid, this strategy is promising in MDR bacteria killing. © The Royal Society of Chemistry 2013

Three-Dimensional Microtissue Assay For High-Throughput Cytotoxicity Of Nanoparticles

Traditional in vitro nanotoxicity researches are conducted on cultured two-dimensional (2D) monolayer cells and thereby cannot reflect organism response to nanoparticle toxicities at tissue levels. This paper describes a new, high-throughput approach to test in vitro nanotoxicity in three-dimensional (3D) microtissue array, where microtissues are formed by seeding cells in nonsticky microwells, and cells are allowed to aggregate and grow into microtissues with defined size and shape. Nanoparticles attach and diffuse into microtissues gradually, causing radial cytotoxicity among cells, with more cells being killed on the outer layers of the microtissue than inside. Three classical toxicity assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT), glucose-6-phosphate dehydrogenase (G6DP), and calcein AM and ethidium homodimer (calcein AM/EthD-1)] have been adopted to verify the feasibility of the proposed approach. Results show that the nanotoxicities derived from this method are significantly lower than that from traditional 2D cultured monolayer cells (p \u3c 0.05). Equipped with a microplate reader or a microscope, the nanotoxicity assay could be completed automatically without transferring the microtissue, ensuring the reliability of toxicity assay. The proposed approach provides a new strategy for high-throughput, simple, and accurate evaluation of nanoparticle toxicities by combining 3D microtissue array with a panel of classical toxicity assays. © 2012 American Chemical Society

X-Ray Enabled Detection And Eradication Of Circulating Tumor Cells With Nanoparticles

The early detection and eradication of circulating tumor cells (CTCs) play an important role in cancer metastasis management. This paper describes a new nanoparticle-enabled technique for integrated enrichment, detection and killing of CTCs by using magnetic nanoparticles and bismuth nanoparticles, X-ray fluorescence spectrometry, and X-ray radiation. The nanoparticles are modified with tumor targeting agents and conjugated with tumor cells through folate receptors over-expressed on cancer cells. A permanent micro-magnet is used to collect CTCs suspended inside a flowing medium that contains phosphate buffered saline (PBS) or whole blood. The characteristic X-ray emissions from collected bismuth nanoparticles, upon excitation with collimated X-rays, are used to detect CTCs. Results show that the method is capable of selectively detecting CTCs at concentrations ranging from 100-100,000. cells/mL in the buffer solution, with a detection limit of ~100. CTCs/mL. Moreover, the dose of primary X-rays can be enhanced to kill the localized CTCs by radiation induced DNA damage, with minimal invasiveness, thus making in vivo personalized CTC management possible. © 2012 Elsevier B.V

Interference-Free Determination Of Ischemia-Modified Albumin Using Quantum Dot Coupled X-Ray Fluorescence Spectroscopy

Ischemia-modified protein (IMA) is the most sensitive diagnostic biomarker of ischemic heart disease, but differentiation of IMA from human serum albumin (HSA), a ubiquitous serum protein, is still challenging owing to the shared antigenicity. In this investigation, we developed a rapid and interference-free approach for IMA determination using quantum dots-coupled X-ray Fluorescence Spectroscopy (Q-XRF). In a typical Q-XRF assay, serum total HSA is quantified using quantum dot-coupled sandwich immunoassay, and intact HSA (iHSA) is determined using a XRF spectroscopy, by measuring XRF intensity of Co (II) bonded to iHSA. IMA concentration is automatically determined within 30min by calculating the difference between total HSA and iHSA. This strategy can effectively eliminate the interference from native HSA level. Results show that no significant influences have been observed from hemolysis or high levels of cholesterol (7mg/L), triglyceride (5.2mg/L), IgG (10g/L), and fibrinogen (4g/L). A linearity of 1-100mg/mL is obtained in iHSA determination using XRF (r2=0.979). The proposed Q-XRF assay demonstrates a lowest detection limit of 0.05U/mL. Receiver-operating characteristic (ROC) curves reveal that Q-XRF assay provide an improved sensitivity than ACB assay (95.9% vs. 82.9%) in differentiating ischemic patients from health individuals, at an optimal cutoff point of 79.2U/mL. The proposed approach provides a new strategy for interference-free, simple and rapid evaluation of IMA concentration by combining sandwich immunoassay and XRF spectroscopy. © 2013 Elsevier B.V

Biomimic Light Trapping Silicon Nanowire Arrays For Laser Desorption/Ionization Of Peptides

This article describes a low cost method of generating silicon nanowire arrays that have similar structure and light trapping ability as moth-eye for matrix-free laser desorption/ionization mass spectrometry analysis of small molecules without matrix peak interference. The nanowire array is produced by combining low cost nanosphere lithography and metal nanoparticle-assisted chemical etching of silicon. Owing to their excellent light trapping ability over broad spectral range, silicon nanowire arrays can absorb incoming laser light efficiently, and convert laser energy to heat, which allows efficient desorption/ionization of intact peptide/proteins without matrix. Compared to existing matrix-free substrate such as porous silicon substrates, the biomimic silicon nanowire arrays are better in terms of lower laser energy, structural tunability, and low spatial resistance. © 2012 American Chemical Society

In Vitro Cytotoxicity Of Surface Modified Bismuth Nanoparticles

This paper describes in vitro cytotoxicity of bismuth nanoparticles revealed by three complementary assays (MTT,G6PD, and calceinAM/EthD-1). The results showthat bismuth nanoparticles are more toxic than most previously reported bismuth compounds. Concentration dependent cytotoxicities have been observed for bismuth nanoparticles and surface modified bismuth nanoparticles. The bismuth nanoparticles are non-toxic at concentration of 0.5 nM. Nanoparticles at high concentration (50 nM) kill 45, 52, 41, 34 % HeLa cells for bare nanoparticles, amine terminated bismuth nanoparticles, silica coated bismuth nanoparticles, and polyethylene glycol (PEG) modified bismuth nanoparticles, respectively;which indicates cytotoxicity in terms of cell viability is in the descending order of amine terminated bismuth nanoparticles, bare bismuth nanoparticles, silica coated bismuth nanoparticles, and PEG modified bismuth nanoparticles. HeLa cells are more susceptible to toxicity from bismuth nanoparticles than MG-63 cells. The simultaneous use of three toxicity assays provides information on how nanoparticles interact with cells. Silica coated bismuth nanoparticles can damage cellular membrane yet keep mitochondria less influenced; while amine terminated bismuth nanoparticles can affect the metabolic functions of cells. The findings have important implications for caution of nanoparticle exposure and evaluating toxicity of bismuth nanoparticles. © Springer Science+Business Media, LLC 2012

On-Chip Radiation Biodosimetry With Three-Dimensional Microtissues

This paper reports an image-based, on-chip microtissue radiation biodosimeter that can simultaneously monitor radiation responses of multiple mammalian cell types. The microtissue chip is fabricated by molding molten agarose gel onto microfabricated patterns to form microwells, and seeding a variety of cell suspensions into different microwells inside the agarose gel. The camera of a mobile phone is used to collect images of an array of microtissues, and the color changes of microtissues upon X-ray irradiation allow accurate determination of cell death, which is related to radiation dose. The images can be transferred wirelessly, allowing the biodosimeter to be used for convenient and field deployable monitoring of radiation exposure. © The Royal Society of Chemistry 2012