X-ray induced photodynamic therapy with copper-cysteamine nanoparticles in mice tumors.

Photodynamic therapy (PDT), a treatment that uses a photosensitizer, molecular oxygen, and light to kill target cells, is a promising cancer treatment method. However, a limitation of PDT is its dependence on light that is not highly penetrating, precluding the treatment of tumors located deep in the body. Copper-cysteamine nanoparticles are a new type of photosensitizer that can generate cytotoxic singlet oxygen molecules upon activation by X-rays. In this paper, we report on the use of copper-cysteamine nanoparticles, designed to be targeted to tumors, for X-ray-induced PDT. In an in vivo study, results show a statistically significant reduction in tumor size under X-ray activation of pH-low insertion peptide-conjugated, copper-cysteamine nanoparticles in mouse tumors. This work confirms the effectiveness of copper-cysteamine nanoparticles as a photosensitizer when activated by radiation and suggests that these Cu-Cy nanoparticles may be good candidates for PDT in deeply seated tumors when combined with X-rays and conjugated to a tumor-targeting molecule.

Gold Nanoparticles Enhance Radiation Therapy at Low Concentrations, and Remain in Tumors for Days.

Gold nanoparticles are a potential method for enhancing radiation therapy, causing extra damage to tumors when irradiated through the Auger effect. One of the major obstacles to using gold nanoparticles in human trials is the relatively large amount of gold required. This paper details an experiment where a relatively small amount of gold (200 µg) was used to significantly reduce tumor volume in mice, as well as the results of an inter-tissue biodistribution experiment. Using a longitudinal analysis, tumor size as a function of time was found to be significantly reduced when mice were given 200 µg of gold nanoparticles and 20 Gray of radiation, compared to radiation alone. 200 µg in a 20-gram mouse would be mass equivalent to 750 mg of gold in a 75 kg person. Biodistribution measurements demonstrated that gold nanoparticles stayed in the tumor for at least one week after injection when targeted to tumors using pH-Low Insertion Peptide and intratumoral injections. These results show gold nanoparticles to be effective at one of the smallest amounts of gold ever attempted in a mouse, and showed that tumor targeting has the potential to keep gold nanoparticles available in tumors long enough to be beneficial to fractionated radiation treatments (a key component of radiation therapy in the clinic).

Nicotine Modulates Growth Factors and MicroRNA to Promote Inflammatory and Fibrotic Processes.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease that destroys the structure and function of the lungs. Risk factors include advanced age and genetic predisposition. However, tobacco use is the chief modifiable risk factor. The prevalence of tobacco use in IPF reaches up to 80%. Although tobacco smoke contains over 5000 chemicals, nicotine is a major component. Nicotine is a bioactive molecule that acts upon nicotinic acetylcholine receptors expressed on neuronal and non-neuronal cells including endothelial cells. Accordingly, it has a pleiotropic effect on cell proliferation and angiogenesis. The angiogenic effect is partly mediated by stimulation of growth factors including fibroblast, platelet-derived, and vascular endothelial growth factors. Nintedanib, a Food and Drug Administration-approved drug for IPF, works by inhibiting receptors for these growth factors, suggesting a pathobiologic role of the growth factors in IPF and a potential mechanism by which tobacco use may exacerbate the disease process; additionally, nicotine downregulates anti-inflammatory microRNAs (miRs) in lung cells. Here, we profiled the expression of miRs in lung tissues explanted from a lung injury model and examined the effect of nicotine on one of the identified miRs (miR-24) and its downstream targets. Our data show that miR-24 is downregulated during lung injury and is suppressed by nicotine. We also found that nicotine upregulates the expression of inflammatory cytokines targeted by miR-24. Finally, nicotine stimulated growth factors, fibroblast proliferation, collagen release, and expression of myofibroblast markers. Taken together, nicotine, alone or as a component of tobacco smoke, may accelerate the disease process in IPF through stimulation of growth factors and downregulation of anti-inflammatory miRs.

Imagining Replications: Graphical Prediction & Discrete Visualizations Improve Recall & Estimation of Effect Uncertainty.

People often have erroneous intuitions about the results of uncertain processes, such as scientific experiments. Many uncertainty visualizations assume considerable statistical knowledge, but have been shown to prompt erroneous conclusions even when users possess this knowledge. Active learning approaches been shown to improve statistical reasoning, but are rarely applied in visualizing uncertainty in scientific reports. We present a controlled study to evaluate the impact of an interactive, graphical uncertainty prediction technique for communicating uncertainty in experiment results. Using our technique, users sketch their prediction of the uncertainty in experimental effects prior to viewing the true sampling distribution from an experiment. We find that having a user graphically predict the possible effects from experiment replications is an effective way to improve one's ability to make predictions about replications of new experiments. Additionally, visualizing uncertainty as a set of discrete outcomes, as opposed to a continuous probability distribution, can improve recall of a sampling distribution from a single experiment. Our work has implications for various applications where it is important to elicit peoples' estimates of probability distributions and to communicate uncertainty effectively.

Gene Expression as a Dosimeter in Irradiated Drosophila melanogaster.

Biological indicators would be of use in radiation dosimetry in situations where an exposed person is not wearing a dosimeter, or when physical dosimeters are insufficient to estimate the risk caused by the radiation exposure. In this work, we investigate the use of gene expression as a dosimeter. Gene expression analysis was done on 15,222 genes of Drosophila melanogaster (fruit flies) at days 2, 10, and 20 postirradiation, with X-ray exposures of 10, 1000, 5000, 10,000, and 20,000 roentgens. Several genes were identified, which could serve as a biodosimeter in an irradiated D. melanogaster model. Many of these genes have human homologues. Six genes showed a linear response (R2 > 0.9) with dose at all time points. One of these genes, inverted repeat-binding protein, is a known DNA repair gene and has a human homologue (XRCC6). The lowest dose, 10 roentgen, is very low for fruit flies. If the lowest dose is excluded, 13 genes showed a linear response with dose at all time points. This includes 5 of 6 genes that were linear with all radiation doses included. Of these 13 genes, 4 have human homologues and 8 have known functions. The expression of this panel of genes, particularly those with human homologues, could potentially be used as the biological indicator of radiation exposure in dosimetry applications.

Gold Nanoparticles for Radiation Enhancement in Vivo.

Enhancing the effect of radiation on tumors would be a significant improvement in radiation therapy. With radiation enhancement, less radiation could be used to achieve the same goals, lessening damage to healthy tissue and lessening side effects. Gold nanoparticles are a promising method for achieving this enhancement, particularly when the gold nanoparticles are targeted to cancer. This literature review discusses the properties of gold nanoparticles as well as existing in vivo radiation enhancement results using both targeted and non-targeted gold nanoparticles.

Enhancement of radiation effect on cancer cells by gold-pHLIP.

Previous research has shown that gold nanoparticles can increase the effectiveness of radiation on cancer cells. Improved radiation effectiveness would allow lower radiation doses given to patients, reducing adverse effects; alternatively, it would provide more cancer killing at current radiation doses. Damage from radiation and gold nanoparticles depends in part on the Auger effect, which is very localized; thus, it is important to place the gold nanoparticles on or in the cancer cells. In this work, we use the pH-sensitive, tumor-targeting agent, pH Low-Insertion Peptide (pHLIP), to tether 1.4-nm gold nanoparticles to cancer cells. We find that the conjugation of pHLIP to gold nanoparticles increases gold uptake in cells compared with gold nanoparticles without pHLIP, with the nanoparticles distributed mostly on the cellular membranes. We further find that gold nanoparticles conjugated to pHLIP produce a statistically significant decrease in cell survival with radiation compared with cells without gold nanoparticles and cells with gold alone. In the context of our previous findings demonstrating efficient pHLIP-mediated delivery of gold nanoparticles to tumors, the obtained results serve as a foundation for further preclinical evaluation of dose enhancement.