Jimmie Colon

Cerium oxide nanoparticles protect gastrointestinal epithelium from radiation-induced damage by reduction of reactive oxygen species and upregulation of superoxide dismutase 2

UNLABELLED The ability of rare earth cerium oxide (CeO(2)) nanoparticles to confer radioprotection against gastrointestinal epithelium was examined. The pretreatment of normal human colon cells (CRL 1541) with varying concentrations of CeO(2) nanoparticles 24 hours before single-dose radiation exposure conferred protection from radiation-induced cell death by reducing the amount of reactive oxygen species produced and increasing the expression of superoxide dismutase 2 (SOD2), in a dose-dependent manner. In subsequent experiments athymic nude mice were pretreated with intraperitoneal injections of CeO(2) nanoparticles before a single dose of radiation to the abdominal area. Immunohistochemical analysis show a decrease in TUNEL- and caspase 3-positive cells in the colonic crypt, 4 hours after radiation. In sharp contrast, a significant increase in SOD2 expression was observed. In the end, these studies suggest that CeO(2) nanoparticles protect the gastrointestinal epithelium against radiation-induced damage by (1) acting as free-radical scavengers and (2) increasing the production of SOD2 before radiation insult. FROM THE CLINICAL EDITOR In this study, the ability of rare earth cerium oxide (CeO(2)) nanoparticles to confer radioprotection was examined. The results suggest that CeO(2) nanoparticles protect the gastrointestinal epithelium against radiation-induced damage both by acting as free-radical scavengers and by increasing the production of SOD2 before radiation insult.

Protection from radiation-induced pneumonitis using cerium oxide nanoparticles

In an effort to combat the harmful effects of radiation exposure, we propose that rare-earth cerium oxide (CeO(2)) nanoparticles (free-radical scavengers) protect normal tissue from radiation-induced damage. Preliminary studies suggest that these nanoparticles may be a therapeutic regenerative nanomedicine that will scavenge reactive oxygen species, which are responsible for radiation-induced cell damage. The effectiveness of CeO(2) nanoparticles in radiation protection in murine models during high-dose radiation exposure is investigated, with the ultimate goal of offering a new approach to radiation protection, using nanotechnology. We show that CeO(2) nanoparticles are well tolerated by live animals, and they prevent the onset of radiation-induced pneumonitis when delivered to live animals exposed to high doses of radiation. In the end, these studies provide a tremendous potential for radioprotection and can lead to significant benefits for the preservation of human health and the quality of life for humans receiving radiation therapy.

Sensitization of pancreatic cancer cells to radiation by cerium oxide nanoparticle-induced ROS production.

UNLABELLED Side effect of radiation therapy (RT) remains the most challenging issue for pancreatic cancer treatment. In this report we determined whether and how cerium oxide nanoparticles (CONPs) sensitize pancreatic cancer cells to RT. CONP pretreatment enhanced radiation-induced reactive oxygen species (ROS) production preferentially in acidic cell-free solutions as well as acidic human pancreatic cancer cells. In acidic environments, CONPs favor the scavenging of superoxide radical over the hydroxyl peroxide resulting in accumulation of the latter whereas in neutral pH CONPs scavenge both. CONP treatment prior to RT markedly potentiated the cancer cell apoptosis both in culture and in tumors and the inhibition of the pancreatic tumor growth without harming the normal tissues or host mice. Taken together, these results identify CONPs as a potentially novel RT-sensitizer as well as protectant for improving pancreatic cancer treatment. FROM THE CLINICAL EDITOR Pancreatic tumors remain some of the most notoriously treatment-unresponsive malignancies. Cerium oxide nanoparticles may be capable of sensitizing such cells to radiotherapy, as demonstrated in this study.

Phosphate ester hydrolysis of biologically relevant molecules by cerium oxide nanoparticles

In an effort to characterize the interaction of cerium oxide nanoparticles (CNPs) in biological systems, we explored the reactivity of CNPs with the phosphate ester bonds of p-nitrophenylphosphate (pNPP), ATP, o-phospho-l-tyrosine, and DNA. The activity of the bond cleavage for pNPP at pH 7 is calculated to be 0.860 ± 0.010 nmol p-nitrophenol/min/μg CNPs. Interestingly, when CNPs bind to plasmid DNA, no cleavage products are detected. While cerium(IV) complexes generally exhibit the ability to break phosphorus-oxygen bonds, the reactions we report appear to be dependent on the availability of cerium(III) sites, not cerium(IV) sites. We investigated the dephosphorylation mechanism from the first principles and find the reaction proceeds through inversion of the phosphate group similar to an S(N)2 mechanism. The ability of CNPs to interact with phosphate ester bonds of biologically relevant molecules has important implications for their use as potential therapeutics.

Multicolored redox active upconverter cerium oxide nanoparticle for bio-imaging and therapeutics

Cytocompatible, co-doped cerium oxide nanoparticles exhibited strong upconversion properties that were found to kill lung cancer cells by inducing apoptosis thereby demonstrating the potential to be used as clinical contrast agents for imaging and as therapeutic agents for treatment of cancer.

Tolfenamic acid enhances pancreatic cancer cell and tumor response to radiation therapy by inhibiting survivin protein expression

Survivin is overexpressed in most human cancers, including pancreatic adenocarcinoma. Expression of survivin is regulated by specificity protein (Sp) proteins and related to resistance to radiation therapy. Tolfenamic acid induces Sp protein degradation in several cancer cell lines. The purpose of this study is to investigate whether tolfenamic acid inhibits survivin expression and sensitizes pancreatic cancer cells/tumor to radiotherapy. Panc1 and L3.6pl cells have been used to study the effect of radiation on survivin expression and to investigate the efficacy of tolfenamic acid in enhancing the response to radiation therapy. In addition, an orthotopic model for human pancreatic cancer has been used to confirm the efficacy of tolfenamic acid to enhance tumor response to radiation in vivo. Pancreatic cancer cell lines express variable levels of survivin mRNA/protein, which correlate with their radiosensitivity. Radiation increased survivin promoter activity and protein expression in Panc1 and L3.6pl cells and tolfenamic acid inhibited both constitutive and radiation-induced survivin protein expression and enhanced the response of pancreatic cancer cells to radiation therapy. In vivo studies show that tolfenamic acid enhanced the radiation-induced apoptosis associated with decreased survivin expression in tumors and this correlates with the enhanced response of these tumors to the radiation. Thus, tolfenamic acid significantly enhances pancreatic cancer cells/tumor response to radiation therapy. The underlying mechanism includes tolfenamic acid-induced degradation of Sp proteins, which in tumor decreases expression of the Sp-dependent antiapoptotic protein survivin. These preclinical data suggest that tolfenamic acid has the potential to increase the response of pancreatic adenocarcinoma to radiation therapy. [Mol Cancer Ther 2009;8(3):533–42]

A Facile Nanoparticle Immunoassay for Cancer Biomarker Discovery

BackgroundGold nanoparticles (AuNPs) scatter light intensely at or near their surface plasmon wavelength region. Using AuNPs coupled with dynamic light scattering (DLS) detection, we developed a facile nanoparticle immunoassay for serum protein biomarker detection and analysis. A serum sample was first mixed with a citrate-protected AuNP solution. Proteins from the serum were adsorbed to the AuNPs to form a protein corona on the nanoparticle surface. An antibody solution was then added to the assay solution to analyze the target proteins of interest that are present in the protein corona. The protein corona formation and the subsequent binding of antibody to the target proteins in the protein corona were detected by DLS.ResultsUsing this simple assay, we discovered multiple molecular aberrations associated with prostate cancer from both mice and human blood serum samples. From the mice serum study, we observed difference in the size of the protein corona and mouse IgG level between different mice groups (i.e., mice with aggressive or less aggressive prostate cancer, and normal healthy controls). Furthermore, it was found from both the mice model and the human serum sample study that the level of vascular endothelial growth factor (VEGF, a protein that is associated with tumor angiogenesis) adsorbed to the AuNPs is decreased in cancer samples compared to non-cancerous or less malignant cancer samples.ConclusionThe molecular aberrations observed from this study may become new biomarkers for prostate cancer detection. The nanoparticle immunoassay reported here can be used as a convenient and general tool to screen and analyze serum proteins and to discover new biomarkers associated with cancer and other human diseases.

A label-free nanoparticle aggregation assay for protein complex/aggregate detection and study

The detection, analysis, and understanding of protein complexes/aggregates and their formation process are extremely important for biomolecular research, diagnosis, and biopharmaceutical development. Unfortunately, techniques that can be used conveniently for protein complex/aggregate detection and analysis are very limited. Using gold nanoparticle immunoprobes coupled with dynamic light scattering (DLS), we developed a label-free nanoparticle aggregation immunoassay (NanoDLSay) for protein aggregate detection and study. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a protein target used routinely in Western blot as a loading control, is demonstrated here as an example. Through this study, we discovered that GAPDH has a strong tendency to form large aggregates in certain buffer solutions at a concentration range of 10-25 microg/ml. The strong light scattering property of gold nanoparticles immunoprobes greatly enhanced the sensitivity of the dynamic light scattering for protein complex/aggregate detection. In contrast to fluorescence techniques for protein complex and aggregation study, the protein targets do not need to be labeled with fluorescent probe molecules in NanoDLSay. NanoDLSay is a very convenient and sensitive tool for protein complex/aggregate detection and study.

Small molecule tolfenamic acid inhibits PC‐3 cell proliferation and invasion in vitro, and tumor growth in orthotopic mouse model for prostate cancer

Specificity protein (Sp) transcription factors are implicated in critical cellular and molecular processes associated with cancer that impact tumor growth and metastasis. The non‐steroidal anti‐inflammatory drug, tolfenamic acid (TA) is known to inhibit Sp proteins in some human cancer cells and laboratory animal models. We evaluated the anti‐cancer activity of TA using in vitro and in vivo models for prostate cancer.

Bioluminescence imaging correlates with tumor progression in an orthotopic mouse model of lung cancer

BACKGROUND AND OBJECTIVES To determine whether bioluminescence imaging of human lung cancer cells growing in an orthotopic murine model provides a sensitive tool for monitoring tumor progression in athymic nude mice. METHODS Human lung cancer (A549) cells were stably transfected with the firefly luciferase gene and inoculated into the right lung of athymic nude mice. Seven days after inoculation tumor growth was evaluated using the Kodak in-vivo Imaging System FX and continued to be monitored on a weekly basis. RESULTS In duplicate experiments, human lung cancer tumors formed in 90% of animals injected orthotopically. The mean intensity of the bioluminescence signal emitted from the lung cancer cells increased logarithmically during the course of study. Mice with positive bioluminescence signaling had confirmed tumors by microscopic histological analysis. Bioluminescence activity had a strong correlation with the tumor volume as determined histologically. CONCLUSIONS Bioluminescence intensity directly correlates with tumor volume and therefore offers a reliable approach for detecting and monitoring the growth of human lung cancer cells in orthotopic murine models.