Pinpin Lin

Persistent Tissue Kinetics and Redistribution of Nanoparticles, Quantum Dot 705, in Mice: ICP-MS Quantitative Assessment

Background Quantum dots (QDs) are autofluorescent semiconductor nanocrystals that can be used for in vivo biomedical imaging. However, we know little about their in vivo disposition and health consequences. Objectives We assessed the tissue disposition and pharmacokinetics of QD705 in mice. Methods We determined quantitatively the blood and tissue kinetics of QD705 in mice after single intravenous (iv) injection at the dose of 40 pmol for up to 28 days. Inductively coupled plasma–mass spectrometry (ICP-MS) measurement of cadmium was the primary method of quantification of QD705. Fluorescence light microscopy revealed the localization of QD705 in tissues. Results Plasma half-life of QD705 in mice was short (18.5 hr), but ICP-MS analyses revealed QD705 persisted and even continued to increase in the spleen, liver, and kidney 28 days after an iv dose. Considerable time-dependent redistribution from body mass to liver and kidney was apparent between 1 and 28 days postdosing. The recoveries at both time points were near 100%; all QD705s reside in the body. Neither fecal nor urinary excretion of QD705 was detected appreciably in 28 days postdosing. Fluorescence microscopy demonstrated deposition of QD705 in the liver, spleen, and kidneys. Conclusion Judging from the continued increase in the liver (29–42% of the administered dose), kidney (1.5–9.2%), and spleen (4.8–5.2%) between 1 and 28 days without any appreciable excretion, QD705 has a very long half-life, potentially weeks or even months, in the body and its health consequences deserve serious consideration.

The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients

DNA methyltransferase 1 (DNMT1) catalyzes DNA methylation and is overexpressed in many human diseases, including cancer. The tobacco-specific carcinogen NNK also induces DNA methylation. However, the role of DNMT1-mediated methylation in tobacco carcinogenesis remains unclear. Here we used human and mouse lung cancer samples and cell lines to determine a mechanism whereby NNK induced DNMT1 expression and activity. We determined that in a human lung cell line, glycogen synthase kinase 3beta (GSK3beta) phosphorylated DNMT1 to recruit beta-transducin repeat-containing protein (betaTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3beta function and thereby attenuating DNMT1 degradation. NNK also induced betaTrCP translocation to the cytoplasm via the heterogeneous nuclear ribonucleoprotein U (hnRNP-U) shuttling protein, resulting in DNMT1 nuclear accumulation and hypermethylation of the promoters of tumor suppressor genes. Fluorescence immunohistochemistry (IHC) of lung adenomas from NNK-treated mice and tumors from lung cancer patients that were smokers were characterized by disruption of the DNMT1/betaTrCP interaction and DNMT1 nuclear accumulation. Importantly, DNMT1 overexpression in lung cancer patients who smoked continuously correlated with poor prognosis. We believe that the NNK-induced DNMT1 accumulation and subsequent hypermethylation of the promoter of tumor suppressor genes may lead to tumorigenesis and poor prognosis and provide an important link between tobacco smoking and lung cancer. Furthermore, this mechanism may also be involved in other smoking-related human diseases.

Cadmium-Based Quantum Dot Induced Autophagy Formation for Cell Survival via Oxidative Stress

Quantum dots (QDs) are one of most utilized nanomaterials in nanocrystalline semiconductors. QDs emit near-infrared fluorescence and can be applied as probes for detecting vasculature and imaging in biological systems. Since QDs have potential in clinical application, the toxicity of QDs needs to be carefully evaluated. In our present study, we elucidate the cytotoxic mechanisms of QDs using a mouse renal adenocarcinoma (RAG) cell line. QDs in RAG cells increased intracellular reactive oxygen species (ROS) levels and induced autophagy at 6 h, leading to subsequent apoptosis at 24 h. QDs entered the cells and were located within the endoplasmic reticulum (ER), endosome, and lysosome at 6 h and endosome, lysosome, and mitochondria at 24 h. However, QDs only affected mitochondrial function and did not induce ER stress. N-Acetylcysteine, an antioxidant agent, reduced intracellular ROS levels and decreased QD-induced autophagy but enhanced QD-induced cell death. Moreover, 3-methylamphetamine (an autophagy inhibitor) also reduced the cell viability in QD-treated cells. These findings suggest that ROS plays an essential role in the regulation of QD-induced autophagy, which subsequently enhances cell survival. Taken together, these results suggest that oxidative stress-induced autophagy is a defense/survival mechanism against the cytotoxicity of QD.

The chemical fate of the Cd/Se/Te-based quantum dot 705 in the biological system: toxicity implications

QD705 is a cadmium/selenium/tellurium (Cd/Se/Te)-based quantum dot with good potential for biomedical applications. Although the biological fate of QD705 is established, its chemical fate in the biological system is still unknown. Since the chemical nature of Cd in QD705 (either stays as bounded Cd or becomes free Cd) is closely related to the toxicity of this nanocrystal, information on its chemical fate is critically needed. In this study we investigated the chemical fate of QD705 in the kidneys of mice. We used the molar ratio of Cd and Te (increased Cd/Te ratio signifies increased Cd release from QD705) and the induction of tissue metallothionein (MT) as markers for elevated free Cd in tissues. Our study indicated that 100% of QD705 (measured as Cd) was still retained in the body 16 weeks after exposure, with significant time redistribution to the kidneys. Furthermore, there were an elevation in both the molar Cd/Te ratio and MT-1 expression in the kidneys, suggesting that free Cd was released from QD705. Thus QD705 is not as stable or biologically inert as many may have once believed. Our study demonstrated that free Cd indeed can be released from QD705 in the kidneys and increases the risk of renal toxicity.

Metal-Based Nanoparticles and the Immune System: Activation, Inflammation, and Potential Applications

Nanomaterials, including metal-based nanoparticles, are used for various biological and medical applications. However, metals affect immune functions in many animal species including humans. Different physical and chemical properties induce different cellular responses, such as cellular uptake and intracellular biodistribution, leading to the different immune responses. The goals of this review are to summarize and discuss the innate and adaptive immune responses triggered by metal-based nanoparticles in a variety of immune system models.

Baicalein induces G1 arrest in oral cancer cells by enhancing the degradation of cyclin D1 and activating AhR to decrease Rb phosphorylation

Baicalein is a flavonoid, known to have anti-inflammatory and anti-cancer effects. As an aryl hydrocarbon receptor (AhR) ligand, baicalein at high concentrations blocks AhR-mediated dioxin toxicity. Because AhR had been reported to play a role in regulating the cell cycle, we suspected that the anti-cancer effect of baicalein is associated with AhR. This study investigated the molecular mechanism involved in the anti-cancer effect of baicalein in oral cancer cells HSC-3, including whether such effect would be AhR-mediated. Results revealed that baicalein inhibited cell proliferation and increased AhR activity in a dose-dependent manner. Cell cycle was arrested at the G1 phase and the expression of CDK4, cyclin D1, and phosphorylated retinoblastoma (pRb) was decreased. When the AhR was suppressed by siRNA, the reduction of pRb was partially reversed, accompanied by a decrease of cell population at G1 phase and an increase at S phase, while the reduction of cyclin D1 and CDK4 did not change. This finding suggests that the baicalein activation of AhR is indeed associated with the reduction of pRb, but is independent of the reduction of cyclin D1 and CDK4. When cells were pre-treated with LiCl, the inhibitor of GSK-3β, the decrease of cyclin D1 was blocked and the reduction of pRb was recovered. The data indicates that in HSC-3 the reduction of pRb is both mediated by baicalein through activation of AhR and facilitation of cyclin D1 degradation, which causes cell cycle arrest at the G1 phase, and results in the inhibition of cell proliferation.

Epigenetic effects and molecular mechanisms of tumorigenesis induced by cigarette smoke: an overview.

Cigarette smoking is one of the major causes of carcinogenesis. Direct genotoxicity induced by cigarette smoke leads to initiation of carcinogenesis. Nongenotoxic (epigenetic) effects of cigarette smoke also act as modulators altering cellular functions. These two effects underlie the mechanisms of tumor promotion and progression. While there is no lack of general reviews on the genotoxic and carcinogenic potentials of cigarette smoke in lung carcinogenesis, updated review on the epigenetic effects and molecular mechanisms of cigarette smoke and carcinogenesis, not limited to lung, is lacking. We are presenting a comprehensive review of recent investigations on cigarette smoke, with special attentions to nicotine, NNK, and PAHs. The current understanding on their molecular mechanisms include (1) receptors, (2) cell cycle regulators, (3) signaling pathways, (4) apoptosis mediators, (5) angiogenic factors, and (6) invasive and metastasis mediators. This review highlighted the complexity biological responses to cigarette smoke components and their involvements in tumorigenesis.

The use of radioactive zinc oxide nanoparticles in determination of their tissue concentrations following intravenous administration in mice

The increasing uses of zinc oxide nanoparticles (ZnONPs) in coatings, paints, personal care products and many other products increase the possibility of the bodys exposure to ZnONPs. Accurate and quantitative profiling on the tissue distribution and body clearance of ZnONPs, which is an important factor to clarify the acute and chronic safety concerns of ZnONPs, is interfered by the abundance of the bodys endogenous zinc moiety. In this report, radioactive zinc oxide nanoparticles (R-ZnONPs) generated from neutron activation were employed for the in vivo bio-distribution studies using mice as the animal model. Gamma-ray emitting radioactive R-ZnONPs were produced from neutron activation. Zeta potentials of the ZnONPs before and after the neutron irradiation remained about the same, and R-ZnONPs largely remained its original nano-particulate form after neutron irradiation. After intravenous administration into ICR mice, R-ZnONPs exhibited a primary retention in lung (43.6% injected dose (ID)/g tissue wet weight) for the first hour and began to be translocated to intestinal tract for feces excretion at a later stage. This type of labeling free and radioactive nanoparticles retains the surface property and can be a convenient protocol for studying bio-distribution of nanoparticles in pristine chemical form.

Quantum dot 705, a cadmium-based nanoparticle, induces persistent inflammation and granuloma formation in the mouse lung

Abstract Some quantum dots (QDs) have been applied for drug delivery and imaging in biological systems. Drug delivery via the lung and lung imaging are potential applications of QDs. QD705 is cadmium based. The aims of the study were to evaluate the biological effects of QD705 in the lungs and the protective effects of polyethylene glycol (PEG) coating against QD705-induced biological responses. Intratracheal instillation of QD705-COOH persistently induced acute neutrophil infiltration, followed by interstitial lymphocyte infiltration and a granulomatous reaction on days 17 and 90. QD705-COOH also induced gene expression of cytokines, chemokines and metalloproteinase 12 in lung tissues. Furthermore, QD705-COOH transiently reduced pulmonary function on day 17. Treatment with QD705–PEG induced similar inflammatory responses and reduced pulmonary function on day 17, but the granulomatous reaction disappeared by day 90 These data indicated that administration of QD705 via the lung caused adverse responses and PEG coating failed to prevent these effects.

Suberoylanilide Hydroxamic Acid, an Inhibitor of Histone Deacetylase, Enhances Radiosensitivity and Suppresses Lung Metastasis in Breast Cancer In Vitro and In Vivo

Triple-negative breast cancer (TNBC), defined by the absence of an estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, is associated with an early recurrence of disease and poor outcome. Furthermore, the majority of deaths in breast cancer patients are from metastases instead of from primary tumors. In this study, MCF-7 (an estrogen receptor-positive human breast cancer cell line), MDA-MB-231 (a human TNBC cell line) and 4T1 (a mouse TNBC cell line) were used to investigate the anti-cancer effects of ionizing radiation (IR) combined with suberoylanilide hydroxamic acid (SAHA, an inhibitor of histone deacetylase (HDAC)) and to determine the underlying mechanisms of these effects in vitro and in vivo. We also evaluated the ability of SAHA to inhibit the metastasis of 4T1 cells. We found that IR combined with SAHA showed increased therapeutic efficacy when compared with either treatment alone in MCF-7, MDA-MB-231 and 4T1 cells. Moreover, the combined treatment enhanced DNA damage through the inhibition of DNA repair proteins. The combined treatment was induced primarily through autophagy and ER stress. In an orthotopic breast cancer mouse model, the combination treatment showed a greater inhibition of tumor growth. In addition, SAHA inhibited the migration and invasion abilities of 4T1 cells and inhibited breast cancer cell migration by inhibiting the activity of MMP-9. In an in vivo experimental metastasis mouse model, SAHA significantly inhibited lung metastasis. SAHA not only enhances radiosensitivity but also suppresses lung metastasis in breast cancer. These novel findings suggest that SAHA alone or combined with IR could serve as a potential therapeutic strategy for breast cancer.