Oxidative metabolism in the cardiorespiratory system after an acute exposure to nickel-doped nanoparticles in mice.

There is an increasing concern over the harmful effects that metallic nanoparticles (NP) may produce on human health. Due to their redox properties, nickel (Ni) and Ni-containing NP are particularly relevant. Hence, the aim of this study was to establish the toxicological mechanisms in the cardiorespiratory oxidative metabolism initiated by an acute exposure to Ni-doped-NP. Mice were intranasally instilled with silica NP containing Ni (II) (Ni-NP) (1 mg Ni (II)/kg body weight) or empty NP as control, and 1 h after exposure lung, plasma, and heart samples were obtained to assess the redox metabolism. Results showed that, NP were mainly retained in the lungs triggering a significantly increased tissue O2 consumption rate, leading to Ni-NP-increased reactive oxygen species production by NOX activity, and mitochondrial H2O2 production rate. In addition, an oxidant redox status due to an altered antioxidant system showed by lung GSH/GSSG ratio decreased, and SOD activity increased, resulting in an increased phospholipid oxidation. Activation of circulating polymorphonuclear leukocytes, along with GSH/GSSG ratio decreased, and phospholipid oxidation were found in the Ni-NP-group plasma samples. Consequently, in distant organs such as heart, Ni-NP inhalation alters the tissue redox status. Our results showed that the O2 metabolism analysis is a critical area of study following Ni-NP inhalation. Therefore, this work provides novel data linking the redox metabolisms alterations elicited by exposure to Ni (II) adsorbed to NP and cardiorespiratory toxicity.

AQPX-cluster aquaporins and aquaglyceroporins are asymmetrically distributed in trypanosomes.

Major Intrinsic Proteins (MIPs) are membrane channels that permeate water and other small solutes. Some trypanosomatid MIPs mediate the uptake of antiparasitic compounds, placing them as potential drug targets. However, a thorough study of the diversity of these channels is still missing. Here we place trypanosomatid channels in the sequence-function space of the large MIP superfamily through a sequence similarity network. This analysis exposes that trypanosomatid aquaporins integrate a distant cluster from the currently defined MIP families, here named aquaporin X (AQPX). Our phylogenetic analyses reveal that trypanosomatid MIPs distribute exclusively between aquaglyceroporin (GLP) and AQPX, being the AQPX family expanded in the Metakinetoplastina common ancestor before the origin of the parasitic order Trypanosomatida. Synteny analysis shows how African trypanosomes specifically lost AQPXs, whereas American trypanosomes specifically lost GLPs. AQPXs diverge from already described MIPs on crucial residues. Together, our results expose the diversity of trypanosomatid MIPs and will aid further functional, structural, and physiological research needed to face the potentiality of the AQPXs as gateways for trypanocidal drugs.

99mTc-Radiolabeled TPGS Nanomicelles Outperform 99mTc-Sestamibi as Breast Cancer Imaging Agent.

D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) is a Food and Drug Administration (FDA) approved biomaterial that can form nanosized micelles in aqueous solution. TPGS micelles stand as an interesting system to perform drug delivery as they can carry lipophilic drugs and overcome P glycoprotein efflux as well. Therefore, TPGS micelles combined with other copolymers have been reported in many cancer research studies as a carrier for therapeutic drugs. Their ability to reach tumoral tissue can also be exploited to develop imaging agents with diagnostic application. A radiolabeling method with 99mTc for TPGS nanosized micelles and their biodistribution in a healthy animal model as well as their pharmacokinetics and radiolabeling stability in vivo was previously reported. The aim of this work was to evaluate the performance of this radioactive probe as a diagnostic imaging agent compared to routinely available SPECT radiopharmaceutical, 99mTc-sestamibi. A small field of view gamma camera was used for scintigraphy studies using radiolabeled TPGS micelles in two animal models of breast cancer: syngeneic 4T1 murine cell line (injected in BALB/c mice) and chemically NMU-induced (Sprague-Dawley rats). Ex vivo radioactivity accumulation in organs of interest was measured by a solid scintillation counter, and a semiquantitative analysis was performed over acquired images as well. Results showed an absence of tumoral visualization in 4T1 model for both radioactive probes by gamma camera imaging. On the contrary, NMU-induced tumors had a clear tumor visualization by scintigraphy. A higher tumor/background ratio and more homogeneous uptake were found for radiolabeled TPGS micelles compared to 99mTc-sestamibi. In conclusion, 99mTc-radiolabeled TPGS micelles might be a potential SPECT imaging probe for diagnostic purposes.

Polymeric mixed micelles as nanomedicines: Achievements and perspectives.

During the past few decades, polymeric micelles have raised special attention as novel nano-sized drug delivery systems for optimizing the treatment and diagnosis of numerous diseases. These nanocarriers exhibit several in vitro and in vivo advantages as well as increased stability and solubility to hydrophobic drugs. An interesting approach for optimizing these properties and overcoming some of their disadvantages is the combination of two or more polymers in order to assemble polymeric mixed micelles. This review article gives an overview on the current state of the art of several mixed micellar formulations as nanocarriers for drugs and imaging probes, evaluating their ongoing status (preclinical or clinical stage), with special emphasis on type of copolymers, physicochemical properties, in vivo progress achieved so far and toxicity profiles. Besides, the present article presents relevant research outcomes about polymeric mixed micelles as better drug delivery systems, when compared to polymeric pristine micelles. The reported data clearly illustrates the promise of these nanovehicles reaching clinical stages in the near future.

Hepato and Cardiotoxicity of Chemotherapeutic Treatment Evaluated by Means of Small Animal Imaging.

BACKGROUND: Chemotherapy is one of the most common approaches for cancer treatment. Particularly Doxorubicin has been proven to be effective in the treatment of many soft and solid tumors for locally advanced and metastatic cancer. It is not easy to clinically evaluate the chemotoxic or chemoprotective effect of some drugs, even more when there is a subclinical toxicity. OBJECTIVE: To determine the usefulness of the hepatobiliary, colloid and cardiac scintigraphies, employing99mTcdisida, 99mTc-phytate and 99mTc-sestamibi respectively, in the evaluation of the hepato and cardiotoxicity of two chemotherapeutic treatments assessed in rats. METHOD: Two groups were submitted to doxorubicin (DOX) treatment and one was co-administered with histamine (DOX+HIS). Static 99mTc-phytate and 99mTc-sestamibi scintigraphies as well as a dynamic 99mTc-disida study were performed in a small field of view gamma camera at: 0 weeks (control), 1 week and 2 weeks of treatment. Imagenological parameters were calculated: Liver/Bone Marrow ratio (L/BM), Heart/Background ratio (H/B) and time to the maximum (Tmax) for 99mTc-phytate, 99mTc-sestamibi and 99mTc-disida extraction, respectively. RESULTS: Control (L/BM= 98±3; H/B=2.3±0.4; Tmax=8±3), DOX (L/BM: 85±3, 80±3; H/B, 3.5±0.5, 3.3±0.5 and Tmax 6±1, 4±1) for 1 and 2 weeks respectively and DOX+HIS (L/BM: 99±0.3, 98±1; H/B 2.9±0.5, 2.9±0.5 and Tmax, 8±2, 9±2) for 1 and 2 weeks, respectively. Histological analysis showed cardio and hepatotoxicity induced by doxorubicin. CONCLUSION: Imagenological parameters showed differences among treated and control groups and between both chemotherapy treatments. Thus, these radiopharmaceutical functional approaches were able to reflect heart and liver toxicity produced by doxorubicin.

Radiolabeling and biological characterization of TPGS-based nanomicelles by means of small animal imaging.

INTRODUCTION: In recent years, nanomedicines have raised as a powerful tool to improve prevention, diagnosis and treatment of different pathologies. Among the most well investigated biomaterials, D-α-tocopheryl polyethylene glycol succinate (also known as TPGS) has been on the spot for the last decade. We therefore designed a method to biologically characterize TPGS-based nanomicelles by labeling them with 99mTc. METHODS: Labeling process was performed by a direct method. The average hydrodynamic diameter of TPGS nanomicelles was measured by dynamic light scattering and radiochemical purity was assessed by thin layer chromatography. Imaging: a dynamic study was performed during the first hour post radioactive micelles administration in a gamma camera (TcO4- was also administered for comparative purposes). Then two static images were acquired in ventral position: 1h and 12h post injection. Blood pharmacokinetics of 99mTc-TPGS during 24h was performed. RESULTS: Images revealed whole body biodistribution at an early and delayed time and semiquantification was performed in organs of interest (%Total counts: soft tissue 6.1±0.5; 3.9±0.1, Bone 1.2±0.2; 1±0.1, Heart 1.5±0.6; 0.7±0.3, Kidneys 16.6±1.3; 26.5±1.7, Liver 8.6±1.1; 11.1±0.1 for 1 and 12 h post injection respectively). CONCLUSION: This work demonstrated that TPGS based nanomicelles are susceptible to be radiolabeled with 99mTc thus they can be used to perform imaging studies in animal models. Moreover radiolabeling of these delivery nano systems reveals their possibility to be used as diagnostic agents in the near future.

Radioactivity decontamination of materials commonly used as surfaces in general-purpose radioisotope laboratories.

UNLABELLED: In accord with as-low-as-reasonably-achievable and good-manufacturing-practice concepts, the present study evaluated the efficiency of radioactivity decontamination of materials commonly used in laboratory surfaces and whether solvent spills on these materials affect the findings. METHODS: Four materials were evaluated: stainless steel, a surface comprising one-third acrylic resin and two-thirds natural minerals, an epoxy cover, and vinyl-based multipurpose flooring. Radioactive material was eluted from a (99)Mo/(99m)Tc generator, and samples of the surfaces were control-contaminated with 37 MBq (100 µL) of this eluate. The same procedure was repeated with samples of surfaces previously treated with 4 solvents: methanol, methyl ethyl ketone, acetone, and ethanol. The wet radioactive contamination was allowed to dry and then was removed with cotton swabs soaked in soapy water. The effectiveness of decontamination was defined as the percentage of activity removed per cotton swab, and the efficacy of decontamination was defined as the total percentage of activity removed, which was obtained by summing the percentages of activity in all the swabs required to complete the decontamination. RESULTS: Decontamination using our protocol was most effective and most efficacious for stainless steel and multipurpose flooring. Moreover, treatment with common organic solvents seemed not to affect the decontamination of these surfaces. Decontamination of the other two materials was less efficient and was interfered with by the organic solvents; there was also great variability in the overall results obtained for these other two materials. CONCLUSION: In expanding our laboratory, it is possible for us to select those surface materials on which our decontamination protocol works best.

Validation of an alternative radiochemical purity method for [99mTc]pentetate ([99mTc]DTPA).

[(99m)Tc]pentetate ([(99m)Tc]DTPA) is the most commonly used radiopharmaceutical renography agent. The aim of this work was to validate an alternative method for assessing [(99m)Tc]DTPA radiochemical purity (RCP), according to the ICH Q2(R1) guidance: "Validation of Analytical Procedures". The proposed method is composed of two chromatographic systems. System A is a miniaturized system of thin layer chromatography (TLC) silica gel impregnated aluminum strips as stationary phase (SP) and distilled water as mobile phase (MP). System B consists of Whatman 1 paper strips as SP and methyl ethyl ketone as MP. Results indicate that the proposed RCP method has been validated, as it is specific, precise, accurate, linear and robust. Therefore, it can be used as an alternative method for RCP quality control purposes and as stability indicator as well.

Diagnóstico y seguimiento de cáncer de piel no-melanoma utilizando 99mTc-MIBI: estudios en un modelo animal / Usefulness of 99mTc-MIBI for the diagnosis and follow up of non-melanoma skin cancer: study in an animal model

El objetivo consistió en evaluar la utilidad del 99mTc-MIBI como marcador para diagnóstico y seguimiento de la progresión tumoral del NMSC en un modelo de carcinogénesis completa en ratones. Los animales en estudio fueron inyectados con 99mTc-MIBI a diferentes tiempos y eutanasiados. Se disecaron muestras de tumor y piel sana para evaluar la captación del radiofármaco y realizar el diagnóstico histológico. En animales con 22 semanas de progresión tumoral se observó una diferencia significativa en la captación del 99mTc-MIBI entre piel sana y NMSC. El protocolo que mejor se adapta al uso del 99mTc-MIBI como marcador para el diagnóstico y seguimiento de la progresión tumoral en ratones portadores de NMSC inducidos es la administración i.v de 1 mCi de 99mTc-MIBI con adquisición de datos a los 30 minutos post inyección. Se observó que a medida que los tumores progresan, la captación de 99mTc-MIBI disminuye respecto a la piel normal.

The aim of the work was to evaluate the usefulness of 99mTc-MIBI as a tracer for the tumor diagnosis and progression of NMSC in a chemically induced model in mice. After administration of 99mTc-MIBI animals were sacrificed at different times. Samples of tumor and healthy skin were dissected in order to perform histological analysis and to evaluate 99mTc-MIBI uptake. Animals under 22 weeks of tumor evolution showed a statistically difference in 99mTc-MIBI uptake between healthy skin and NMSC. Our results showed that the better protocol for the study of the tumor diagnosis and progression of NMSC in mice is the administration of 1 mCi of 99mTc-MIBI and acquisition of images 30 minutes post injection. Results showed that, as tumor progresses, the uptake of 99mTc-MIBI is significantly lower than healthy skin.