Nanomicellar Formulations Loaded with Histamine and Paclitaxel as a New Strategy to Improve Chemotherapy for Breast Cancer.

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Currently, paclitaxel (PTX) represents the first-line therapy for TNBC; however it presents a hydrophobic behavior and produces severe adverse effects. The aim of this work is to improve the therapeutic index of PTX through the design and characterization of novel nanomicellar polymeric formulations composed of a biocompatible copolymer Soluplus® (S), surface-decorated with glucose (GS), and co-loaded either with histamine (HA, 5 mg/mL) and/or PTX (4 mg/mL). Their micellar size, evaluated by dynamic light scattering, showed a hydrodynamic diameter between 70 and 90 nm for loaded nanoformulations with a unimodal size distribution. Cytotoxicity and apoptosis assays were performed to assess their efficacy in vitro in human MDA-MB-231 and murine 4T1 TNBC cells rendering optimal antitumor efficacy in both cell lines for the nanoformulations with both drugs. In a model of TNBC developed in BALB/c mice with 4T1 cells, we found that all loaded micellar systems reduced tumor volume and that both HA and HA-PTX-loaded SG micelles reduced tumor weight and neovascularization compared with the empty micelles. We conclude that HA-PTX co-loaded micelles in addition to HA-loaded formulations present promising potential as nano-drug delivery systems for cancer chemotherapy.

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.

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 a paper chromatographic methodology as an alternative for determination of the radiochemical purity of Na18F.

UNLABELLED: The aim of the present work was to validate a paper chromatography system as an alternative way to determine the radiochemical purity of Na(18)F. METHODS: The evaluated parameters were specificity, limit of quantification, measurement interval, linearity, precision, accuracy, and robustness. RESULTS: The proposed method proved to be linear (P > 0.05; r(2) = 1.000), precise (relative SD, 8.6%), accurate (mean recovery, 95.9%; relative SD, 1.5%-1.8%), and robust under different conditions since no influence of the operative variables on the chromatographic performance was observed. CONCLUSION: This system can be used as a reliable alternative method to determine the radiochemical purity of Na(18)F samples that can be easily performed in PET radiopharmacies at low cost.

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.

Effect of a probiotic food as an adjuvant to triple therapy for eradication of Helicobacter pylori infection in children.

OBJECTIVE: Current recommendations for treatment of Helicobacter pylori infection include a proton pump inhibitor in combination with two antibiotics. We evaluated the potential activity of a probiotic food as an adjuvant to antibiotic triple therapy for eradication of H. pylori infection in children from Buenos Aires, Argentina. METHODS: Sixty-five children who tested positive for H. pylori, as diagnosed by (13)C-urea breath test and endoscopy, were included in this study. Patients were randomized to receive 1-wk triple therapy plus probiotic food (treated group) or milk placebo (control) that was administered for 3 mo. Probiotic food consisted of 250 mL of a commercial yogurt containing Bifidobacterium animalis and Lactobacillus casei (10(7) colony-forming units/mL). Post-treatment urea breath test controls were performed 1 and 3 mo after the end of triple therapy. RESULTS: We found no significant differences in H. pylori eradication rates (ERs) at 1 and 3 mo between the treated group (ER = 45.5% and 42.4%) and the control group (ER = 37.5% and 40.6%). Relative risks between groups were 0.87 (95% confidence interval 0.58-1.32, P = 0.345) in the first month and 0.97 (95% confidence interval 0.64-1.46, P = 0.542) in the third month. CONCLUSIONS: We could not demonstrate an adjuvant effect of the studied probiotic food to triple therapy in the eradication of H. pylori infection in children in Buenos Aires, Argentina. However, we found lower ERs than those reported for the same therapeutic scheme in developed countries, indicating that bacterial resistance and alternative therapeutic strategies should be studied.

Effect of iron deficiency anemia on the biodistribution of 99mTc radiopharmaceuticals.

The distribution of colloids and labeled cells in organs is influenced by their intrinsic properties and by the state of the investigated subject. Iron deficiency remains an unsolved nutritional problem all over the world; one of its severe consequences is anemia. Because iron metabolism principally takes place in the liver, spleen, bone marrow, skeletal muscle and blood, we studied the effect of iron deficiency anemia on the biodistribution of 99mTc phytate, 99mTc gelatin colloid and 99mTc RBC (red blood cells labeled with 99mTc). Our results show that iron deficiency anemia modifies the pattern of biodistribution of the two colloids assayed. However, this behavior is different for both of them. This work contributes to studies that kinetically and statistically establish that iron deficiency anemia induces a significant inversion in the spleen-liver activity relationship when centellographic studies are performed with colloids such as 99mTc phytate.

Quality control validation for exogenous natural surfactant labeled with 99mTc.

OBJECTIVE: Exogenous natural surfactant (ENS) labeled with 99mTc shows an elevated lung specificity allowing the acquisition of high-quality images for ventilation scintigraphy. METHODS: The methods for 99mTc-ENS quality control (physical properties, pH determination, radiochemical studies, and biologic studies) were evaluated and validated. RESULTS: The physical properties of the nonradioactive precursor and of the radiopharmaceutical were analyzed as general descriptors of the product. The pH of the radiopharmaceutical was determined by using pH test papers, a method described and validated in the United States Pharmacopeia. Chromatographic studies performed using the acetone/Whatman-1 paper system were validated as a method to evaluate the radiochemical purity of the 99mTc-ENS. Biodistribution studies on rats after intratracheal administration were validated as a method to estimate the radiopharmaceutical biodistribution in humans. CONCLUSION: The proposed method for 99mTc-ENS quality control studies and stability studies was evaluated and validated following international standards.

Stabilized ferrous gluconate as iron source for food fortification: bioavailability and toxicity studies in rats.

The iron bioavailability and acute oral toxicity in rats of a ferrous gluconate compound stabilized with glycine (SFG), designed for food fortification, was studied in this work by means of the prophylactic method and the Wilcoxon method, respectively. For the former studies, SFG was homogeneously added to a basal diet of low iron content, reaching a final iron concentration of 20.1 +/- 2.4 mg Fe/kg diet. A reference standard diet using ferrous sulfate as an iron-fortifying source (19.0 +/- 2.1 mg Fe/kg diet) and a control diet without iron additions (9.3 +/- 1.4 mg Fe/kg diet) were prepared in the laboratory in a similar way. These diets were administered to three different groups of weaning rats during 23 d as the only type of solid nourishment. The iron bioavailability of SFG was calculated as the relationship between the mass of iron incorporated into hemoglobin during the treatment and the total iron intake per animal. This parameter resulted in 36.6 +/- 6.2% for SFG, whereas a value of 35.4 +/- 8.0% was obtained for ferrous sulfate. The acute toxicological studies were performed in two groups of 70 female and 70 male Sprague-Dawley rats that were administered increasing doses of iron from SFG. The LD50 values of 1775 and 1831 mg SFG/kg body wt were obtained for female and male rats, respectively, evidencing that SFG can be considered as a safe compound from a toxicological point of view.

Bioavailability of Petit-Suisse cheese as food vehicle for iron fortification estimated by the prophylactic method.

Microencapsulated ferrous sulfate (SFE-171) and ferric orthophosphate in Petit-Suisse cheese were examined for iron bioavailability by the prophylactic method. The iron sources were industrially added to different samples of Petit-Suisse cheese, which were mixed with other food components in our laboratory before use. A reference standard diet inclusive of nonmicroencapsulated ferrous sulfate and a control diet low in iron content were prepared in the laboratory. The final iron content in the fortified diets was approximately 15 mg Fe/kg diet. These diets were administered to weaning rats for 23 days. The iron bioavailability was evaluated as the ratio of iron incorporated into hemoglobin to oral iron intake, thereby being estimated as 62.6 +/- 8.8% for ferrous sulfate and 59.2 +/- 10.6% for SFE-171, which were significantly effective at p < 0.01 compared to 43.4 +/- 10.5% for ferric orthophosphate. It thus turned out that SFE-171 was stable through industrial processing with Petit-Suisse cheese as the food vehicle and served as an iron fortifier equal to ferrous sulfate in bioavailability.

The role of zinc in the growth and development of children.

This review concerns the importance of zinc in growth, development, and cognitive function in children and the deleterious consequences of its deficiency on children's health. Possible strategies to overcome zinc deficiency and the results of some supplementation trials are discussed.

Bioavailability of microencapsulated ferrous sulfate in powdered milk produced from fortified fluid milk: a prophylactic study in rats.

OBJECTIVE: We investigated the iron bioavailability of microencapsulated ferrous sulfate (SFE-171) in a diet based on powdered milk by using the prophylactic method in rats. METHODS: The SFE-171 was added into fluid milk and industrially processed into powdered milk, which was then mixed in our laboratory with a normalized diet (17.2 +/- 2.1 mg Fe/kg). A reference standard diet using ferrous sulfate as iron-fortifying source (19.8 p+/- 2.9 mg Fe/kg) and a control diet without added iron (4.6 +/- 0.8 mg Fe/kg) were prepared in the laboratory in a similar way. These diets were administered to different groups of weaning rats for 28 d as the only solid nourishment. The iron bioavailability of the different sources was calculated as the relation between the mass of iron incorporated into hemoglobin during the treatment and the total iron intake per animal. RESULTS: The iron bioavailability values of SFE-171 and ferrous sulfate in the fortified diets were 41.6 +/- 6.6% and 42.6 +/- 4.2%, respectively; these results were significantly higher (P < 0.01) than the iron bioavailability of the control diet (28.8 +/- 8.1%). CONCLUSION: These results showed that iron-fortified powdered milk can be produced from fluid milk fortified with SFE-171. The bioavailability of SFE-171 in this rat model was not altered by the manufacturing process.