Polymeric Nanomicelles Loaded with Anandamide and Their Renal Effects as a Therapeutic Alternative for Hypertension Treatment by Passive Targeting.

We have previously demonstrated significant in vitro natriuretic effects of anandamide (AEA) nanoformulation in polymeric nanoparticles, whose size prevents their accumulation in organs, such as the kidneys. Therefore, it is of particular interest to design and test nanostructures that can pharmacologically accumulate in these organs. In this regard, we prepared and characterized polymeric nanomicelles (~14 and 40 nm). Likewise, their biodistribution was determined. Spontaneously hypertensive rats (SHR) and normotensive rats (WKY), n = 3 per group, were divided into five treatment conditions: control, sham, free AEA freshly dispersed in aqueous solution or 24 h after its dispersion, and AEA encapsulated in nanomicelles. The kidneys were the main site of accumulation of the nanoformulation after 24 h. Freshly dispersed free AEA showed its classical triphasic response in SHR, which was absent from all other treatments. Nanoformulated AEA produced a sustained antihypertensive effect over 2 h, accompanied by a significant increase in fractional sodium excretion (FSE %). These effects were not observed in WKY, sham, or free AEA-treated rats after 24 h of its aqueous dispersion. Without precedent, we demonstrate in vivo natriuretic, diuretic, and hypotensive effects of AEA nanoformulation in polymeric nanomicelles, suggesting its possible use as a new antihypertensive agent with intravenous administration and passive renal accumulation.

Inhalable Mannosylated Rifampicin-Curcumin Co-Loaded Nanomicelles with Enhanced In Vitro Antimicrobial Efficacy for an Optimized Pulmonary Tuberculosis Therapy.

Among respiratory infections, tuberculosis was the second deadliest infectious disease in 2020 behind COVID-19. Inhalable nanocarriers offer the possibility of actively targeting anti-tuberculosis drugs to the lungs, especially to alveolar macrophages (cellular reservoirs of the Mycobacterium tuberculosis). Our strategy was based on the development of a mannose-decorated micellar nanoformulation based in Soluplus® to co-encapsulate rifampicin and curcumin. The former is one of the most effective anti-tuberculosis first-line drugs, while curcumin has demonstrated potential anti-mycobacterial properties. Mannose-coated rifampicin (10 mg/mL)-curcumin (5 mg/mL)-loaded polymeric micelles (10% w/v) demonstrated excellent colloidal properties with micellar size ~108 ± 1 nm after freeze-drying, and they remain stable under dilution in simulated interstitial lung fluid. Drug-loaded polymeric micelles were suitable for drug delivery to the deep lung with lung accumulation, according to the in vitro nebulization studies and the in vivo biodistribution assays of radiolabeled (99mTc) polymeric micelles, respectively. Hence, the nanoformulation did not exhibit hemolytic potential. Interestingly, the addition of mannose significantly improved (5.2-fold) the microbicidal efficacy against Mycobacterium tuberculosis H37Rv of the drug-co-loaded systems in comparison with their counterpart mannose-free polymeric micelles. Thus, this novel inhaled nanoformulation has demonstrated its potential for active drug delivery in pulmonary tuberculosis therapy.

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.

Radioactive treatment of a murine melanoma using a (32)P-patch.

OBJECTIVE: To evaluate the therapeutic effects of a (32)P-patch in the treatment of a murine melanoma. MATERIALS AND METHODS: Thirty male C57BL6 mice were divided into two groups: treated and control. Superficial tumors were induced in both groups by injecting B16F1 melanoma at about 10 cells/mouse subcutaneously. Tumors developed 10-15 days after transplantation and the (32)P-patch was applied on palpable tumors of the treated group. Tumor growth was followed up in both groups by measuring tumor size with a caliper. After the follow-up period, the animals were killed and tumor samples of the treated and control groups were collected for histological study by preparing paraffin sections stained with hematoxylin-eosin. RESULTS: The (32)P-patch showed the absence of radioactivity leakage in vitro and the homogeneous distribution of the radionuclide. The skin surface at the application site of the (32)P-patch appeared hairless, and erythema developed, but reversed to normal after a few days in the treated group. Control of tumor growth was achieved in the treated group compared with the control group, although complete remission did not occur. CONCLUSION: The (32)P-patch tested for the treatment of a murine melanoma model showed its efficacy, as tumor growth was retarded after application of the patch Nevertheless, adjustment of some therapeutic parameters and/or combining the patch with other treatment modalities may be necessary to achieve complete regression. The P-patch represents a powerful tool to individualize the treatment of melanoma.

Bioevaluation of 32P patch designed for the treatment of skin diseases.

OBJECTIVE: The objective of this study was to design and evaluate a 32P patch for the treatment of skin diseases. MATERIALS AND METHODS: The patch was prepared from chromic phosphate 32P and silicone. Bioelimination and biodistribution in healthy and treated animals, and the therapeutic efficacy of two treatment schemes (single dose and fractionated dose) in an animal model of skin cancer were studied. RESULTS: Based on the bioelimination and biodistribution studies, no leakage of 32P from the patch was observed. The treated tumors reduced their mean diameter compared to controls. The single-dose therapeutic scheme showed a higher number of complete and partial remissions compared to the fractionated scheme. These results were confirmed by histopathological analysis of the samples. CONCLUSION: The 32P patch was designed and produced according to specifications for the treatment of superficial lesions of the skin. Although the 32P patch is an open source, it behaves like a sealed one for use in brachytherapy treatments.

Modificación de la biodistribución de los glóbulos rojos marcados con 99mtc en la anemia ferropénica / Alteration in the biodistribution of 99mTc-RBC in an animal model of ferropenic anemia

Objetivo: Evaluar la biodistribución de 99mTc-GR en un modelo animal de anemia ferropénica. Materiales y métodos: Se utilizaron ratas alimentadas con dietas con diferente contenido de Fe: grupo A (anemia severa, 6.5 ppm), grupo B (anemia moderada, 18 ppm) y grupo C (control, 100 ppm). Se realizó la marcación in vivo de los 99mTc-GR y se evaluó la EBM y su biodistribución a los 30 minutos y a las 24 horas en sangre, hígado, bazo, tracto gastrointestinal, riñones, corazón y pulmones. Los resultados se expresaron como concentración de actividad porcentual (CA por ciento). Resultados: En todos los grupos la EBM fue superior al 98 por ciento. Se observó un aumento de CA por ciento en bazo a las 24 horas en el grupo A, acompañado de una disminución de la CA por ciento del pool sanguíneo posiblemente por aumento del secuestro esplénico de los GR. En los tres grupos hubo un aumento de la CA por ciento en riñón a las 24 horas. Conclusión: La biodistribución de 99mTc-GR se ve modificada en la anemia ferropénica.

Aim: To evaluate the biodistribution of 99mTc-RBC in an animal model of ferropenic anemia. Materials and methods: We used rats which were fed with different iron contents diets: group A (severeanemia, 6.5 ppm), group B (moderate anemia, 18 ppm) and group C (control, 100 ppm). We performed the in vivo labeling of RBC and evaluated the labeling efficiency and the biodistribution at 30 minutes and 24 hours in blood, liver, spleen, gastrointestinal tract, kidneys, heart and lungs. The results were expressed as activity concentration percentage (CA percent). Results: In all groups the labeling efficiency was higher than 98 percent. We observed an increase of CA percent in spleen at 24 hours in the group A, followed by a decrease of CA percent in blood. This could be a consequence of an increase of splenic uptake of RBC. An increase in CA percent in kidney was obtained at 24 hours for all the groups. Conclusion: An alteration in the RBC biodistribution is observed in an animal model of ferropenic anemia.

Fortification strategies to combat zinc and iron deficiency.

Food fortification is an important strategy to combat iron and zinc deficiency. This review covers the basic concepts of food fortification, as well as its advantages and disadvantages. The main characteristics of the most common zinc and iron compounds used in this procedure are also analyzed.