Optimization of micelle-encapsulated extremely small sized iron oxide nanoparticles as a T1 contrast imaging agent: biodistribution and safety profile.

BACKGROUND: Iron oxide nanoparticles (IONPs) have been cleared by the Food and Drug Administration (FDA) for various clinical applications, such as tumor-targeted imaging, hyperthermia therapy, drug delivery, and live-cell tracking. However, the application of IONPs as T1 contrast agents has been restricted due to their high r2 values and r2/r1 ratios, which limit their effectiveness in T1 contrast enhancement. Notably, IONPs with diameters smaller than 5 nm, referred to as extremely small-sized IONPs (ESIONs), have demonstrated potential in overcoming these limitations. To advance the clinical application of ESIONs as T1 contrast agents, we have refined a scale-up process for micelle encapsulation aimed at improving the hydrophilization of ESIONs, and have carried out comprehensive in vivo biodistribution and preclinical toxicity assessments. RESULTS: The optimization of the scale-up micelle-encapsulation process, specifically employing Tween60 at a concentration of 10% v/v, resulted in ESIONs that were uniformly hydrophilized, with an average size of 9.35 nm and a high purification yield. Stability tests showed that these ESIONs maintained consistent size over extended storage periods and dispersed effectively in blood and serum-mimicking environments. Relaxivity measurements indicated an r1 value of 3.43 mM- 1s- 1 and a favorable r2/r1 ratio of 5.36, suggesting their potential as T1 contrast agents. Biodistribution studies revealed that the ESIONs had extended circulation times in the bloodstream and were primarily cleared via the hepatobiliary route, with negligible renal excretion. We monitored blood clearance and organ distribution using positron emission tomography and magnetic resonance imaging (MRI). Additionally, MRI signal variations in a dose-dependent manner highlighted different behaviors at varying ESIONs concentrations, implying that optimal dosages might be specific to the intended imaging application. Preclinical safety evaluations indicated that ESIONs were tolerable in rats at doses up to 25 mg/kg. CONCLUSIONS: This study effectively optimized a scale-up process for the micelle encapsulation of ESIONs, leading to the production of hydrophilic ESIONs at gram-scale levels. These optimized ESIONs showcased properties conducive to T1 contrast imaging, such as elevated r1 relaxivity and a reduced r2/r1 ratio. Biodistribution study underscored their prolonged bloodstream presence and efficient clearance through the liver and bile, without significant renal involvement. The preclinical toxicity tests affirmed the safety of the ESIONs, supporting their potential use as T1 contrast agent with versatile clinical application.

The effect of a 4-week, remotely administered, post-exercise passive leg heating intervention on determinants of endurance performance.

PURPOSE: Post-exercise passive heating has been reported to augment adaptations associated with endurance training. The current study evaluated the effect of a 4-week remotely administered, post-exercise passive leg heating protocol, using an electrically heated layering ensemble, on determinants of endurance performance. METHODS: Thirty recreationally trained participants were randomly allocated to either a post-exercise passive leg heating (PAH, n = 16) or unsupervised training only control group (CON, n = 14). The PAH group wore the passive heating ensemble for 90-120 min/day, completing a total of 20 (16 post-exercise and 4 stand-alone leg heating) sessions across 4 weeks. Whole-body (peak oxygen uptake, gas exchange threshold, gross efficiency and pulmonary oxygen uptake kinetics), single-leg exercise (critical torque and NIRS-derived muscle oxygenation), resting vascular characteristics (flow-mediated dilation) and angiogenic blood measures (nitrate, vascular endothelial growth factor and hypoxia inducible factor 1-α) were recorded to characterize the endurance phenotype. All measures were assessed before (PRE), at 2 weeks (MID) and after (POST) the intervention. RESULTS: There was no effect of the intervention on test of whole-body endurance capacity, vascular function or blood markers (p > 0.05). However, oxygen kinetics were adversely affected by PAH, denoted by a slowing of the phase II time constant; τ (p = 0.02). Furthermore, critical torque-deoxygenation ratio was improved in CON relative to PAH (p = 0.03). CONCLUSION: We have demonstrated that PAH had no ergogenic benefit but instead elicited some unfavourable effects on sub-maximal exercise characteristics in recreationally trained individuals.

Conventional extraction of fucoidan from Irish brown seaweed Fucus vesiculosus followed by ultrasound-assisted depolymerization.

Fucoidan has attracted considerable attention from scientists and pharmaceutical companies due to its antioxidant, anticoagulant, anti-inflammatory, anti-tumor, and health-enhancing properties. However, the extraction of fucoidan from seaweeds often involves the use of harsh chemicals, which necessitates the search for alternative solvents. Additionally, the high viscosity and low cell permeability of high molecular weight (Mw) fucoidan can limit its effectiveness in drug action, while lower Mw fractions exhibit increased biological activity and are also utilized as dietary supplements. The study aimed to (1) extract fucoidan from the seaweed Fucus vesiculosus (FV) using an environmentally friendly solvent and compare it with the most commonly used extraction solvent, hydrochloric acid, and (2) assess the impact of ultrasound-assisted depolymerization on reducing the molecular weight of the fucoidan extracts and examine the cytotoxic effect of different molecular weight fractions. The findings indicated that the green depolymerization solvent, in conjunction with a brief ultrasound treatment, effectively reduced the molecular weight. Moreover, a significant decrease in cell viability was observed in selected samples, indicating potential anticancer properties. As a result, ultrasound was determined to be an effective method for depolymerizing crude fucoidan from Fucus Vesiculosus seaweed.