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Background: Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device that provides life-saving complete respiratory and cardiac support in patients with cardiorespiratory failure. The majority of drugs prescribed to patients on ECMO lack a dosing strategy optimized for ECMO patients. Several studies demonstrated that dosing is different in this population because the ECMO circuit components can adsorb drugs and affect drug exposure substantially. Saturation of ECMO circuit components by drug disposition has been posited but has not been proven. In this study, we have attempted to determine if propofol adsorption is saturable in ex vivo ECMO circuits. Methods: We injected ex vivo ECMO circuits with propofol, a drug that is highly adsorbed to the ECMO circuit components. Propofol was injected as a bolus dose (50 μg/mL) and a continuous infusion dose (6 mg/h) to investigate the saturation of the ECMO circuit. Results: After the bolus dose, only 27% of propofol was recovered after 30 minutes which is as expected. However, >80% propofol was recovered after the infusion dose which persisted even when the infusion dose was discontinued. Conclusion: Our results suggest that if ECMO circuits are dosed directly with propofol, drug adsorption can be eliminated as a cause for altered drug exposure. Field of Research: Artificial Lung/ECMO

Eukaryotic elongation factor 2 kinase (eEF2K) is overexpressed in a wide variety of cancer types, including hormone receptor positive breast cancer. Targeting of eEF2K has demonstrated anti-tumor activity with the potential of enhanced treatment efficacy in combination with chemotherapy. Here, we describe gold nanoparticle (AuNPs) based delivery of siRNAs enabling eEF2K knockdown in combination with doxorubicin (DOX) to estrogen receptor (ER) positive breast cancer (MCF7) cells. The siRNAs and DOX were co-delivered on the same NP or delivered on separate NPs in a mixture at various siRNA:drug ratios. Effective inhibition of eEF2K expression was provided together with delivery of DOX leading to the enhanced inhibition of cancer cell proliferation compared to DOX delivery alone. siRNA:DOX ratio of 1:2.25 demonstrated synergistic inhibition of cancer cell proliferation. Delivery of eEF2K siRNAs and DOX on separate NPs showed anti-proliferative activity superior to co-delivery on the same NP. These results suggest that eEF2K inhibition enhanced the anticancer activity of chemotherapy on MCF7 breast cancer cells and that the delivery method of the therapeutics had an influence on cytotoxicity. [ABSTRACT FROM AUTHOR]

Titanium dioxide nanoparticles (TiO2 NPs) have been widely used in food, cosmetics, and biomedical research. However, human safety following exposure to TiO2 NPs remains to be fully understood. The aim of this study was to evaluate the in vitro safety and toxicity of TiO2 NPs synthesized via the Stöber method under different washing and temperature conditions. TiO2 NPs were characterized by their size, shape, surface charge, surface area, crystalline pattern, and band gap. Biological studies were conducted on phagocytic (RAW 264.7) and non-phagocytic (HEK-239) cells. Results showed that washing amorphous as-prepared TiO2 NPs (T1) with ethanol while applying heat at 550 °C (T2) resulted in a reduction in the surface area and charge compared to washing with water (T3) or a higher temperature (800 °C) (T4) and influenced the formation of crystalline structures with the anatase phase in T2 and T3 and rutile/anatase mixture in T4. Biological and toxicological responses varied among TiO2 NPs. T1 was associated with significant cellular internalization and toxicity in both cell types compared to other TiO2 NPs. Furthermore, the formation of the crystalline structure induced toxicity independent of other physicochemical properties. Compared with anatase, the rutile phase (T4) reduced cellular internalization and toxicity. However, comparable levels of reactive oxygen species were generated following exposure to the different types of TiO2, indicating that toxicity is partially driven via non-oxidative pathways. TiO2 NPs were able to trigger an inflammatory response, with varying trends among the two tested cell types. Together, the findings emphasize the importance of standardizing engineered nanomaterial synthesis conditions and evaluating the associated biological and toxicological consequences arising from changes in synthesis conditions. [ABSTRACT FROM AUTHOR]

Background: Altered neovascularity is typically observed in chronic inflammatory diseases with overlapping pathophysiology to that observed in chronic rhinosinusitis (CRS). However, characterization of these inflammatory‐induced vascular‐mediated changes in CRS is limited. Understanding the underlying vascular changes in CRS will allow for strategic design and development of new drug‐delivery technologies that exploit vascular permeability for increased extravasation into the target sinonasal tissues. Methods: Patients with CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP) and non‐CRS controls were enrolled in this prospective, observational study. The extent of angiogenesis in tissue was characterized using immunohistochemical and multiplex gene expression analyses. Vascular permeability, interendothelial junction structures, and endothelial barrier morphology were evaluated using transmission electron microscopy. Results: Sinonasal vascularity was increased significantly in CRSsNP and CRSwNP (p < 0.05) when compared with controls, as assessed by enumerating the platelet endothelial cell adhesion molecule (PECAM‐1)‒positive blood vessels. Pro‐angiogenic gene expression, including PECAM1 and platelet‐activating factor receptor, was elevated significantly in patients with CRSwNP when compared with controls (p < 0.05). The fenestration sizes between endothelial cells (17‐280 nm) were larger in CRSwNP compared with CRSsNP (10‐33 nm) patients and controls (4‐12 nm). Global thinning of the endothelial cell lining was observed in CRS patients but not in controls. Conclusion: Significant increases in vascularity, the pro‐angiogenic gene, and protein expression and blood vessel morphogenesis were observed in CRS patients compared with controls. In addition, fenestration sizes between interendothelial junction structures were larger in CRS patients than in controls, suggesting inflammation‐driven vascular dysregulation in CRS pathology. [ABSTRACT FROM AUTHOR]

Small non-coding RNAs (e.g. siRNA, miRNA) are involved in a variety of melanocyte-associated skin conditions and act as drivers for alterations in gene expression within melanocytes. These molecular changes can potentially affect the cellular stability of melanocytes and promote their oncogenic transformation. Thus, small RNAs can be considered as therapeutic targets for these conditions, however, their topical delivery to the melanocytes through the epidermal barrier is challenging. We synthesized and extensively evaluated ultradeformable cationic liposome (UCLs) carriers complexed with synthetic microRNAs (miR211-5p; UCL-211) for transdermal delivery to melanocytes. UCL-211 complexes were characterized for their physicochemical properties, encapsulation efficiency, and deformability, which revealed a significant advantage over conventional liposomal carriers. Increased expression of miR211-5p stabilizes melanocytic nevi and keeps them in growth-arrested state. We did a comprehensive assessment of cellular delivery, and biological activity of the miR211-5p carried by UCL-211 in vitro and their permeation through the epidermis of intact skin using ex vivo human skin tissue explants. We also demonstrated, in vivo , that topical delivery of miR211-5p by UCL-211 stabilized BRAFV600E+ nevi melanocytes in a benign nevi state., Competing Interests: Competing interests: The authors have no competing interests to declare.