Anticancer and antiangiogenic activity of surfactant-free nanoparticles based on self-assembled polymeric derivatives of vitamin E: structure-activity relationship.

α-Tocopheryl succinate (α-TOS) is a well-known mitochondrially targeted anticancer compound, however, it is highly hydrophobic and toxic. In order to improve its activity and reduce its toxicity, new surfactant-free biologically active nanoparticles (NP) were synthesized. A methacrylic derivative of α-TOS (MTOS) was prepared and incorporated in amphiphilic pseudoblock copolymers when copolymerized with N-vinylpyrrolidone (VP) by free radical polymerization (poly(VP-co-MTOS)). The selected poly(VP-co-MTOS) copolymers formed surfactant-free NP by nanoprecipitation with sizes between 96 and 220 nm and narrow size distribution, and the in vitro biological activity was tested. In order to understand the structure-activity relationship three other methacrylic monomers were synthesized and characterized: MVE did not have the succinate group, SPHY did not have the chromanol ring, and MPHY did not have both the succinate group and the chromanol ring. The corresponding families of copolymers (poly(VP-co-MVE), poly(VP-co-SPHY), and poly(VP-co-MPHY)) were synthesized and characterized, and their biological activity was compared to poly(VP-co-MTOS). Both poly(VP-co-MTOS) and poly(VP-co-MVE) presented triple action: reduced cell viability of cancer cells with little or no harm to normal cells (anticancer), reduced viability of proliferating endothelial cells with little or no harm to quiescent endothelial cells (antiangiogenic), and efficiently encapsulated hydrophobic molecules (nanocarrier). The anticancer and antiangiogenic activity of the synthesized copolymers is demonstrated as the active compound (vitamin E or α-tocopheryl succinate) do not need to be cleaved to trigger the biological action targeting ubiquinone binding sites of complex II. Poly(VP-co-SPHY) and poly(VP-co-MPHY) also formed surfactant-free NP that were also endocyted by the assayed cells; however, these NP did not selectively reduce cell viability of cancer cells. Therefore, the chromanol ring of the vitamin E analogues has an important role in the biological activity of the copolymers. Moreover, when succinate moiety is substituted and vitamin E is directly linked to the macromolecular chain through an ester bond, the biological activity is maintained.

Timing of elective tracheotomy and duration of mechanical ventilation among patients admitted to intensive care with severe COVID-19: A multicenter prospective cohort study.

BACKGROUND: Optimal timing for tracheotomy for critically ill COVID-19 patients requiring invasive mechanical ventilation (IMV) is not established. METHODS: Multicenter prospective cohort including all COVID-19 patients admitted to intensive care units (ICUs) in 36 hospitals who required tracheotomy during first pandemic wave. With a target emulation trial framework, we studied the causal effects of early (7-10 days) versus late (>10 days) tracheotomy (LT) on time from tracheotomy to weaning, postoperative mortality, and tracheotomy complications. RESULTS: Of 696 patients, 20.4% received early tracheotomy (ET). ET was associated with faster weaning (hazard ratio [HR] [95% confidence interval, CI]: 1.25 [1.00-1.56]) without differences in mortality (HR [95% CI]: 0.85 [0.60-1.21]) or complications (adjusted rate ratio [95% CI]: 0.56 [0.23-1.33]). CONCLUSIONS: ET had a similar or lower post-tracheotomy weaning time than LT, potentially shortening IMV and ICU stays, without changing complication or mortality rates in COVID-19 patients.

α-Tocopheryl Succinate-Based Polymeric Nanoparticles for the Treatment of Head and Neck Squamous Cell Carcinoma.

The aim of this work is to study, in an in vitro head and neck squamous cell carcinomas model the anti-angiogenic and anti-migratory properties of self-assembled polymeric nanoparticles (NPs) with demonstrated selective anticancer activity. The NPs are based on α-tocopheryl succinate (α-TOS) encapsulated in the hydrophobic core of the NPs. We analyzed the effect of the newly synthetized α-TOS-loaded NPs in proliferating endothelial cells and hypopharynx carcinoma squamous cells and measured markers of angiogenesis, apoptosis and reactive oxygen species (ROS). α-TOS-loaded NPs suppressed angiogenesis by inducing accumulation of ROS and inducing apoptosis of proliferating endothelial cells. These NPs also decrease the number and quality of capillary-like tubes in an in vitro three-dimensional (3D) experiment, decrease the production of the pro-angiogenic vascular endothelial growth factor and down-regulate the expression of its receptor. The anti-migratory efficacy of α-TOS is corroborated in hypopharynx carcinoma cells by decreasing the secretion of matrix metalloproteases 2 and 9 (MMP-2 and MMP-9) and inhibiting cell migration. These results confirm that α-TOS-based NPs not only present anticancer properties, but also antiangiogenic properties, therefore making them promising candidates for multi-active combinatorial anticancer therapy.

Mitochondrially Targeted Nanoparticles Based on α-TOS for the Selective Cancer Treatment.

The aim of this work is the preparation of an active nanovehicle for the effective administration of α-tocopheryl succinate (α-TOS). α-TOS is loaded in the core of nanoparticles (NPs) based on amphiphilic pseudo-block copolymers of N-vinyl pyrrolidone and a methacrylic derivative of α-TOS. These well-defined spherical NPs have sizes below 165 nm and high encapsulation efficiencies. In vitro activity of NPs is tested in hypopharynx squamous carcinoma (FaDu) cells and nonmalignant epithelial cells, demonstrating that the presence of additional α-TOS significantly enhances its antiproliferative activity; however, a range of selective concentrations is observed. These NPs induce apoptosis of FaDu cells by activating the mitochondria death pathway (via caspase-9). Both loaded and unloaded NPs act via complex II and produce high levels of reactive oxygen species that trigger apoptosis. Additionally, these NPs effectively suppress the vascular endothelial growth factor (VEGF) expression of human umbilical vein endothelial cells (HUVECs). These results open the possibility to use this promising nanoformulation as an α-TOS delivery system for the effective cancer treatment, effectively resolving the current limitations of free α-TOS administration.

Control of vertigo after intratympanic corticoid therapy for unilateral Ménière's disease: a comparison of weekly versus daily fixed protocols.

OBJECTIVE: This study aimed to evaluate the long-term effects of intratympanic corticoid therapy on vertigo control and hearing changes. STUDY DESIGN: The study design was retrospective. SETTING: Tertiary medical centers. PATIENTS: Fifty-six patients with definite unilateral Ménière's disease, diagnosed using the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guidelines, were included. Twenty-two patients were treated with a fixed protocol of 3 consecutive daily intratympanic injections of a 4 mg/ml dexamethasone commercial preparation. Thirty-four patients were treated with a fixed protocol of 3 consecutive weekly injections of the same preparation. MAIN OUTCOME MEASURE: The 1995 AAO-HNS criteria for reporting treatment outcome in MD were used. The treatment results were expressed in terms of vertigo control. A Kaplan-Meier analysis was used to evaluate the control of vertigo over a 2-year period. Separate curves were created depending on the protocol used and the class of vertigo control obtained. RESULTS: Complete vertigo control (class A) was achieved in 40.9% and 44.1% of patients on the daily and weekly protocols, respectively. Substantial vertigo control was obtained in an additional 18.2% and 14.7% of patients on the daily and weekly protocols, respectively. No significant differences were found between the 2 fixed protocols. CONCLUSION: Intratympanic dexamethasone (4 mg/ml) perfusion provides an alternative treatment for definite Ménière's disease. The Kaplan-Meier analysis was useful for analyzing the control of vertigo and the recurrence of Ménière's disease.