Addressing the Biochemical Foundations of a Glucose-Based "Trojan Horse"-Strategy to Boron Neutron Capture Therapy: From Chemical Synthesis to In Vitro Assessment

Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing toward the significant potential embedded in this approach

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

Synthesis and characterisation of Y2O3 co-doped with Co (III) or Eu (III) and Ba (II) or Ca (II)

Treball Final de Grau en Química. Codi: QU0943. Curs: 2014/2015Two years ago, the solid state chemistry research group at Jaume I University studied the possibility of developing new lanthanide-based inorganic pigments. The synthesis of M (II) (Ca or Ba) and Tb (III) co-doped Y2O3 ceramics by a modified Pechini method was reported to obtain new environmental friendly yellow pigments as an alternative to the toxic existing ones Different solid solutions were prepared to accomplish the best composition. The general structure was Y1.86−xMxTb0.14O3−x/2 where M represents calcium or barium ions and x ranges from 0.06 to 0.64. Spectroscopic measurements and thermal treatments showed that all samples incorporated terbium (IV) and terbium (III) ions into the Y2O3 structure. However, samples with calcium showed more intense yellow colouration due to the higher amount of terbium (IV) ions, whereas samples with barium were pale beige. It was concluded that the presence of calcium (rCa (II) (IC=6) = 114 pm) or barium (rBa (II) (IC=6)= 149 pm) alters the structure of the Y2O3 lattice varying the distance terbium-oxygen. A possible explanation to those results was that calcium, with a similar radius to yttrium (rY(III) (IC=6)= 104 pm) allows the charge transfer between terbium and oxygen ions and thus the oxidation of terbium ions, but barium is bigger than yttrium and the charge transfer transitions are hindered. Additional studies on the same structure were performed substituting terbium (IV) ions for other chromophores such as chromium (III) or iron (III). Results also showed a major deviation in colour for the samples containing calcium in the matrix. The present project deepens into the reasons behind the change in colour between samples doped with barium and calcium

Synthesis of novel carbohydrate delivery agents for Boron Neutron Capture Therapy

Boron neutron capture therapy is an emerging cancer treatment due to its unique capability to selectively remove tumor cells and spare healthy ones. The bottleneck of the technique are the current boron delivery agents which do not display enough selectivity towards cancer cells. To overcome this challenge our aim was to synthesize novel delivery agents entailing a glucose molecule functionalized with a polyhedral boron cluster in the form of dicarba-closo-ortho-dodecaborane which target glucose transporters overexpressed on the surface of cancer cells. Some carbohydrate conjugates have previously been prepared with positive biological response but none of them incorporate the boron cage at the sixth position. In this study, three end products were prepared: 6-O-o-carboranylmethyl-D-glucopyranose, methyl 6-O-o-carboranylmethyl-α-D-glucopyrano-side and methyl 6-O-o-carboranylmethyl-β-D-glucopyranoside starting from commercially available compounds. Multistep synthetic routes were investigated and the characterization of the intermediates and the target molecules by means of NMR spectroscopy and mass spectrometry is described in detail. The three final products have been summited for cytotoxicity studies and cellular accumulation studies in tumor cell lines

Addressing the Biochemical Foundations of a Glucose-Based "Trojan Horse"-Strategy to Boron Neutron Capture Therapy : From Chemical Synthesis to In Vitro Assessment

Boron neutron capture therapy (BNCT) for cancer is on the rise worldwide due to recent developments of in-hospital neutron accelerators which are expected to revolutionize patient treatments. There is an urgent need for improved boron delivery agents, and herein we have focused on studying the biochemical foundations upon which a successful GLUT1-targeting strategy to BNCT could be based. By combining synthesis and molecular modeling with affinity and cytotoxicity studies, we unravel the mechanisms behind the considerable potential of appropriately designed glucoconjugates as boron delivery agents for BNCT. In addition to addressing the biochemical premises of the approach in detail, we report on a hit glucoconjugate which displays good cytocompatibility, aqueous solubility, high transporter affinity, and, crucially, an exceptional boron delivery capacity in the in vitro assessment thereby pointing toward the significant potential embedded in this approach.Peer reviewe