Síntesis de los péptidos TAT, DV3 y BH3 liberación por irradiación del péptido BH3 con actividad antitumoral funcionalizado a nanopartículas de oro

Tesis (Licenciado en Química)Proyecto FONDECYT No.11130494Proyecto FONDAP 15130011Proyecto UNAB DI 1309-16/RLa nanotecnología ha contribuido al desarrollo de nuevas modalidades terapéuticas para el tratamiento del cáncer, entre otras enfermedades. Se usan nanopartículas (NPs) como portadores para el suministro eficiente de compuestos bioactivos a los sitios de acción deseados. En particular, las nanopartículas de oro (NPAu) se han utilizado para la liberación de fármacos controlada espacialmente, porque aumentan la selectividad y previenen efectos secundarios adversos. Las NPAu tienen la capacidad de absorber la radiación electromagnética y disipar la energía localmente (nanométricamente). Esto facilita la llamada "cirugía molecular", en la que las células malignas se eliminan selectivamente, y también permite la liberación de un compuesto antitumoral en un sitio específico en el cuerpo. Esta alta absorción de energía resulta de la interacción de NPAu con radiación electromagnética que causa la oscilación coherente de electrones en la superficie de la nanopartícula (NP), que es un fenómeno conocido como resonancia de plasmón de superficie (SPR) (SPR; del inglés Surface Plasmon Resonance). La SPR ocurre a diferentes longitudes de onda y depende de la forma, tamaño y composición de NPAu. Las nanobarras de oro (NPAu-b) presentan bandas SPR en longitudes de onda del infrarrojo cercano (NIR). Aunque se ha demostrado el uso de NPAu junto con la radiación NIR para el control espacial y temporal de la liberación del fármaco, una limitación importante es que los fármacos utilizados no estuvieran unidos covalentemente a NPs y por lo tanto pudieran ser liberados abruptamente en cualquier parte del cuerpo causando efectos indeseables (por ejemplo, efectos secundarios en la terapia antitumoral). El objetivo de esta unidad de investigación es el de obtener NPAu-b multifuncionalizadas con tres péptidos; TAT, DV3 y BH3. El péptido TAT es capaz de penetrar membranas, mientras que el péptido DV3 se une a un receptor ubicado en las células tumorales y finalmente el péptido BH3 que tiene actividad antitumoral, el cual fue unido covalentemente a la superficie de la NPAu-b usando un espaciador del tipo Diels-Alder. Las NPAu-b multifuncionalizadas fueron irradiadas produciendo una reacción retro Diels-Alder liberando el péptido antitumoral BH

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. METHODS: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. FINDINGS: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2-11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75-1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58-1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91-1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70-1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11-0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50-0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38-0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45-0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. INTERPRETATION: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. FUNDING: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health