RESUMEN
Primary intracerebral hemorrhage (ICH) is a leading cause of long-term disability and death worldwide. Drug delivery vehicles to treat ICH are less than satisfactory because of their short circulation lives, lack of specific targeting to the hemorrhagic site, and poor control of drug release. To exploit the fact that metal ions such as Fe2+ are more abundant in peri-hematomal tissue than in healthy tissue because of red blood cell lysis, we developed a metal ion-responsive nanocarrier based on a phosphonated calix[4]arene derivative in order to deliver the neuroprotective agent dauricine (DRC) specifically to sites of primary and secondary brain injury. The potential of the dauricine-loaded nanocarriers for ICH therapy was systematically evaluated in vitro and in mouse models of autologous whole blood double infusion. The nanocarriers significantly reduced brain water content, restored blood-brain barrier integrity and attenuated neurological deficits by inhibiting the activation of glial cells, infiltration by neutrophils as well as production of pro-inflammatory factors (IL-1ß, IL-6, TNF-α) and matrix-metalloprotease-9. These results suggest that our dauricine-loaded nanocarriers can improve neurological outcomes in an animal model of ICH by reducing inflammatory injury and inhibiting apoptosis and ferroptosis.
Asunto(s)
Bencilisoquinolinas/química , Calixarenos/química , Hemorragia Cerebral/patología , Portadores de Fármacos/química , Metales/química , Nanoestructuras/química , Fármacos Neuroprotectores/química , Fenoles/química , Tetrahidroisoquinolinas/química , Animales , Bencilisoquinolinas/administración & dosificación , Bencilisoquinolinas/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Hemorragia Cerebral/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Interleucina-1beta/metabolismo , Iones/química , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/farmacología , Organofosfonatos/química , Especies Reactivas de Oxígeno/metabolismo , Tetrahidroisoquinolinas/administración & dosificación , Tetrahidroisoquinolinas/farmacologíaRESUMEN
Calix[4]arene derivative (1), bearing four α-l-C-fucosyl units linked via a flexible spacer, and a monomeric analogous (2) bearing a single moiety of fucose, were synthesized. Compounds 1 and 2 were assayed for antibiofilm activity against Pseudomonas aeruginosa (Gram-) and Staphylococcus epidermidis (Gram+). The macrocyclic compound 1 showed very high percentage of biofilm inhibition against two different bacterial strains while compound 2, which does not possess a macrocyclic structure, showed only moderate biofilm inhibition against P. aeruginosa and no biofilm inhibition against S. epidermidis. The fucose multivalent derivative could be a new broad-spectrum antibiofilm agent.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Calixarenos/síntesis química , Calixarenos/farmacología , Fucosa/química , Fenoles/síntesis química , Fenoles/farmacología , Antibacterianos/química , Biopelículas/crecimiento & desarrollo , Calixarenos/química , Técnicas de Química Sintética , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Fenoles/química , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/fisiología , Staphylococcus epidermidis/efectos de los fármacos , Staphylococcus epidermidis/fisiologíaRESUMEN
Herein, the report on a new class of self-healing and pH/temperature responsive mixed solvent (ethanol and water) gels shows unusual mechanical properties to resist slicing, sustain high compression, and withstand stretching as evidenced by the cutting breaking stress, the fracture compressive stress, and the stretching ratio of one of the gels as obtained can reach or exceed 26.4 MPa, 9.2 MPa, and ≈5 times, respectively. The gels are designed by introducing dynamic covalent bond, acylhydrazone, which is believed to combine the merits of conventional chemical bonds and those of supramolecular interactions. Specifically, a hydrazide-modified calix[4]arene derivative and linear benzaldehyde-terminated poly(ethylene glycol)s are synthesized and used as reactive components to build gel networks. Interestingly, acid-degradable hydrogel can be obtained via natural drying of the mixed solvent gel first and then swelling in pure water.