RESUMEN
The greatest challenge standing in the way of effective in vivo siRNA delivery is creating a delivery vehicle that mediates a high degree of efficacy with a broad therapeutic window. Key structure-activity relationships of a poly(amide) polymer conjugate siRNA delivery platform were explored to discover the optimized polymer parameters that yield the highest activity of mRNA knockdown in the liver. At the same time, the poly(amide) backbone of the polymers allowed for the metabolism and clearance of the polymer from the body very quickly, which was established using radiolabeled polymers to demonstrate the time course of biodistribution and excretion from the body. The fast degradation and clearance of the polymers provided for very low toxicity at efficacious doses, and the therapeutic window of this poly(amide)-based siRNA delivery platform was shown to be much broader than a comparable polymer platform. The results of this work illustrate that the poly(amide) platform has a promising future in the development of a siRNA-based drug approved for human use.
Asunto(s)
Materiales Biocompatibles/síntesis química , Portadores de Fármacos/síntesis química , Hígado/metabolismo , Nylons/síntesis química , Péptidos/síntesis química , ARN Interferente Pequeño/administración & dosificación , Animales , Autorradiografía , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacocinética , Materiales Biocompatibles/toxicidad , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidad , Diseño de Fármacos , Estabilidad de Medicamentos , Femenino , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Hígado/diagnóstico por imagen , Macaca mulatta , Nylons/química , Nylons/farmacocinética , Nylons/toxicidad , Péptidos/química , Péptidos/farmacocinética , Péptidos/toxicidad , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacocinética , ARN Interferente Pequeño/toxicidad , Cintigrafía , Ratas Sprague-Dawley , Especificidad de la Especie , Relación Estructura-Actividad , Distribución TisularRESUMEN
The synthesis of the first high specific activity S-35-labeled hERG radioligand, [(35)S]MK-0499, for use in HTS assays of drug candidates for hERG interaction is described. The radioligand is prepared by [(35)S]sulfonylation of a high diastereomeric excess (de) aniline precursor prepared from unlabeled MK-0499.