Assuntos
Neoplasias da Mama/diagnóstico , Carcinoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Abdome , Dorso , Neoplasias da Mama/patologia , Carcinoma/secundário , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Cutâneas/secundário , TóraxRESUMO
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.
Assuntos
Materiais Biocompatíveis/síntese química , Portadores de Fármacos/síntese química , Fígado/metabolismo , Nylons/síntese química , Peptídeos/síntese química , RNA Interferente Pequeno/administração & dosagem , Animais , Autorradiografia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacocinética , Materiais Biocompatíveis/toxicidade , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidade , Desenho de Fármacos , Estabilidade de Medicamentos , Feminino , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Fígado/diagnóstico por imagem , Macaca mulatta , Nylons/química , Nylons/farmacocinética , Nylons/toxicidade , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/toxicidade , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacocinética , RNA Interferente Pequeno/toxicidade , Cintilografia , Ratos Sprague-Dawley , Especificidade da Espécie , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
A series of amphiphilic, biodegradable polypeptide copolymers were prepared for the delivery of siRNA (short interfering ribonucleic acid). The molecular weight (or polymer chain length) of the linear polymer was controlled by reaction stoichiometry for the 11.5, 17.2, and 24.6 kDa polypeptides, and the highest molecular weight polypeptide was prepared using a sequential addition method to obtain a polypeptide having a molecular weight of 38.6 kDa. These polymers were used to prepare polymer conjugate systems designed to target and deliver an apolipoprotein B (ApoB) siRNA to hepatocyte cells and to help delineate the effect of polymer molecular weight or polymer chain length on siRNA delivery in vivo. A clear trend in increasing potency was found with increasing molecular weight of the polymers examined (at a constant polymer:siRNA (w/w) ratio), with minimal toxicity found. Furthermore, the biodegradability of these polymer conjugates was examined and demonstrates the potential of these systems as siRNA delivery vectors.