RESUMO
Peptides are an important class of endogenous ligands that regulate key biological cascades. As such, peptides represent a promising therapeutic class with the potential to alleviate many severe disease states. Despite their therapeutic potential, peptides frequently pose drug delivery challenges to scientists. This review introduces the physicochemical, biophysical, biopharmaceutical, and formulation developability aspects of peptides pertinent to the drug discovery-to-development interface. It introduces the relevance of these properties with respect to the delivery modalities available for peptide pharmaceuticals, with the parenteral route being the most prevalent route of administration. This review also presents characterization strategies for oral delivery of peptides with the aim of illuminating developability issues with the drug candidate. A brief overview of other routes of administration, including inhaled, transdermal, and intranasal routes, is provided as these routes are generally preferred by patients over injectables. Finally, this review presents formulation techniques to mitigate some of the developability obstacles associated with peptide delivery. The authors emphasize opportunities for the thoughtful application of pharmaceutical science to the development of peptide drugs and to the general advancement of this promising class of pharmaceuticals.
Assuntos
Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Peptídeos/administração & dosagem , Química Farmacêutica/métodos , Vias de Administração de Medicamentos , Humanos , Preferência do PacienteRESUMO
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.
Assuntos
Apolipoproteínas B/genética , Ornitina/química , Peptídeos/administração & dosagem , Fenilalanina/química , Polímeros/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Animais , Feminino , Fígado/metabolismo , Peso Molecular , Peptídeos/química , Polímeros/química , RNA Mensageiro/genética , RNA Interferente Pequeno/química , Ratos Sprague-DawleyRESUMO
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
Efficient siRNA delivery is dependent not only on the ability of the delivery vehicle to target a specific organ but also on its ability to enable siRNA entry into the cytoplasm of the target cells. Polymers with endosomolytic properties are increasingly being used as siRNA delivery vehicles due to their potential to facilitate endosomal escape and intracellular delivery. Addition of disulfide bonds in the backbone of these polymers was expected to provide degradability through reduction by glutathione in cytosol. This paper describes the synthesis of new endosomolytic bioreducible poly(amido amine disulfide) polymers whose lytic potential can be masked at physiological pH, but can be restored at acidic endosomal pH. These polymer conjugates gave good in vitro knockdown (KD) and did not demonstrate cytotoxicity in a MTS assay. Efficient mRNA KD for apolipoprotein B in mouse liver was observed with these polyconjugates following intravenous dosing.