RESUMO
Peptide drugs delivered orally need to be protected from degradation for achieving their functions. To fulfill the complicated task of oral drug delivery, we present a hierarchically structured drug-delivery system that can undertake structural changes, so multiple functions can be triggered by a sequence of stimuli. Such hierarchical system is achieved in a nanoparticle-in-nanofiber configuration, in which both the nanofibers and the nanoparticles are pH-responsive and biocompatible. A model peptide is efficiently encapsulated under mild condition, and the nanocarriers are further electrospun with a pH-responsive mucoadhesive polymer. The nanoparticles are released from the nanofibers, and thereafter the peptides are released from the nanoparticles in a pH-responsive manner. The nanoparticles are compatible with caco-2 cells, and the endocytosis of the nanoparticles is described in detail.
RESUMO
The thermophilic Geobacillus thermodenitrificans and Geobacillus kaustophilus are able to use citrate or C4-dicarboxylates like fumarate or succinate as the substrates for growth. The genomes of the sequenced Geobacillus strains (nine strains) each encoded a two-component system of the CitA family. The sensor kinase of G. thermodenitrificans (termed CitAGt) was able to replace CitA of Escherichia coli (CitAEc) in a heterologous complementation assay restoring expression of the CitAEc-dependent citC-lacZ reporter gene and anaerobic growth on citrate. Complementation was specific for citrate. The sensor kinase of G. kaustophilus (termed DcuSGk) was able to replace DcuSEc of E. coli. It responded in the heterologous expression system to C4-dicarboxylates and to citrate, suggesting that DcuSGk is, like DcuSEc, a C4-dicarboxylate sensor with a side-activity for citrate. DcuSGk, unlike the homologous DctS from Bacillus subtilis, required no binding protein for function in the complementation assay. Thus, the thermophilic G. thermodenitrificans and G. kaustophilus contain citrate and C4-dicarboxylate sensor kinases of the CitA and DcuS type, respectively, and retain function and substrate specificity under mesophilic growth conditions in E. coli.
Assuntos
Proteínas de Bactérias/metabolismo , Geobacillus/enzimologia , Proteínas Quinases/metabolismo , Sequência de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Ácido Cítrico/metabolismo , Ácidos Dicarboxílicos/metabolismo , Regulação Bacteriana da Expressão Gênica , Geobacillus/química , Geobacillus/genética , Geobacillus/metabolismo , Dados de Sequência Molecular , Proteínas Quinases/química , Proteínas Quinases/genética , Alinhamento de SequênciaRESUMO
The use of self-assembled nanostructures consisting of red-light-responsive Ru(II)-containing block copolymers (BCPs) for anticancer phototherapy is demonstrated. Three Ru-containing BCPs with different molecular weights are synthesized. Each BCP contains a hydrophilic poly(ethylene glycol) block and an Ru-containing block. In the Ru-containing block, more than half of the side chains are coordinated with [Ru(2,2':6',2''-terpyridine)(2,2'-biquinoline)](2+) , resulting in more than 40 wt% Ru complex in the BCPs. The Ru complex acts as both a red-light-cleavable moiety and a photoactivated prodrug. Depending on their molecular weights, the BCPs assemble into micelles, vesicles, and large compound micelles. All of the BCP assemblies are taken up by cancer cells. Red-light irradiation releases the Ru complex and generates singlet oxygen ((1) O2 ) in cancer cells. The released Ru complex and (1) O2 inhibit the growth of cancer cells. Among the three BCP assemblies, the BCP micelle exhibits the most efficient cellular uptake and best anticancer performance.
Assuntos
Nanoestruturas/química , Neoplasias/terapia , Fototerapia/métodos , Polímeros/química , Rutênio/química , Sobrevivência Celular , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Luz , Micelas , Peso Molecular , Polietilenoglicóis/química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Rutênio/farmacologiaRESUMO
The hydrophilic peptide YY (PYY) is a promising hormone-based antiobesity drug. We present a new concept for the delivery of PYY from pH-responsive chitosan-based nanocarriers. To overcome the drawbacks while retaining the merits of the polyelectrolyte complex (PEC) method, we propose a one-pot approach for the encapsulation of a hydrophilic peptide drug in cross-linked PEC nanocarriers. First, the hydrophilic peptide is encapsulated via polyelectrolyte complexation within water-in-oil miniemulsion droplets. In a second step, the PEC surface is reinforced by controlled interfacial cross-linking. PYY is efficiently encapsulated and released upon pH change. Such nanocarriers are promising candidates for the fight against obesity and, in general, for the oral delivery of protein drugs.
