RESUMO
Enzyme-responsive micelles have great potential as drug delivery platforms due to the high selectivity of the activating enzymes. Here we report a highly modular design for the efficient and simple synthesis of amphiphilic block copolymers based on a linear hydrophilic polyethyleneglycol (PEG) and an enzyme-responsive hydrophobic dendron. These amphiphilic hybrids self-assemble in water into micellar nanocontainers that can disassemble and release encapsulated molecular cargo upon enzymatic activation. The utilization of monodisperse dendrons as the stimuli-responsive block enabled a detailed kinetic study of the molecular mechanism of the enzymatically triggered disassembly. The modularity of these PEG-dendron hybrids allows control over the disassembly rate of the formed micelles by simply tuning the PEG length. Such smart amphiphilic hybrids could potentially be applied for the fabrication of nanocarriers with adjustable release rates for delivery applications.
Assuntos
Amidoidrolases/metabolismo , Dendrímeros/química , Micelas , Nanoestruturas , Polietilenoglicóis/química , Tensoativos/síntese química , Amidoidrolases/química , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Tensoativos/químicaRESUMO
We present a robust scheme for preparation of semiconductor quantum dots (QDs) and cognate partners in a conjugation ready format. Our approach is based on bis-aryl hydrazone bond formation mediated by aromatic aldehyde and hydrazinonicotinate acetone hydrazone (HyNic) activated peptide coated quantum dots. We demonstrate controlled preparation of antibody--QD bioconjugates for specific targeting of endogenous epidermal growth factor receptors in breast cancer cells and for single QD tracking of transmembrane proteins via an extracellular epitope. The same approach was also used for optical mapping of RNA polymerases bound to combed genomic DNA in vitro.
Assuntos
Aldeídos/química , Materiais Revestidos Biocompatíveis/química , Hidrazinas/química , Imagem Molecular/métodos , Peptídeos/química , Pontos Quânticos , Animais , Anticorpos/imunologia , Células CHO , Linhagem Celular Tumoral , Sobrevivência Celular , Materiais Revestidos Biocompatíveis/síntese química , Cricetinae , Cricetulus , Receptores ErbB/imunologia , Feminino , Células HeLa , Humanos , Teste de Materiais , Estrutura Molecular , Peptídeos/síntese química , SemicondutoresRESUMO
This study evaluates the influence of particle size, PEGylation, and surface coating on the quantitative biodistribution of near-infrared-emitting quantum dots (QDs) in mice. Polymer- or peptide-coated 64Cu-labeled QDs 2 or 12 nm in diameter, with or without polyethylene glycol (PEG) of molecular weight 2000, are studied by serial micropositron emission tomography imaging and region-of-interest analysis, as well as transmission electron microscopy and inductively coupled plasma mass spectrometry. PEGylation and peptide coating slow QD uptake into the organs of the reticuloendothelial system (RES), liver and spleen, by a factor of 6-9 and 2-3, respectively. Small particles are in part renally excreted. Peptide-coated particles are cleared from liver faster than physical decay alone would suggest. Renal excretion of small QDs and slowing of RES clearance by PEGylation or peptide surface coating are encouraging steps toward the use of modified QDs for imaging living subjects.