RESUMO
Alkaline phosphatase (ALP) responsive polymers, which can unzip from head to tail are reported. Hydrophilic and hydrophobic modification of the polymer was carried out for the formation of a polyelectrolyte complex and an amphiphilic nanoassembly, respectively, which offered distinct enzyme-triggered disassembly kinetics.
Assuntos
Fosfatase Alcalina/metabolismo , Nanopartículas/química , Polieletrólitos/metabolismo , Polímeros/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Cinética , Polieletrólitos/química , Polímeros/químicaRESUMO
CD4+ T lymphocytes play an important role in controlling many malignancies. The modulation of CD4+ T cells through immunomodulatory or cytotoxic drugs could change the course of disease progression for disorders such as autoimmunity, immunodeficiency, and cancer. Here, we demonstrate that anti-CD4 conjugated polymeric nanogels can deliver a small molecule cargo to primary CD4+ T cells and a CD4high T cell lymphoma. The antibody conjugation not only increased the uptake efficiency of the nanogel (NG) by CD4+ T cells but also decreased the non-specific uptake of the NG by CD4- lymphocytes. For T lymphoma cell lines, the mertansine-loaded conjugate displayed a dose-dependent cell growth inhibition at 17 ng/mL antibody concentration. On the other hand, antibody-drug conjugate (ADC)-type formulation of the anti-CD4 reached similar levels of cell growth inhibition only at the significantly higher concentration of 1.8 µg/mL. NG and antibody conjugates have the advantage of carrying a large payload to a defined target in a more efficient manner as it needs far less antibody to achieve a similar outcome.
Assuntos
Antineoplásicos , Imunoconjugados , Maitansina , Linfócitos T CD4-Positivos , NanogéisRESUMO
Using fluorinated probes for 19F MRI imaging is an emerging field with potential utility in cellular imaging and cell tracking in vivo, which complements conventional 1H MRI. An attractive feature of 19F-based imaging is that this is a bio-orthogonal nucleus and the naturally abundant isotope is NMR active. A significant hurdle however in the 19F MRI arises from the tendency of organic macromolecules, with multiple fluorocarbon substitutions, to aggregate in the aqueous phase. This aggregation results in significant loss of sensitivity, because the T2 relaxation times of these aggregated 19F species tend to be significantly lower. In this report, we have developed a strategy to covalently trap nanoscopic states with an optimal degree of 19F substitutions, followed by significant enhancement in T2 relaxation times through increased segmental mobility of the side chain substituents facilitated by the stimulus-responsive elements in the polymeric nanogel. In addition to NMR relaxation time based evaluations, the ability to obtain such signals are also evaluated in mouse models. The propensity of these nanoscale assemblies to encapsulate hydrophobic drug molecules and the availability of surfaces for convenient introduction of fluorescent labels suggest the potential of these nanoscale architectures for use in multimodal imaging and therapeutic applications.
Assuntos
Flúor/química , Imageamento por Ressonância Magnética/métodos , Nanogéis/química , Células HeLa , HumanosRESUMO
Specific response to the concurrent presence of two different inputs is one of the hallmarks of incorporating specificities in nature. Artificial nanoassemblies that concurrently respond to two very different inputs are of great interest in a variety of applications, especially in biomedicine. Here, we present a design strategy for amphiphilic nanoassemblies with such capabilities, enabled by photocaging a ligand moiety that is capable of binding to a specific protein. New molecular designs that offer nanoassemblies that respond to either of two inputs or only to the concurrent presence of two inputs are outlined. Such biomimetic nanoassemblies could find use in many applications, including drug delivery and diagnostics.
RESUMO
Aromatic interactions were found to greatly influence the temperature-dependent dynamic behavior within supramolecular assemblies. Using an amphiphilic dendron, we systematically changed the hydrophobic groups introducing increasing levels of aromaticity while keeping the hydrophilic part constant. We show that the supramolecular assemblies become less sensitive to temperature changes when aromatic interactions in the aggregate are increased. Conversely, the absence of aromaticity in the hydrophobic moieties produces temperature-sensitive aggregates. These results show that subtle molecular-level interactions can be utilized to control temperature-sensitive behavior in the nanoscale. These findings open up new design strategies to rationally tune the behavior of stimuli-responsive supramolecular assemblies on multiple spatiotemporal scales.
Assuntos
Dendrímeros/química , Hidrocarbonetos Aromáticos/química , Tensoativos/química , Dendrímeros/síntese química , Transferência Ressonante de Energia de Fluorescência , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Tamanho da Partícula , Perileno/química , Pirenos/química , Tensoativos/síntese química , Temperatura , ÁguaRESUMO
CONSPECTUS: Supramolecular assemblies formed from spontaneous self-assembly of amphiphilic macromolecules are explored as biomimetic architectures and for applications in areas such as sensing, drug delivery, and diagnostics. Macromolecular assemblies are usually preferred, compared with their simpler small molecule counterparts, due to their low critical aggregate concentrations (CAC) and high thermodynamic stability. This Account focuses on the structural and functional aspects of assemblies formed from dendrimers, specifically facially amphiphilic dendrons that form micelle or inverse micelle type supramolecular assemblies depending on the nature of the solvent medium. The micelle type assemblies formed from facially amphiphilic dendrons sequester hydrophobic guest molecules in their interiors. The stability of these assemblies is dependent on the relative compatibility of the hydrophilic and hydrophobic functionalities with water, often referred to as hydrophilic-lipophilic balance (HLB). Disruption of the HLB, using an external stimulus, could lead to disassembly of the aggregates, which can then be utilized to cause an actuation event, such as guest molecule release. Studying these possibilities has led to (i) a robust and general strategy for stimulus-induced disassembly and molecular release and (ii) the introduction of a new approach to protein-responsive supramolecular disassembly. The latter strategy provides a particularly novel avenue for impacting biomedical applications. Most of the stimuli-sensitive supramolecular assemblies have been designed to be responsive to factors such pH, temperature, and redox conditions. The reason for this interest stems from the fact that certain disease microenvironments have aberrations in these factors. However, these variations are the secondary imbalances in biology. Imbalances in protein activity are the primary reasons for most, if not all, human pathology. There have been no robust strategies in stimulus-responsive assemblies that respond to these variations. The facially amphiphilic dendrimers provide a unique opportunity to explore this possibility. Similarly, the propensity of these molecules to form inverse micelles in apolar solvents and thus bind polar guest molecules, combined with the fact that these assemblies do not thermodynamically equilibrate in biphasic mixtures, was used to predictably simplify peptide mixtures. The structure-property relationships developed from these studies have led to a selective and highly sensitive detection of peptides in complex mixtures. Selectivity in peptide extraction was achieved using charge complementarity between the peptides and the hydrophilic components present in inverse micellar interiors. These findings will have implications in areas such as proteomics and biomarker detection.