RESUMO
Photochemical regulation provides a promising approach for controlling enzyme activity on demand owing to its high spatiotemporal resolution. However, reversible regulation of the enzyme activity by light usually requires genetic mutations and covalent modifications of the target enzymes, which may lead to irreversible changes in the enzyme structure and subsequent loss of the enzymatic activity. Herein, we have developed a novel strategy based on a polymeric inhibitor-encapsulated enzyme, which noncovalently anchors the azobenzene-modified inhibitors to the enzyme active site, thereby achieving reversible control of the activity of native enzymes using light. As neither genetic mutation nor chemical modification of enzymes is required for this method, negligible loss of the enzymatic activity was observed for the encapsulated enzymes compared to their native counterparts. Thus, this approach has demonstrated a promising strategy for achieving reversible regulation of the activity of native enzymes.
RESUMO
Combination therapy based on molecular drugs and therapeutic genes provides an effective strategy for malignant tumor treatment. However, effective gene and drug combinations for cancer treatment are limited by the widespread antagonism between therapeutic genes and molecular drugs. Herein, a calixarene-embedded nanoparticle (CENP) is developed to co-deliver molecular drugs and therapeutic genes without compromising their biological functions, thereby achieving interference-free gene-drug combination cancer therapy. CENP is composed of a cationic polyplex core and an acid-responsive polymer shell, allowing CENP loading and delivering therapeutic genes with improved circulation stability and enhanced tumor accumulation. Moreover, the introduction of carboxylated azocalix[4]arene, which is a hypoxia-responsive calixarene derivatives, in the polyplex core endows CENP with the capability to load molecular drugs through the host-guest complexation as well as inhibit the interference between the drugs and genes by encapsulating the drugs into its cavity. By loading doxorubicin and a plasmid DNA-based CRISPR interference system that targets miR-21, CENP exhibits the significantly enhanced anti-tumor effects in mice. Considering the wide variety of calixarene derivatives, CENP can be adapted to deliver almost any combination of drugs and genes, providing the potential as a universal platform for the development of interference-free gene-drug combination cancer therapy.
Assuntos
Calixarenos , Nanopartículas , Neoplasias , Animais , Linhagem Celular Tumoral , Terapia Combinada , Doxorrubicina , CamundongosRESUMO
The release of tumor-associated antigens (TAAs) and their cross-presentation in dendritic cells (DCs) are crucial for radio-immunotherapy. However, the irradiation resistance of tumor cells usually results in limited TAA generation and release. Importantly, TAAs internalized by DCs are easily degraded in lysosomes, resulting in unsatisfactory extent of TAA cross-presentation. Herein, an antigen-capturing stapled liposome (ACSL) with a robust structure and bioactive surface is developed. The ACSLs capture and transport TAAs from lysosomes to the cytoplasm in DCs, thereby enhancing TAA cross-presentation. l-arginine encapsulated in ACSLs induces robust T cell-dependent antitumor response and immune memory in 4T1 tumor-bearing mice after local irradiation, resulting in significant tumor suppression and an abscopal effect. Replacing l-arginine with radiosensitizers, photosensitizers, and photothermal agents may make ACSL a universal platform for the rapid development of various combinations of anticancer therapies.
Assuntos
Apresentação Cruzada , Lipossomos , Animais , Antígenos de Neoplasias , Células Dendríticas , Imunoterapia/métodos , Lipossomos/metabolismo , CamundongosRESUMO
We developed a polymer-encapsulated DNase, n(DNase), which can efficiently accumulate in biofilm and expose the DNase to cleave the eDNA of the biofilm. CLSM and crystal violet staining results demonstrated effective biofilm disintegration (92.2%) when treated with n(DNase). This work demonstrated a general approach for coating matrix-dispersion enzymes to achieve biofilm disintegration and provided a promising strategy for treating biofilm-associated infections.
Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Desoxirribonucleases/farmacologia , Enzimas Imobilizadas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/administração & dosagem , Desoxirribonucleases/administração & dosagem , Portadores de Fármacos/química , Sinergismo Farmacológico , Enzimas Imobilizadas/administração & dosagem , Humanos , Polímeros/química , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/fisiologiaRESUMO
Triplet excitons can be effectively harvested in organic light-emitting diodes employing thermally activated delayed fluorescence (TADF) molecules as the emitter and host. A design strategy for blue and green emitters with small S1-T1 splitting (ΔEST) is to construct a donor-acceptor (D-A) type molecule with moieties combining a high T1 level with a strong electron-donating/withdrawing character. Here, we report a new kind of TADF emitter with an indolo[2,3-b]indole (IDID) donor. In comparison to other reported indolocarbazole and indoloindole donors, IDID has a higher T1 level, which is comparable to that of the classical donor 9,9-dimethyl-9,10-dihydroacridine (DMAC) for blue TADF emitters. The sky-blue and green TADF emitters based on the IDID donor and a phenyltriazine acceptor exhibit high photoluminescence quantum yields (0.78-0.92) and short TADF lifetimes (1.1-1.7 µs) in doped films. Devices employing these IDID-based emitters offer an external quantum efficiency of 19.2%, which is comparable to that obtained for a device employing an analogous compound with a DMAC donor, while the stability of the former is higher than that of the latter owing to the just-right D-A twisting angles (â¼59°) in the IDID-based emitters leading to a balance between ΔEST and the fluorescence rate. The utilization of host materials with a similar polarity to the emitter is found to be an effective strategy to improve device stability.