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1.
Proc Natl Acad Sci U S A ; 120(18): e2204621120, 2023 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-37098055

RESUMEN

The unique cancer-associated immunosuppression in brain, combined with a paucity of infiltrating T cells, contributes to the low response rate and poor treatment outcomes of T cell-based immunotherapy for patients diagnosed with glioblastoma multiforme (GBM). Here, we report on a self-assembling paclitaxel (PTX) filament (PF) hydrogel that stimulates macrophage-mediated immune response for local treatment of recurrent glioblastoma. Our results suggest that aqueous PF solutions containing aCD47 can be directly deposited into the tumor resection cavity, enabling seamless hydrogel filling of the cavity and long-term release of both therapeutics. The PTX PFs elicit an immune-stimulating tumor microenvironment (TME) and thus sensitizes tumor to the aCD47-mediated blockade of the antiphagocytic "don't eat me" signal, which subsequently promotes tumor cell phagocytosis by macrophages and also triggers an antitumor T cell response. As adjuvant therapy after surgery, this aCD47/PF supramolecular hydrogel effectively suppresses primary brain tumor recurrence and prolongs overall survivals with minimal off-target side effects.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Paclitaxel , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Macrófagos Asociados a Tumores/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Hidrogeles/uso terapéutico , Inmunoterapia/métodos , Microambiente Tumoral , Línea Celular Tumoral , Neoplasias Encefálicas/tratamiento farmacológico
2.
Opt Lett ; 48(19): 5009-5012, 2023 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-37773372

RESUMEN

Terahertz (THz) absorbers are highly desired with the rapid development of THz technology. Although metasurface-based absorbers can realize perfect absorption, their fabrication often requires complicated micro-nano-processing with a high cost. In this paper, fast printable and low-cost metasurface absorbers based on a laser-induced graphene (LIG) technique are proposed. Experimental results demonstrate that these two metasurfaces can achieve maximum absorptions of 99.3% and 99.9% at their resonant frequencies in an incident angle range of ±55°. Fabrication of a metasurface with a size of 1 × 1 cm costs only 11 s. The absorbers may be applied in THz dichroism and communications.

3.
Bioorg Chem ; 138: 106609, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37207595

RESUMEN

Cardiac tissue suffers much from sepsis, and the incidence of myocardial injury is high in septic patients. The treatment of sepsis myocardial injury (SMI) has been the focus of clinical medicine. Salidroside shows myocardial cell protection, anti-oxidation and anti- inflammation effects, and it is thought as one of the potential compounds to treat sepsis myocardial injury. However, its anti-inflammatory activity is lower and its pharmacokinetic properties are not ideal, which is far from clinical application. Here, a series of salidroside analogs were synthesized, and their bioactivities were evaluated from several aspects, including their anti-oxidant and anti-inflammatory activities in vitro and anti-sepsis myocardial injury activities in vivo. Of all the compounds which synthesized, compounds 2 and 3 exhibited stronger anti-inflammatory activities than the others; after treating LPS-stimulated RAW264.7 or H9c2 cells with each of them, the levels of IL-1ß, IL-6 and TNF-α were down-regulated in a dose-dependent manner. In the anti-oxidative stress injury test, compounds 2 and 3 not only markedly increased the survival rate of cells, and but also improved the cellular oxidative stress-related indicators MDA, SOD and cell damage marker LDH in a dose-dependent manner. In the LPS-induced septic rat myocardial injury models (in vivo), the two compounds also showed good bioactivities. They also reduced the expression of IL-1ß, IL-6 and TNF-α, and blocked cell damage by suppressing overhauled oxidation in septic rats. In addition, the myocardial injury was significantly improved and the inflammatory infiltration was reduced after treatment with the two compounds. In conclusion, the salidroside analogs (2 and 3) showed promising therapeutical effect on septic myocardial injury in LPS-model rats, and they could be good candidates for clinical trials against inflammation and septic myocardial injury.


Asunto(s)
Sepsis , Factor de Necrosis Tumoral alfa , Ratas , Animales , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Antiinflamatorios/farmacología , Sepsis/tratamiento farmacológico , Inflamación
4.
Proc Natl Acad Sci U S A ; 117(9): 4518-4526, 2020 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-32071209

RESUMEN

The inception and development of supramolecular chemistry have provided a vast library of supramolecular structures and materials for improved practice of medicine. In the context of therapeutic delivery, while supramolecular nanostructures offer a wide variety of morphologies as drug carriers for optimized targeting and controlled release, concerns are often raised as to how their morphological stability and structural integrity impact their in vivo performance. After intravenous (i.v.) administration, the intrinsic reversible and dynamic feature of supramolecular assemblies may lead them to dissociate upon plasma dilution to a concentration below their critical micellization concentration (CMC). As such, CMC represents an important characteristic for supramolecular biomaterials design, but its pharmaceutical role remains elusive. Here, we report the design of a series of self-assembling prodrugs (SAPDs) that spontaneously associate in aqueous solution into supramolecular polymers (SPs) with varying CMCs. Two hydrophobic camptothecin (CPT) molecules were conjugated onto oligoethylene-glycol (OEG)-decorated segments with various OEG repeat numbers (2, 4, 6, 8). Our studies show that the lower the CMC, the lower the maximum tolerated dose (MTD) in rodents. When administrated at the same dosage of 10 mg/kg (CPT equivalent), SAPD 1, the one with the lowest CMC, shows the best efficacy in tumor suppression. These observations can be explained by the circulation and dissociation of SAPD SPs and the difference in molecular and supramolecular distribution between excretion and organ uptake. We believe these findings offer important insight into the role of supramolecular stability in determining their therapeutic index and in vivo efficacy.


Asunto(s)
Portadores de Fármacos/química , Micelas , Profármacos/administración & dosificación , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/farmacocinética , Camptotecina/uso terapéutico , Portadores de Fármacos/toxicidad , Femenino , Células HT29 , Humanos , Dosis Máxima Tolerada , Ratones , Ratones Desnudos , Polietilenglicoles/química , Polimerizacion , Profármacos/farmacocinética , Profármacos/uso terapéutico , Ratas , Ratas Sprague-Dawley
5.
Bioorg Chem ; 119: 105542, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34902645

RESUMEN

A series of glycyrrhetinic acid (GA, aglycone of glycyrrhizic acid) derivatives containing disulfide bond were synthesized and their anti-inflammatory and anti-fibrosis activities were evaluated in vivo and in vitro. Among them, compound 7 displayed the highest toxicity to all the tested cell lines including macrophages. Compounds 3 and 4 showed higher activities than GA in the cell and animal model. In the anti-inflammatory tests, compounds 3 and 4 down-regulated the expressions of several inflammatory factors, such as HMGB1, TLR4, IL-1ß, TNF-α and TGF-ß1 in LPS-treated RAW264.7 cells in a dose-dependent manner. Compounds 3 and 4 at 30 µM respectively reduced the levels of HMGB1 in the LPS group to 42.7% and 38.2%. In addition, the level of TLR4 decreased to close to that of control group when treated by compound 4 at the concentration of 30 µM. In the process of anti-fibrosis tests using TGF-ß1-induced A549 cell line as the model, compounds 3 and 4 also decreased the expression levels of Col1 and α-SMA in a dose-dependent manner. Compound 3 and 4 at 30 µM respectively reduced the expression of α-SMA level by 2.2-fold and 2.6-fold compared to the TGF-ß1-treated control group. Moreover, they influenced the ROS level and mitochondrial membrane potential (MMP) in A549 cells. In the paraquat-induced pulmonary fibrosis mice model, the symptoms of inflammation and fibrosis of mice were alleviated after administration of compound 3 or 4. The above results suggest that compounds 3 and 4 may be promising candidates for inflammation and lung fibrosis treatment.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Disulfuros/farmacología , Ácido Glicirretínico/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Células Cultivadas , Citocinas/análisis , Disulfuros/química , Relación Dosis-Respuesta a Droga , Femenino , Fibrosis/tratamiento farmacológico , Fibrosis/metabolismo , Ácido Glicirretínico/síntesis química , Ácido Glicirretínico/química , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Estructura Molecular , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Células RAW 264.7 , Relación Estructura-Actividad
6.
Opt Express ; 28(23): 35179-35191, 2020 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-33182969

RESUMEN

Graphene-based terahertz (THz) metasurfaces have the advantages of ultra-small thickness, electrical tunability, and fast tuning speed. However, many such structures suffer low efficiency, especially for transmissive devices. Here we propose a hybrid structure for focusing THz waves with tunability and enhanced focusing efficiency, which is composed of a graphene-loaded metallic metasurface sandwiched by two mutually orthogonal gratings. Experimental results show that due to the multi-reflection between the metasurface layer and the grating layer, the focusing efficiency is enhanced by 1.8 times, and the focal length of the metalens is increased by 0.61 mm when the applied gate voltage on the graphene is increased from 0 V to 1.4 V. We hope the proposed structure may open a new avenue for reconfigurable THz metasurfaces with high efficiencies.

7.
Opt Express ; 28(3): 2789-2798, 2020 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-32121959

RESUMEN

Metasurfaces have proven their great application potentials in terahertz (THz) wave modulations. However, realizing an active metasurface retaining lensing functionality in the THz frequency regime is still highly desired. Here a metalens, featuring electrically tunable focal length, based on propagation phase delay, is proposed and demonstrated experimentally. To have full control over the designed lens functionality, a gold thin film etched with a C-shaped aperture antenna array covered by monolayer graphene is used. By applying a bias voltage to the graphene, the phase control of the antenna array is changed, and thus the focus of the linearly polarized THz beam can be flexibly tuned from 7.13mm to 8.25mm. The proposed approach has a promising perspective for a variety of applications in communication, reconfigurable flat optics and real-time imaging in THz regime.

8.
Health Commun ; 32(3): 298-309, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27230029

RESUMEN

This article presents the results of a study testing the direct and indirect effects of identity, media use, cognitions and conversations on physical activity (PA). The study was guided by the O-S-O-R model (Markus & Zajonc, 1985), and it used data collected from a sample of Hispanic adults (N = 268) living in the U.S. Southwest. Exercise identity and ethnic identity were defined as pre-orientations (O1); use of PA-related media content was defined as the stimulus (S); reflective integration and conversations about PA-related media were post-orientations (O2); and self-reported physical activity was the behavioral response (R). Structural equation modeling was used to analyze the data, and several compelling results emerged. Exercise identity had a significant positive direct effect on PA and PA-related media use, as well as a significant positive indirect effect on conversations about PA-related media. PA-related media use exerted a strong and significant positive effect on conversations about PA-related media, as well as a significant positive indirect effect on PA. Finally, conversations about PA-related media content had a significant positive direct effect on PA. The results indicate that identity acts as a filter influencing what media content are selected and that cognitions and conversations about media content can serve as a link between media use and health behavior. Key words: O-S-O-R model, physical activity, Hispanic adults, identity, media use, conversation.


Asunto(s)
Cognición , Comunicación , Medios de Comunicación/estadística & datos numéricos , Ejercicio Físico/psicología , Hispánicos o Latinos , Autoinforme , Adulto , Femenino , Conductas Relacionadas con la Salud/etnología , Humanos , Masculino , Autoeficacia , Teoría Social
9.
ACS Appl Mater Interfaces ; 16(12): 15193-15201, 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38491983

RESUMEN

Chiral metasurfaces are capable of generating a huge superchiral field, which has great potential in optoelectronics and biosensing. However, the conventional fabrication process suffers greatly from time consumption, high cost, and difficult multilayer alignment, which hinder its commercial application. Herein, we propose a twisted stacking carbon-based terahertz (THz) chiral metasurface (TCM) based on laser-induced graphene (LIG) technology. By repeating a two-step process of sticking a polyimide film, followed by laser direct writing, the two layers of the TCM are aligned automatically in the fabrication. Laser manufacturing also brings such high processing speed that a TCM with a size of 15 × 15 mm can be prepared in 60 s. In addition, due to the greater dissipation of LIG than that of metals in the THz band, a giant circular dichroism (CD) of +99.5 to -99.6% is experimentally realized. The THz biosensing of bovine serum albumin enhanced by the proposed TCMs is then demonstrated. A wide sensing range (0.5-50 mg mL-1) and a good sensitivity [ΔCD: 2.09% (mg mL-1)-1, Δf: 0.0034 THz (mg mL-1)-1] are proved. This LIG-based TCM provides an environment-friendly platform for chiral research and has great application potential in rapid and low-cost commercial biosensing.


Asunto(s)
Carbono , Grafito , Dicroismo Circular , Albúmina Sérica Bovina , Escritura
10.
J Colloid Interface Sci ; 665: 526-534, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38547634

RESUMEN

Single-atom catalysts (SACs) have received much attention in the realm of energy and catalytic conversion due to their maximum atomic efficiency. Herein, we report a cascade anchoring strategy for the preparation of a Cu-S1O2 species of single-atom catalyst attached to a carbon carrier containing P and S (Cu-S1O2 SA/CPS) with a content of 12.4 wt%. Over the Cu-S1O2 SA/CPS catalyst, the conversion of 95.8% and selectivity of 87.2% for acetylene hydration could still be achieved at 70 h (T = 200°C, GHSV(C2H2) = 90 h-1 and VH2O/VC2H2 = 4). X-ray absorption spectroscopy (XAS) and X-ray photoelectron spectroscopy (XPS) tests reveal that the Cu atoms of Cu-S1O2 SA/CPS are predominantly coordinated in a trinary manner (Cu-S1O2). Based on high-resolution aberration-corrected high-angle annular dark-field scanning transmission electron microscope (HAADF-STEM), it is demonstrated that the Cu single-atom sites are highly dispersed in Cu-S1O2 SA/CPS. It is evident from the scanning electron microscopy (SEM) that Cu-S1O2 SA/CPS has a two-dimensional layered structure. The specific structure of the active site Cu is primarily attributed to the coordination of S and O atoms, resulting in its superior stability for acetylene hydration towards the synthesis of acetaldehyde. Density functional theory (DFT) calculations confirm that the formation of the Cu-S1O2 site facilitates the activation of acetylene, which is a pivotal step in the acetylene hydration process and considered as the rate-determining step. This article not only introduces an innovative strategy in the synthesis of Cu SACs but also represents a significant breakthrough in the stability of Cu SACs in acetylene hydration.

11.
Materials (Basel) ; 16(19)2023 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-37834499

RESUMEN

The development of flexible sensors based on laser-induced graphene (LIG) has recently attracted much attention. It was commonly generated by laser-ablating commercial polyimide (PI). However, the weak mechanical extensibility of PI limits the development and diversified applications of LIG-based sensors. In this work, we adopted medical polyurethane (PU) tapes to peel off the LIG generated on PI and developed flexible and wearable sensors based on the proposed LIG/PU composite structure. Compared with other methods for LIG transfer, PU tape has many advantages, including a simplified process and being less time-consuming. We characterized the LIG samples generated under different laser powers and analyzed the property differences introduced by the transfer operation. We then studied the impact of fabrication mode on the strain sensitivity of the LIG/PU and optimized the design of a LIG/PU-based strain sensor, which possessed a gauge factor (GF) of up to 263.6 in the strain range of 75-90%. In addition, we designed a capacitive pressure sensor for tactile sensing, which is composed of two LIG/PU composite structures and a PI space layer. These LIG flexible devices can be used for human motion monitoring and tactile perception in sports events. This work provides a simple, fast, and low-cost way for the preparation of multifunctional sensor systems with good performance, which has a broad application prospect in human motion monitoring.

12.
Eur J Med Chem ; 259: 115696, 2023 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-37542990

RESUMEN

Glycyrrhizin (GL) is one of the antagonists of highly conserved nuclear protein (HMGB1). The researches have shown that the glycosyl of GL is an important pharmacophore for GL binding to HMGB1, and it is the determinant factor for mechanism of action. To get the HMGB1 inhibitors with higher activity and good pharmacokinetic properties, two classes of GL analogues containing C-N glycoside bond were synthesized, and their anti-inflammatory, anti-oxidative stress and anti-septic kidney injury were evaluated. The results are as follows. First, in the anti-inflammatory assay, all the compounds inhibited NO release in some degree; among them, compound 6 displayed the strongest NO inhibitory effect with IC50 value of 15.9 µM, and compound 15 with IC50 of 20.2 µM. The two compounds not only decreased IL-1ß and TNF-α levels in RAW264.7 cells and HK-2 cells, but also downregulated the levels of NLRP3, P-NF-κB p65 and HMGB1 in activated HK-2 cells in a dose-dependent manner. Second, in the renal protection assay with H2O2-stimulated HK-2 cell line, they reduced MDA level and increased SOD in HK-2 cells; additionally, they also inhibited the HK-2 cell apoptosis and downregulated the Caspase-1 p20 level. Third, in the in vivo activity tests of the septic mouse, they also showed good activities just like in vitro, decreasing the IL-1ß, TNF-α, MDA, blood creatinine (Scr) and urea nitrogen (BUN) in serum, and increasing SOD levels in a dose-dependent manner. The immunoblotting results showed the two compounds downregulated the levels of HMGB1, P-NF-κB p65, NLRP3 and Caspase-1 p20 protein. All in all, the two compounds improved the renal injury of septic mice, and alleviated the tube wall structure damage and renal tubular dilation in kidney, which further proved by H&E staining. This suggests the two compounds have septic acute kidney injury activity, and they will be potential therapeutic drugs for septic acute kidney injury.


Asunto(s)
Lesión Renal Aguda , Proteína HMGB1 , Sepsis , Ratones , Animales , Ácido Glicirrínico/farmacología , Ácido Glicirrínico/uso terapéutico , FN-kappa B/metabolismo , Proteína HMGB1/metabolismo , Proteína HMGB1/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Peróxido de Hidrógeno , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Caspasas , Superóxido Dismutasa
13.
Comput Human Behav ; 127: 107058, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34690416

RESUMEN

In the context of the Covid-19, the present study designed a longitudinal study to examine the relationship among interpersonal alienation, meaning in life and smartphone addiction. Meanwhile, with the development of the epidemic whether there would be changes in the three variables was also examined. A sample of 579 university students (baseline mean age = 20.59, SD = 2.20) finished the anonymous questionnaires about interpersonal alienation, meaning in life and smartphone addiction. Three repeated measurements were obtained in June, September and December 2020. The finding indicated that university students' interpersonal alienation and meaning in life significantly increased, and the risk of smartphone addiction significantly decreased with the epidemic under control. Besides, meaning in life in the middle mitigating period of the epidemic mediated the relationship between interpersonal alienation in the early severe period of the epidemic and smartphone addiction in the basic end period of the epidemic. The study contributes to our understanding of how low levels of interpersonal alienation may improve meaning in life and reduce the risk of smartphone addiction. What' s more, it provides scientific suggestions for the prevention and intervention of the adverse effects during public health emergencies.

14.
Materials (Basel) ; 15(18)2022 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-36143785

RESUMEN

As one essential indicator of surface integrity, residual stress has an important influence on the fatigue performance of aero engines' thin-walled parts. Larger compressive or smaller tensile residual stress is more prone to causing fatigue cracks. To optimize the state of residual stress, the relationship between the surface residual stress and the machining conditions is studied in this work. A radial basis function (RBF) neural network model based on simulated and experimental data is developed to predict the surface residual stress for multi-axis milling of Ti-6Al-4V titanium alloy. Firstly, a 3D numerical model is established and verified through a cutting experiment. These results are found to be in good agreement with average absolute errors of 11.6% and 15.2% in the σx and σy directions, respectively. Then, the RBF neural network is introduced to relate the machining parameters with the surface residual stress using simulated and experimental samples. A good correlation is observed between the experimental and the predicted results. The verification shows that the average prediction error rate is 14.4% in the σx direction and 17.2% in the σy direction. The effects of the inclination angle, cutting speed, and feed rate on the surface residual stress are investigated. The results show that the influence of machining parameters on surface residual stress is nonlinear. The proposed model provides guidance for the control of residual stress in the precision machining of complex thin-walled structures.

15.
RSC Med Chem ; 13(11): 1391-1409, 2022 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-36439975

RESUMEN

Bile acids (BAs) containing both hydrophilic hydroxyl and carboxyl groups and hydrophobic methyl and steroid nuclei can promote the absorption of fat and other substances in the intestine, and they are synthesized by cholesterol in the liver and then returned to the liver through enteric liver circulation. Because there are many BA receptors on the cell membrane of colon tissues, BAs can improve the specific delivery and transport of medicines to colon tissues. Moreover, BAs have a certain anticancer and inflammation activity by themselves. Based on this theory, a series of BA derivatives against colon cancer including cholic acid (CA), chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA) and lithocholic acid (LCA) were designed and synthesized, and their antitumor activity was evaluated. For in vitro anti-tumor tests, all the compounds displayed cell proliferative inhibition to nine human malignant tumor cell lines to some degree, and in particular they showed stronger inhibition to the colon cancer cells than the other cell lines. Among them, four compounds (4, 5, 6, and 7) showed stronger activity than the other compounds as well as the positive control 5-FU against HCT116 cells, and their IC50 was between 21.32 µmol L-1 and 28.90 µmol L-1; cell clone formation and migration tests showed that they not only effectively inhibited the formation of HCT116 cell colonies, but also inhibited the HCT116 cell migration and invasion; moreover, they induced apoptosis, arrested the mitotic process at the G2/M phase of the cell cycle, reduced the mitochondrial membrane potential, increased the intracellular ROS levels, and reduced the expression of Bcl-2 and p-STAT3 in HCT 116 cells. In addition, they also displayed intermediate anti-inflammatory activity by inhibiting inflammatory mediators NO and downregulating TNF-α expression, which also is one of the causes of colon cancer. This suggests that they deserve to be further investigated as candidates for colon cancer treatment drugs.

16.
Biomaterials ; 279: 121182, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34688987

RESUMEN

The clinical benefit of PD-1/PD-L1 blockade immunotherapy is substantially restricted by insufficient infiltration of T lymphocytes into tumors and compromised therapeutic effects due to immune-related adverse events following systemic administration. Some chemotherapeutic agents have been reported to trigger tumor-associated T cell responses, providing a promising strategy to achieve potent immune activation in a synergistic manner with PD-1 blockade immunotherapy. In light of this, a localized chemoimmunotherapy system was developed using an anti-cancer drug-based supramolecular polymer (SP) hydrogel to "re-edit" the host's immune system to combat cancer. This in situ forming injectable aPD1/TT6 SP hydrogel serves as a drug-delivery depot for sustained release of bioactive camptothecin (CPT) and aPD1 into the tumor microenvironment, priming the tumor for robust infiltration of tumor-associated T cells and subsequently prompting a response to the immune checkpoint blockade. Our in vivo results demonstrate that this chemoimmunotherapy hydrogel provokes a long-term and systemic anticancer T cell immune response, which elicits tumor regression while also inhibiting tumor recurrence and potential metastasis.


Asunto(s)
Hidrogeles , Neoplasias , Línea Celular Tumoral , Humanos , Inmunoterapia , Neoplasias/tratamiento farmacológico , Linfocitos T , Microambiente Tumoral
17.
ACS Nano ; 14(8): 10083-10094, 2020 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-32806082

RESUMEN

Local chemotherapy is a clinically proven strategy in treating malignant brain tumors. Its benefits, however, are largely limited by the rapid release and clearance of therapeutic agents and the inability to penetrate through tumor tissues. We report here on a supramolecular tubustecan (TT) hydrogel as both a therapeutic and drug carrier that enables long-term, sustained drug release and improved tumor tissue penetration. Covalent linkage of a tissue penetrating cyclic peptide to two camptothecin drug units creates a TT prodrug amphiphile that can associate into tubular supramolecular polymers and subsequently form a well-defined sphere-shaped hydrogel after injection into tumor tissues. The hollow nature of the resultant tubular assemblies allows for encapsulation of doxorubicin or curcumin for combination therapy. Our in vitro and in vivo studies reveal that these dual drug-bearing supramolecular hydrogels enhance tumor retention and penetration, serving as a local therapeutic depot for potent tumor regression, inhibition of tumor metastasis and recurrence, and mitigation of the off-target side effects.


Asunto(s)
Sistemas de Liberación de Medicamentos , Hidrogeles , Línea Celular Tumoral , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Liberación de Fármacos , Resultado del Tratamiento
18.
Nat Biomed Eng ; 4(11): 1090-1101, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32778697

RESUMEN

Tumours with an immunosuppressive microenvironment respond poorly to therapy. Activation of the stimulator of interferon genes (STING) pathway can enhance intratumoural immune activation, but STING agonists are associated with high toxicity and degrade prematurely, which limits their effectiveness. Here, we show that the extended intratumoural release of the STING agonist cyclic di-AMP transforms the tumour microenvironment from immunosuppressive to immunostimulatory, increasing the efficacy of antitumour therapies. The STING agonist was electrostatically complexed with nanotubes comprising a peptide-drug conjugate (a peptide that binds to the protein neuropilin-1, which is highly expressed in tumours, and the chemotherapeutic agent camptothecin) that self-assemble in situ into a supramolecular hydrogel. In multiple mouse models of murine tumours, a single low dose of the STING agonist led to tumour regression and increased animal survival, and to long-term immunological memory and systemic immune surveillance, which protected the mice against tumour recurrence and the formation of metastases. Locally delivered STING agonists could help to reduce tumour immunosuppression and enhance the efficacy of a wide range of cancer therapies.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/química , Camptotecina/administración & dosificación , Camptotecina/química , Sistemas de Liberación de Medicamentos/métodos , Inmunoterapia/métodos , Animales , Antineoplásicos Fitogénicos/inmunología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/terapia , Camptotecina/inmunología , Línea Celular Tumoral , Neoplasias del Colon/inmunología , Neoplasias del Colon/terapia , Femenino , Hidrogeles/administración & dosificación , Hidrogeles/química , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Nanotubos/química , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología
19.
Sci Adv ; 6(18): eaaz8985, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32490201

RESUMEN

Immune checkpoint blockers (ICBs) have shown great promise at harnessing immune system to combat cancer. However, only a fraction of patients can directly benefit from the anti-programmed cell death protein 1 (aPD1) therapy, and the treatment often leads to immune-related adverse effects. In this context, we developed a prodrug hydrogelator for local delivery of ICBs to boost the host's immune system against tumor. We found that this carrier-free therapeutic system can serve as a reservoir for extended tumoral release of camptothecin and aPD1 antibody, resulting in an immune-stimulating tumor microenvironment for boosted PD-1 blockade immune response. Our in vivo results revealed that this combination chemoimmunotherapy elicits robust and durable systemic anticancer immunity, inducing tumor regression and inhibiting tumor recurrence and metastasis. This work sheds important light into the use of small-molecule prodrugs as both chemotherapeutic and carrier to awaken and enhance antitumor immune system for improved ICBs therapy.

20.
ACS Appl Mater Interfaces ; 10(25): 21321-21327, 2018 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-29856210

RESUMEN

Pt-based materials are the most efficient catalysts for the oxygen reduction reaction (ORR) in proton-exchange membrane fuel cells. However, fabrication of active and stable Pt catalysts still remains challenging. In this work, Pt-l-phenylalanine (Pt-LPHE) films, with highly dispersed Pt nanoparticles (NPs) featuring predominately (111) facets, have been prepared via a room-temperature electron reduction method. Loading Pt-LPHE onto carbon support produces a novel nanomaterial (Pt-AL/C), resulting in a simultaneous loading of highly dispersed Pt NPs and N doping. Density functional theory calculations demonstrate that the N dopants stabilize the Pt NPs and reduce the *O/*OH binding energies on the Pt NPs. As a result, the Pt-AL/C nanomaterial shows significantly enhanced ORR activity and stability over commercial Pt/C after 10 000 cycle stability tests. This work provides a novel eco-friendly and energy-neutral approach for preparing metal NPs with controllable structures and sizes.

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