RESUMEN

Inflammation-resident cells within arthritic sites undergo a metabolic shift towards glycolysis, which greatly aggravates rheumatoid arthritis (RA). Reprogramming glucose metabolism can suppress abnormal proliferation and activation of inflammation-related cells without affecting normal cells, holding potential for RA therapy. Single 2-deoxy-d-glucose (2-DG, glycolysis inhibitor) treatment often cause elevated ROS, which is detrimental to RA remission. The rational combination of glycolysis inhibition with anti-inflammatory intervention might cooperatively achieve favorable RA therapy. To improve drug bioavailability and exert synergetic effect, stable co-encapsulation of drugs in long circulation and timely drug release in inflamed milieu is highly desirable. Herein, we designed a stimulus-responsive hyaluronic acid-triglycerol monostearate polymersomes (HTDD) co-delivering 2-DG and dexamethasone (Dex) to arthritic sites. After intravenous injection, HTDD polymersomes facilitated prolonged circulation and preferential distribution in inflamed sites, where overexpressed matrix metalloproteinases and acidic pH triggered drug release. Results indicated 2-DG can inhibit the excessive cell proliferation and activation, and improve Dex bioavailability by reducing Dex efflux. Dex can suppress inflammatory signaling and prevent 2-DG-induced oxidative stress. Thus, the combinational strategy ultimately mitigated RA by inhibiting glycolysis and hindering inflammatory signaling. Our study demonstrated the great potential in RA therapy by reprogramming glucose metabolism in arthritic sites.

Asunto(s)

Artritis Reumatoide , Desoxiglucosa , Dexametasona , Glucosa , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/metabolismo , Animales , Glucosa/metabolismo , Dexametasona/farmacología , Dexametasona/uso terapéutico , Ratones , Desoxiglucosa/farmacología , Inflamación/tratamiento farmacológico , Glucólisis/efectos de los fármacos , Polímeros/química , Ácido Hialurónico/química , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Masculino , Humanos , Proliferación Celular/efectos de los fármacos

RESUMEN

The impact of electrical stimulation has been widely investigated on the wound healing process; however, its practicality is still challenging. This study explores the effect of electrical stimulation on fibroblasts in a culture medium containing different electrically-charged polysaccharide derivatives including alginate, hyaluronate, and chitosan derivatives. For this aim, an electrical stimulation, provided by a zigzag triboelectric nanogenerator (TENG), was exerted on fibroblasts in the presence of polysaccharides' solutions. The analyses showed a significant increase in cell proliferation and an improvement in wound closure (160 % and 90 %, respectively) for the hyaluronate-containing medium by a potential of 3 V after 48 h. In the next step, a photo-crosslinkable hydrogel was prepared based on hyaluronic acid methacrylate (HAMA). Then, the cells were cultured on HAMA hydrogel and treated by an electrical stimulation. Surprisingly, the results showed a remarkable increase in cell growth (280 %) and migration (82 %) after 24 h. Attributed to the electroosmosis phenomenon and an amplified transfer of soluble growth factors, a dramatic promotion was underscored in cell activities. These findings highlight the role of electroosmosis in wound healing, where TENG-based electrical stimulation is combined with bioactive polysaccharide-based hydrogels to promote wound healing.

Asunto(s)

Alginatos , Proliferación Celular , Fibroblastos , Ácido Hialurónico , Hidrogeles , Cicatrización de Heridas , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Alginatos/química , Proliferación Celular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/citología , Hidrogeles/química , Hidrogeles/farmacología , Cicatrización de Heridas/efectos de los fármacos , Estimulación Eléctrica , Polielectrolitos/química , Animales , Ratones , Quitosano/química , Movimiento Celular/efectos de los fármacos , Humanos , Células 3T3 NIH

RESUMEN

Over the last few decades, scientists have recognized the critical role that various components of the extracellular matrix (ECM) play in maintaining homeostatic immunity. Besides, dysregulation in the synthesis or degradation levels of these components directly impacts the mechanisms of immune response during tissue injury caused by tumor processes or the regeneration of the tissue itself in the event of damage. ECM is a complex network of protein compounds, proteoglycans and glycosaminoglycans (GAGs). Hyaluronic acid (HA) is one of the major GAGs of this network, whose metabolism is strictly physiologically regulated and quickly altered in injury processes, affecting the behavior of different cells, from stem cells to differentiated immune cells. In this revision we discuss how the native or chemically modified HA interacts with its specific receptors and modulates intra and intercellular communication of immune cells, focusing on cancer and tissue regeneration conditions.

Asunto(s)

Homeostasis , Ácido Hialurónico , Neoplasias , Regeneración , Humanos , Ácido Hialurónico/metabolismo , Ácido Hialurónico/química , Neoplasias/metabolismo , Neoplasias/inmunología , Neoplasias/patología , Animales , Matriz Extracelular/metabolismo , Inmunidad

RESUMEN

Breast cancer is a malignant tumor that poses a significant threat to women's health and single therapy fails to play a good oncological therapeutic effect. Synergistic treatment with multiple strategies may make up for the deficiencies and has gained widespread attention. In this study, sulfhydryl-modified hyaluronic acid (HA-SH) was covalently crosslinked with polydopamine (PDA) via a Michael addition reaction to develop an injectable hydrogel, in which PDA can be used not only as a matrix but also as a photothermal agent. After HSA and paclitaxel were spontaneously organized into nanoparticles via hydrophobic interaction, hyaluronic acid with low molecular weight was covalently linked to HSA, thus conferring effectively delivery. This photothermal injectable hydrogel incorporates PTX@HSA-HA nanoparticles, thereby initiating a thermochemotherapeutic response to target malignancy. Our results demonstrated that this injectable hydrogel possesses consistent drug delivery capability in a murine breast cancer model, collaborating with photothermal therapy to effectively suppress tumor growth, represented by low expression of Ki-67 and increasing apoptosis. Photothermal therapy (PTT) can effectively stimulate immune response by increasing IL-6 and TNF-α. Notably, the treatment did not elicit any indications of toxicity. This injectable hydrogel holds significant promise as a multifaceted therapeutic agent that integrates photothermal and chemotherapeutic modalities.

Asunto(s)

Neoplasias de la Mama , Ácido Hialurónico , Hidrogeles , Paclitaxel , Terapia Fototérmica , Animales , Ácido Hialurónico/química , Hidrogeles/química , Hidrogeles/farmacología , Femenino , Neoplasias de la Mama/terapia , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Ratones , Terapia Fototérmica/métodos , Paclitaxel/farmacología , Paclitaxel/química , Paclitaxel/administración & dosificación , Humanos , Indoles/química , Indoles/farmacología , Ratones Endogámicos BALB C , Polímeros/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Nanopartículas/química , Portadores de Fármacos/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Fototerapia/métodos

RESUMEN

Chemical crosslinking is a method widely used to enhance the mechanical strength of biopolymer-based scaffolds. Polysaccharides are natural and biodegradable carbohydrate polymers that can act as crosslinking agents to promote the formation of scaffolds. Compared to synthetic crosslinking agents, Polysaccharide-based crosslinking agents have better biocompatibility for cell adhesion and growth. Traditional Chinese medicine has special therapeutic effects on various diseases and is rich in various bioactive ingredients. Among them, polysaccharides have immune regulatory, antioxidant, and anti-inflammation effects, which allow them to not only act as crosslinking agents but endow the scaffold with greater bioactivity. This article focuses on the latest developments of polysaccharide-based crosslinking agents for biomedical scaffolds, including hyaluronic acid, chondroitin sulfate, dextran, alginate, cellulose, gum polysaccharides, and traditional Chinese medicine polysaccharides. Also, we provide a summary and prospects on the research of polysaccharide-based crosslinking agents.

Asunto(s)

Materiales Biocompatibles , Reactivos de Enlaces Cruzados , Polisacáridos , Bases de Schiff , Andamios del Tejido , Polisacáridos/química , Polisacáridos/farmacología , Reactivos de Enlaces Cruzados/química , Andamios del Tejido/química , Bases de Schiff/química , Bases de Schiff/farmacología , Humanos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Ingeniería de Tejidos/métodos , Animales , Ácido Hialurónico/química , Ácido Hialurónico/farmacología

RESUMEN

Background: The formation of adhesion after tendon injury represents a major obstacle to tendon repair, and currently there is no effective anti-adhesion method in clinical practice. Oxidative stress, inflammation, and fibrosis can occur in tendon injury and these factors can lead to tendon adhesion. Antioxidant carbon dots and ursolic acid (UA) both possess antioxidant and anti-inflammatory properties. In this experiment, we have for the first time created RCDs/UA@Lipo-HAMA using red fluorescent carbon dots and UA co-encapsulated liposomes composite hyaluronic acid methacryloyl hydrogel. We found that RCDs/UA@Lipo-HAMA could better attenuate adhesion formation and enhance tendon healing in tendon injury. Materials and Methods: RCDs/UA@Lipo-HAMA were prepared and characterized. In vitro experiments on cellular oxidative stress and fibrosis were performed. Reactive oxygen species (ROS), and immunofluorescent staining of collagens type I (COL I), collagens type III (COL III), and α-smooth muscle actin (α-SMA) were used to evaluate anti-oxidative and anti-fibrotic abilities. In vivo models of Achilles tendon injury repair (ATI) and flexor digitorum profundus tendon injury repair (FDPI) were established. The major organs and blood biochemical indicators of rats were tested to determine the toxicity of RCDs/UA@Lipo-HAMA. Biomechanical testing, motor function analysis, immunofluorescence, and immunohistochemical staining were performed to assess the tendon adhesion and repair after tendon injury. Results: In vitro, the RCDs/UA@Lipo group scavenged excessive ROS, stabilized the mitochondrial membrane potential (ΔΨm), and reduced the expression of COL I, COL III, and α-SMA. In vivo, assessment results showed that the RCDs/UA@Lipo-HAMA group improved collagen arrangement and biomechanical properties, reduced tendon adhesion, and promoted motor function after tendon injury. Additionally, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) in the RCDs/UA@Lipo-HAMA group increased; the levels of cluster of differentiation 68 (CD68), inducible Nitric Oxide Synthase (iNOS), COL III, α-SMA, Vimentin, and matrix metallopeptidase 2 (MMP2) decreased. Conclusion: In this study, the RCDs/UA@Lipo-HAMA alleviated tendon adhesion formation and enhanced tendon healing by attenuating oxidative stress, inflammation, and fibrosis. This study provided a novel therapeutic approach for the clinical treatment of tendon injury.

Asunto(s)

Antioxidantes , Carbono , Hidrogeles , Liposomas , Ratas Sprague-Dawley , Traumatismos de los Tendones , Triterpenos , Ácido Ursólico , Animales , Triterpenos/farmacología , Triterpenos/química , Antioxidantes/farmacología , Antioxidantes/química , Liposomas/química , Traumatismos de los Tendones/tratamiento farmacológico , Adherencias Tisulares/tratamiento farmacológico , Carbono/química , Carbono/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Ratas , Estrés Oxidativo/efectos de los fármacos , Masculino , Cicatrización de Heridas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Puntos Cuánticos/química , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Tendón Calcáneo/efectos de los fármacos , Tendón Calcáneo/lesiones

RESUMEN

The combination of the standard platinum-based chemotherapy with EGFR-tyrosine kinase inhibitor Gefitinib (Gef) principally boosts the anticancer efficacy of advanced non-small cell lung cancer (NSCLC) through non-overlapping mechanisms of action, however the clinical trials of cisplatin (Cis) and Gef combination failed to show a therapeutic improvement likely due to compromised cellular influx of Cis with the Gef interference. To overcome the antagonism between Cis and Gef in anti-NSCLC therapy, here we demonstrated a self-targeted hyaluronan (HA) nanogel to facilitate the anticancer co-delivery by utilizing the HA's intrinsic targeting towards CD44, a receptor frequently overexpressed on lung cancer cells. The co-assembly between HA, Cis and Gef generated a HA/Cis/Gef nanogel of 177.8 nm, featuring a prolonged drug release. Unlike the Gef inhibited the Cis uptake, the HA/Cis/Gef nanogel efficiently facilitated the drug internalization through CD44-targeted delivery as verified by HA competition and CD44 knocking down in H1975 NSCLC model both in vitro and in vivo. Moreover, the HA/Cis/Gef nanogel significantly improved the anticancer efficacy and meanwhile diminished the side effects in reference to the combination of free Cis and Gef. This CD44-targeted HA/Cis/Gef nanogel provided a potent strategy to advance the platinum-based combination therapy towards optimized NSCLC therapy.

Asunto(s)

Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Cisplatino , Gefitinib , Receptores de Hialuranos , Ácido Hialurónico , Neoplasias Pulmonares , Nanogeles , Ácido Hialurónico/química , Receptores de Hialuranos/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Humanos , Cisplatino/farmacología , Cisplatino/administración & dosificación , Cisplatino/química , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Gefitinib/farmacología , Gefitinib/química , Gefitinib/administración & dosificación , Animales , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Ratones , Nanogeles/química , Línea Celular Tumoral , Ratones Desnudos , Liberación de Fármacos , Ratones Endogámicos BALB C , Sistemas de Liberación de Medicamentos , Portadores de Fármacos/química

RESUMEN

Oral squamous cell carcinoma (OSCC) is highly heterogeneous and aggressive, but therapies based on single-targeted nanoparticles frequently address these tumors as a single illness. To achieve more efficient drug transport, it is crucial to develop nanodrug-carrying systems that simultaneously target two or more cancer biomarkers. In addition, combining chemotherapy with near-infrared (NIR) light-mediated thermotherapy allows the thermal ablation of local malignancies via photothermal therapy (PTT), and triggers drug release to improve chemosensitivity. Thus, a novel dual-targeted nano-loading system, DOX@GO-HA-HN-1 (GHHD), was created for synergistic chemotherapy and PTT by the co-modification of carboxylated graphene oxide (GO) with hyaluronic acid (HA) and HN-1 peptide and loading with the anticancer drug doxorubicin (DOX). Targeted delivery using GHHD was shown to be superior to single-targeted nanoparticle delivery. NIR radiation will encourage the absorption of GHHD by tumor cells and cause the site-specific release of DOX in conjunction with the acidic microenvironment of the tumor. In addition, chemo-photothermal combination therapy for cancer treatment was realized by causing cell apoptosis under the irradiation of 808-nm laser. In summary, the application of GHHD to chemotherapy combined with photothermal therapy for OSCC is shown to have important potential as a means of combatting the low accumulation of single chemotherapeutic agents in tumors and drug resistance generated by single therapeutic means, enhancing therapeutic efficacy.

Asunto(s)

Carcinoma de Células Escamosas , Doxorrubicina , Sistemas de Liberación de Medicamentos , Grafito , Rayos Infrarrojos , Neoplasias de la Boca , Doxorrubicina/farmacología , Doxorrubicina/química , Humanos , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Neoplasias de la Boca/terapia , Grafito/química , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Concentración de Iones de Hidrógeno , Portadores de Fármacos/química , Nanopartículas/química , Liberación de Fármacos , Animales , Apoptosis/efectos de los fármacos , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/administración & dosificación , Proliferación Celular/efectos de los fármacos , Terapia Fototérmica , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Ácido Hialurónico/química , Supervivencia Celular/efectos de los fármacos , Ratones , Tamaño de la Partícula , Propiedades de Superficie

RESUMEN

In the realm of intracellular drug delivery, overcoming the barrier of endosomal entrapment stands as a critical factor influencing the effectiveness of nanodrug delivery systems. This study focuses on the synthesis of an acid-sensitive fatty acid derivative called imidazole-stearic acid (IM-SA). Leveraging the proton sponge effect attributed to imidazole groups, IM-SA was anticipated to play a pivotal role in facilitating endosomal escape. Integrated into the lipid core of solid lipid nanoparticles (SLNs), IM-SA was paired with hyaluronic acid (HA) coating on the surface of SLNs loading with curcumin (CUR). The presence of IM-SA and HA endowed HA-IM-SLNs@CUR with dual functionalities, enabling the promotion of endosomal escape, and specifical targeting of liver cancer. HA-IM-SLNs@CUR exhibited a particle size of ∼228 nm, with impressive encapsulation efficiencies (EE) of 87.5 % ± 2.3 % for CUR. Drugs exhibit significant pH sensitive release behavior. Cellular experiments showed that HA-IM-SLN@CUR exhibits enhanced drug delivery capability. The incorporation of IM-SA significantly improved the endosomal escape of HA-IM-SLN@CUR, facilitating accelerated intracellular drug release and increasing intracellular drug concentration, exhibiting excellent growth inhibitory effects on HepG2 cells. Animal experiments revealed a 3.4-fold increase in CUR uptake at the tumor site with HA-IM-SLNs@CUR over the free CUR, demonstrating remarkable tumor homing potential with the tumor growth inhibition rate of 97.2 %. These findings indicated the significant promise of HA-IM-SLNs@CUR in the realm of cancer drug delivery.

Asunto(s)

Antineoplásicos , Curcumina , Endosomas , Nanopartículas , Tamaño de la Partícula , Curcumina/farmacología , Curcumina/química , Humanos , Nanopartículas/química , Animales , Endosomas/metabolismo , Endosomas/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Células Hep G2 , Liberación de Fármacos , Ratones , Lípidos/química , Sistemas de Liberación de Medicamentos , Proliferación Celular/efectos de los fármacos , Hígado/metabolismo , Hígado/efectos de los fármacos , Propiedades de Superficie , Portadores de Fármacos/química , Ácidos Esteáricos/química , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Imidazoles/química , Imidazoles/farmacología , Ratones Desnudos , Ácido Hialurónico/química , Ratones Endogámicos BALB C , Liposomas

RESUMEN

Background: Triple negative breast cancer (TNBC) is one of the worst prognosis types of breast cancer that urgently needs effective therapy methods. However, cancer is a complicated disease that usually requires multiple treatment modalities. Methods: A tumor microenvironment (TME)-responsive PFC/TRIM37@Fe-TA@HA (abbreviated as PTFTH) nanoplatform was constructed by coating Fe3+ and tannic acid (TA) on the surface of TRIM37-siRNA loaded phase-transition perfluorocarbon (PFC) nanodroplets and further modifying them with hyaluronic acid (HA) to achieve tumor-specific mild photothermal/gene/ferroptosis synergistic therapy (MPTT/GT/ Ferroptosis) in vitro. Once internalized into tumor cells through CD44 receptor-mediated active targeting, the HA shell of PTFTH would be preliminarily disassembled by hyaluronidase (HAase) to expose the Fe-TA metal-phenolic networks (MPNs), which would further degrade in response to an acidic lysosomal environment, leading to HAase/pH dual-responsive release of Fe3+ and PFC/TRIM37. Results: PTFTH showed good biocompatibility in vitro. On the one hand, the released Fe3+ could deplete the overexpressed glutathione (GSH) through redox reactions and produce Fe2+, which in turn converts endogenous H2O2 into highly cytotoxic hydroxyl radicals (•OH) for chemodynamic therapy (CDT). On the other hand, the local hyperthermia generated by PTFTH under 808 nm laser irradiation could not only improve CDT efficacy through accelerating the Fe2+-mediated Fenton reaction, but also enhance TRIM37-siRNA delivery for gene therapy (GT). The consumption of GSH and accumulation of •OH synergistically augmented intracellular oxidative stress, resulting in substantial tumor cell ferroptosis. Moreover, PTFTH possessed outstanding contrast enhanced ultrasound (CEUS), photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) ability. Conclusion: This PTFTH based multiple-mode therapeutic strategy has successfully achieved a synergistic anticancer effect in vitro and has the potential to be translated into clinical application for tumor therapy in future.

Asunto(s)

Ferroptosis , Glutatión , Ácido Hialurónico , Nanopartículas , Terapia Fototérmica , ARN Interferente Pequeño , Taninos , Neoplasias de la Mama Triple Negativas , Microambiente Tumoral , Humanos , Ferroptosis/efectos de los fármacos , Glutatión/metabolismo , Glutatión/química , Microambiente Tumoral/efectos de los fármacos , Línea Celular Tumoral , Taninos/química , Taninos/farmacología , Nanopartículas/química , Ácido Hialurónico/química , Femenino , Neoplasias de la Mama Triple Negativas/terapia , Neoplasias de la Mama Triple Negativas/genética , ARN Interferente Pequeño/química , ARN Interferente Pequeño/farmacología , ARN Interferente Pequeño/genética , Terapia Fototérmica/métodos , Fluorocarburos/química , Fluorocarburos/farmacología , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Terapia Genética/métodos , Terapia Combinada/métodos , Animales , Hierro/química , Hialuronoglucosaminidasa/genética , Hialuronoglucosaminidasa/metabolismo

RESUMEN

As a novel therapeutic approach, photothermal therapy (PTT) combined with chemotherapy can synergistically produce antitumor effects. Herein, dithiodipropionic acid (DTDP) was used as a donor of disulfide bonds sensitive to the tumor microenvironment for establishing chemical bonding between the photosensitizer indocyanine green amino (ICG-NH2) and acidified single-walled carbon nanotubes (CNTs). The CNT surface was then coated with conjugates (HD) formed by the targeted modifier hyaluronic acid (HA) and 1,2-tetragacylphosphatidyl ethanolamine (DMPE). After doxorubicin hydrochloride (DOX), used as the model drug, was loaded by CNT carriers, functional nano-delivery systems (HD/CNTs-SS-ICG@DOX) were developed. Nanosystems can effectively induce tumor cell (MCF-7) death in vitro by accelerating cell apoptosis, affecting cell cycle distribution and reactive oxygen species (ROS) production. The in vivo antitumor activity results in tumor-bearing model mice, further verifying that HD/CNTs-SS-ICG@DOX inhibited tumor growth most significantly by mediating a synergistic effect between chemotherapy and PTT, while various functional nanosystems have shown good biological tissue safety. In conclusion, the composite CNT delivery systems developed in this study possess the features of high biocompatibility, targeted delivery, and responsive drug release, and can achieve the efficient coordination of chemotherapy and PTT, with broad application prospects in cancer treatment.

Asunto(s)

Doxorrubicina , Nanotubos de Carbono , Terapia Fototérmica , Microambiente Tumoral , Nanotubos de Carbono/química , Animales , Humanos , Microambiente Tumoral/efectos de los fármacos , Terapia Fototérmica/métodos , Ratones , Doxorrubicina/farmacología , Doxorrubicina/química , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Verde de Indocianina/química , Células MCF-7 , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Femenino , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Endogámicos BALB C , Terapia Combinada/métodos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Ácido Hialurónico/química

RESUMEN

Rheumatoid arthritis (RA) involves chronic inflammation, oxidative stress, and complex immune cell interactions, leading to joint destruction. Traditional treatments are often limited by off-target effects and systemic toxicity. This study introduces a novel therapeutic approach using hyaluronic acid (HA)-conjugated, redox-responsive polyamino acid nanogels (HA-NG) to deliver tacrolimus (TAC) specifically to inflamed joints. The nanogels' disulfide bonds enable controlled TAC release in response to high intracellular glutathione (GSH) levels in activated macrophages, prevalent in RA-affected tissues. In vitro results demonstrated that HA-NG/TAC significantly reduced TAC toxicity to normal macrophages and showed high biocompatibility. In vivo, HA-NG/TAC accumulated more in inflamed joints compared to non-targeted NG/TAC, enhancing therapeutic efficacy and minimizing side effects. Therapeutic evaluation in collagen-induced arthritis (CIA) mice revealed HA-NG/TAC substantially reduced paw swelling, arthritis scores, synovial inflammation, and bone erosion while suppressing pro-inflammatory cytokine levels. These findings suggest that HA-NG/TAC represents a promising targeted drug delivery system for RA, offering potential for more effective and safer clinical applications.

Asunto(s)

Artritis Experimental , Artritis Reumatoide , Ácido Hialurónico , Nanogeles , Péptidos , Tacrolimus , Animales , Ácido Hialurónico/química , Artritis Reumatoide/tratamiento farmacológico , Ratones , Tacrolimus/farmacología , Tacrolimus/uso terapéutico , Tacrolimus/química , Tacrolimus/farmacocinética , Artritis Experimental/tratamiento farmacológico , Péptidos/química , Péptidos/farmacología , Nanogeles/química , Masculino , Células RAW 264.7 , Sistemas de Liberación de Medicamentos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones Endogámicos DBA , Portadores de Fármacos/química , Humanos

RESUMEN

Intracellular pathogens can survive inside the macrophages to protect themselves from eradication by the innate immune system and conventional antibiotics, resulting in severe bacterial infections. In this work, an antibiotic-free nanocomplex (HA/GA-Fe@NO-DON), exhibiting macrophage-targeted synergistic gas therapy (nitric oxide, NO)/chemodynamic therapy/immunotherapy, was reported. HA/GA-Fe nanoparticles were synthesized by the strong coordination interactions among carboxyl groups of hyaluronic acid (HA), polyphenol groups of gallic acid (GA), and Fe(II) ions. The hydrophobic glutathione (GSH)-responsive NO donor (NO-DON) was encapsulated in HA/GA-Fe nanoparticles to form the final nanocomplexes (HA/GA-Fe@NO-DON). HA on the nanocomplexes guides the macrophage-specific uptake and intracellular accumulation. After the uptake, HA/GA-Fe@NO-DON nanocomplexes could not only generate highly toxic hydroxyl radicals (•OH) by the Fenton reaction and GSH depletion but also release NO when stimulated by intracellular GSH. Meanwhile, the nanocomplexes could trigger an efficient proinflammation immune response to reinforce the antibacterial activity. This work presents the development of antibiotic-free macrophage-targeted HA/GA-Fe@NO-DON nanocomplexes as an effective adjuvant nanomedicine with synergistic gas therapy/chemodynamic therapy/immunotherapy for eliminating intracellular bacterial infection.

Asunto(s)

Ácido Gálico , Glutatión , Macrófagos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Ratones , Animales , Glutatión/química , Glutatión/metabolismo , Células RAW 264.7 , Ácido Gálico/química , Ácido Gálico/farmacología , Inmunoterapia/métodos , Óxido Nítrico/metabolismo , Óxido Nítrico/química , Ácido Hialurónico/química , Infecciones Bacterianas/tratamiento farmacológico , Nanopartículas/química , Hierro/química

RESUMEN

Engineered vascularized tissues in vitro exhibit the potential for transplantation therapy and disease modeling. Despite efforts to design hydrogels as cell culture platforms for in vitro vascularization, development of vascularized tissues recapitulating the natural structures and functions remains difficult due to a poor understanding of the relationships between the matrix microstructures and tube formation of endothelial cells. Herein, we developed microfiber network hydrogels with microporous structures by controlling the liquid-liquid phase separation (LLPS) of proteins and matrix structures in hydrogels. Extracellular matrix protein gelatin was modified with hydrogen-bonding moieties and mixed with hyaluronic acid sodium salt to form microfiber network structures. Gelatin gelation and hyaluronic acid sodium salt dissolution led to the formation of a microporous microfiber network hydrogel formation. Matrix structures of hydrogels were modified by controlling LLPS that affects endothelial cell tube formation. Vascularization was improved using laminin peptides and coculturing with mesenchymal stem cells. Overall, our approach exhibits the potential to induce in vitro vascularization for regenerative medicine and disease modeling applications.

Asunto(s)

Células Endoteliales de la Vena Umbilical Humana , Ácido Hialurónico , Hidrogeles , Células Madre Mesenquimatosas , Neovascularización Fisiológica , Hidrogeles/química , Hidrogeles/farmacología , Humanos , Neovascularización Fisiológica/efectos de los fármacos , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Gelatina/química , Ingeniería de Tejidos/métodos , Laminina/química , Laminina/farmacología

RESUMEN

Synovial fluid lubricates articular joints by forming a hydrated layer between the cartilage surfaces. In degenerative joint diseases like osteoarthritis (OA), the synovial fluid is compromised, which leads to less effective innate lubrication and exacerbated cartilage degeneration. Studies over the years have led to the development of partially or fully synthetic biolubricants to reduce the coefficient of friction with cartilage in knee joints. Cartilage-adhering, hydrated lubricants are particularly important to provide cartilage lubrication and chondroprotection under high normal load and slow speed. Here, we report the development of a hyaluronic acid (HA)-based lubricant functionalized with cationic branched poly-L-lysine (BPL) molecules that bind to cartilage via electrostatic interactions. We surmised that the electrostatic interactions between the BPL-modified HA molecules (HA-BPL) and the cartilage facilitate localization of the HA molecules to the cartilage surface. The number of BPL molecules on the HA backbone was varied to determine the optimal grafting density for cartilage binding and HA localization. Collectively, our results show that our HA-BPL molecules adhered readily to cartilage and were effective as a lubricant in cartilage-on-cartilage shear measurements where the modified HA molecules significantly reduce the coefficient of friction compared to phosphate-buffered saline or HA alone. This proof-of-concept study shows how the incorporation of cartilage adhering moieties, such as cationic molecules, can be used to enhance cartilage binding and lubrication properties of HA.

Asunto(s)

Cartílago Articular , Cationes , Ácido Hialurónico , Lubrificación , Polilisina , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Adsorción , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Cationes/química , Animales , Polilisina/química , Polilisina/farmacología , Bovinos , Lubricantes/química , Lubricantes/farmacología , Fricción/efectos de los fármacos , Líquido Sinovial/metabolismo , Líquido Sinovial/química , Líquido Sinovial/efectos de los fármacos

RESUMEN

The development of products with skin-protective effects has been driven by the increasing incidence of skin diseases that are exacerbated by increasing pollution, urbanization, poor living, working, fatigue, dietary habits, and general treatment. The ability of antioxidants to protect the skin from oxidative stress and its effects makes them one of the most important ingredients in today's cosmetics. This article aims first to characterize the plant extracts obtained from Acmella oleracea (A. oleracea) and then to evaluate the preliminary criteria for a new marketed product: the stability, antioxidant activity, and in vitro behavior of certain serums based on A. oleracea plant extract and hyaluronic acid. The extracts were obtained by liquid-solid extraction methods (maceration (M), ultrasound-assisted extraction (UEA), and a combined method between these two (UEA + M) using an aqueous solution of ethyl alcohol as the extraction solvent. The determination of the amounts of compounds with antioxidant activity highlighted the fact that the extract obtained from the whole plant of A. oleracea using maceration in conditions of S/L = 1:30, 20 days, and an extraction solvent percentage of 50% led to obtaining the highest amount of polyphenols (30.42 µg GAE/g), while using the combined UAE + M method under conditions of S/L = 1:30, 6 min + 20 days, and 50% extraction solvent led to obtaining the highest amount of flavonoids (32.88 mg QE/g). The tests performed on dermato-cosmetic serums based on the plant extract and multimolecular hyaluronic acid (HA) (1 HA with HMW-1.0 mDa-1.6 mDa; HA with LMW-10 kDa-200 kDa; and HA OLIGO, MW < 10 kDa) led to the conclusion that they exhibit structural stability, good shear behavior revealing a satisfactory texture, and high physical stability during storage. These results encourage the transition to in-depth testing, both microbiological and dermatological, as a final step in the consideration of a new commercial product.

Asunto(s)

Antioxidantes , Estrés Oxidativo , Extractos Vegetales , Extractos Vegetales/química , Extractos Vegetales/farmacología , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/química , Humanos , Cosméticos/química , Piel/metabolismo , Piel/efectos de los fármacos , Piel/química , Ácido Hialurónico/química , Asteraceae/química

RESUMEN

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor. Standard therapy includes maximal surgical resection, radiotherapy, and adjuvant temozolomide (TMZ) administration. However, the rapid development of TMZ resistance and the impermeability of the blood-brain barrier (BBB) significantly hinder the therapeutic efficacy. Herein, we developed spatiotemporally controlled microneedle patches (BMNs) loaded with TMZ and niclosamide (NIC) to overcome GBM resistance. We found that hyaluronic acid (HA) increased the viscosity of bovine serum albumin (BSA) and evidenced that concentrations of BSA/HA exert an impact degradation rates exposure to high-temperature treatment, showing that the higher BSA/HA concentrations result in slower drug release. To optimize drug release rates and ensure synergistic antitumor effects, a 15% BSA/HA solution constituting the bottoms of BMNs was chosen to load TMZ, showing sustained drug release for over 28 days, guaranteeing long-term DNA damage in TMZ-resistant cells (U251-TR). Needle tips made from 10% BSA/HA solution loaded with NIC released the drug within 14 days, enhancing TMZ's efficacy by inhibiting the activity of O6-methylguanine-DNA methyltransferase (MGMT). BMNs exhibit superior mechanical properties, bypass the BBB, and gradually release the drug into the tumor periphery, thus significantly inhibiting tumor proliferation and expanding median survival in mice. The on-demand delivery of BMNs patches shows a strong translational potential for clinical applications, particularly in synergistic GBM treatment.

Asunto(s)

Glioblastoma , Ácido Hialurónico , Niclosamida , Albúmina Sérica Bovina , Temozolomida , Temozolomida/química , Temozolomida/farmacología , Temozolomida/farmacocinética , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/metabolismo , Animales , Humanos , Ratones , Niclosamida/farmacología , Niclosamida/química , Niclosamida/farmacocinética , Albúmina Sérica Bovina/química , Ácido Hialurónico/química , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Agujas , Sistemas de Liberación de Medicamentos/instrumentación , Ratones Desnudos , Liberación de Fármacos

RESUMEN

Neurofibromatosis Type 1 (NF1) is a complex genetic disorder characterized by the development of benign neurofibromas, which can cause significant morbidity in affected individuals. While the molecular mechanisms underlying NF1 pathogenesis have been extensively studied, the development of effective therapeutic strategies remains a challenge. This paper presents the development and validation of a novel biomaterial testing model to enhance our understanding of NF1 pathophysiology, disease mechanisms and evaluate potential therapeutic interventions. Our long-term goal is to develop an invitro model of NF1 to evaluate drug targets. We have developed an in vitro system to test the cellular behavior of NF1 patient derived cells on electroconductive aligned nanofibrous biomaterials with electrical stimulatory cues. We hypothesized that cells cultured on electroconductive biomaterial will undergo morphological changes and variations in cell proliferation that could be further enhanced with the combination of exogenous electrical stimulation (ES). In this study, we developed electrospun Hyaluronic Acid-Carbon Nanotube (HA-CNT) nanofiber scaffolds to mimic the axon's topographical and bioelectrical cues that influence neurofibroma growth and development. The cellular behavior was qualitatively and quantitively analyzed through immunofluorescent stains, Alamar blue assays and ELISA assays. Schwann cells from NF1 patients appear to have lost their ability to respond to electrical stimulation in the development and regeneration range, which was seen through changes in morphology, proliferation and NGF release. Without stimulation, the conductive material enhances NF1 SC behavior. Wild-type SC respond to electrical stimulation with increased cell proliferation and NGF release. Using this system, we can better understand the interaction between axons and SC that lead to tumor formation, homeostasis and regeneration.

Asunto(s)

Proliferación Celular , Estimulación Eléctrica , Ácido Hialurónico , Nanotubos de Carbono , Células de Schwann , Células de Schwann/metabolismo , Nanotubos de Carbono/química , Humanos , Ácido Hialurónico/química , Nanofibras/química , Neurofibromatosis 1/patología , Neurofibromatosis 1/metabolismo , Andamios del Tejido/química , Células Cultivadas , Materiales Biocompatibles/química

RESUMEN

Human hyaluronidase 1 (HYAL1) and PH20 play vital roles in degrading hyaluronic acids through the substrate-assisted double displacement mechanism. While HYAL1, a lysosomal enzyme, functions optimally under acidic conditions, PH20, a sperm surface hyaluronidase, displays a broader pH range, from acidic to neutral. Our objective was to extend HYAL1's pH range towards neutral pH by introducing repulsive charge-charge interactions involving the catalytic Glu131, increasing its pKa as the proton donor. Substituting individual acidic residues in the ß3-loop (S77D), ß3'-ß3″ hairpin (T86D and P87E), and at Ala132 (A132D and A132E) enabled HYAL1 to demonstrate enzyme activity at pH 7, with the mutants S77D, P87E, and A132E showing the highest activity in the substrate gel assay. However, double and triple substitutions, including S77D/T86D/A132E as found in the PH20 configuration, did not result in enhanced activity compared to single substitutions. Conversely, PH20 mutants with non-acidic substitutions, such as D94S in the ß3-loop and D103T in the ß3'-ß3″ hairpin, significantly reduced activity within the pH range of 4 to 7. However, the PH20 mutant E149A, reciprocally substituted compared to A132E in HYAL1, exhibited activity similar to PH20 wild-type (WT) at pH 7. In a turbidimetric assay, HYAL1 mutants with single acidic substitutions exhibited activity similar to that of PH20 WT at pH 7. These results suggest that substituting acidic residues near Glu131 results in HYAL1 activity at neutral pH through electrostatic repulsion. This study highlights the significance of charge-charge interactions in both HYAL1 and PH20 in regulating the pH-dependent activity of hyaluronidases.

Asunto(s)

Hialuronoglucosaminidasa , Humanos , Sustitución de Aminoácidos , Dominio Catalítico , Moléculas de Adhesión Celular , Ácido Glutámico/metabolismo , Ácido Glutámico/química , Ácido Hialurónico/metabolismo , Ácido Hialurónico/química , Hialuronoglucosaminidasa/química , Hialuronoglucosaminidasa/metabolismo , Hialuronoglucosaminidasa/genética , Concentración de Iones de Hidrógeno , Modelos Moleculares , Mutación

RESUMEN

Although minimally invasive interventional occluders can effectively seal heart defect tissue, they still have some limitations, including poor endothelial healing, intense inflammatory response, and thrombosis formation. Herein, a polyphenol-reinforced medicine/peptide glycocalyx-like coating was prepared on cardiac occluders. A coating consisting of carboxylated chitosan, epigallocatechin-3-gallate (EGCG), tanshinone IIA sulfonic sodium (TSS), and hyaluronic acid grafted with 3-aminophenylboronic acid was prepared. Subsequently, the mercaptopropionic acid-GGGGG-Arg-Glu-Asp-Val peptide was grafted by the thiol-ene "click" reaction. The coating showed good hydrophilicity and free radical-scavenging ability and could release EGCG-TSS. The results of biological experiments suggested that the coating could reduce thrombosis by promoting endothelialization, and promote myocardial repair by regulating the inflammatory response. The functions of regulating cardiomyocyte apoptosis and metabolism were confirmed, and the inflammatory regulatory functions of the coating were mainly dependent on the NF-kappa B and TNF signaling pathway.

Asunto(s)

Glicocálix , Hidrogeles , Polifenoles , Animales , Hidrogeles/química , Hidrogeles/farmacología , Polifenoles/química , Polifenoles/farmacología , Glicocálix/metabolismo , Glicocálix/química , Glicocálix/efectos de los fármacos , Inmunomodulación/efectos de los fármacos , Regeneración/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Ratas , Apoptosis/efectos de los fármacos , Ratones , Miocardio/metabolismo , Catequina/química , Catequina/análogos & derivados , Catequina/farmacología , Ratas Sprague-Dawley , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Masculino