RESUMO
Lipid nanoparticles (LNPs)-based messenger RNA (mRNA) therapeutics have emerged with promising potentials in the fields of infectious diseases, cancer vaccines, and protein replacement therapies; however, their therapeutic efficacy and safety can still be promoted by the optimization of LNPs formulations. Unfortunately, current LNPs suffer from increased production of reactive oxygen species during translation, which leads to a decreased translation efficiency and the onset of inflammation and other side effects. Herein, we synthesize a lipid-modified poly(guanidine thioctic acid) polymer to fabricate novel LNPs for mRNA vaccines. The acquired G-LNPs significantly promote the translation efficiency of loaded mRNA and attenuate inflammation after vaccination through the elimination of reactive oxygen species that are responsible for translational inhibition and inflammatory responses. In vivo studies demonstrate the excellent antitumor efficacy of the G-LNPs@mRNA vaccine, and two-dose vaccination dramatically increases the population and infiltration of cytotoxic T cells due to the intense antitumor immune responses, thus generating superior antitumor outcomes compared with the mRNA vaccine prepared from traditional LNPs. By synergy with immune checkpoint blockade, the tumor inhibition of G-LNPs@mRNA is further boosted, indicating that G-LNPs-based mRNA vaccines will be powerful and versatile platforms to combat cancer.
Assuntos
Vacinas Anticâncer , Lipídeos , Lipossomos , Nanopartículas , RNA Mensageiro , Vacinas Anticâncer/química , Vacinas Anticâncer/imunologia , Nanopartículas/química , Animais , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Lipídeos/química , Humanos , Ácido Tióctico/química , Ácido Tióctico/farmacologia , Polímeros/química , Guanidinas/química , Guanidinas/farmacologia , Linhagem Celular TumoralRESUMO
A low-triggering potential and a narrow-potential window are anticipated to decrease the electrochemical interference and cross talk of electrochemiluminescence (ECL). Herein, by exploiting the low oxidative potential (0.82 V vs Ag/AgCl) of dihydrolipoic acid-capped sliver nanoclusters (DHLA-AgNCs), a coreactant ECL system of DHLA-AgNCs/hydrazine (N2H4) is proposed to achieve efficient and oxidative-reduction ECL with a low-triggering potential of 0.82 V (vs Ag/AgCl) and a narrow-potential window of 0.22 V. The low-triggering-potential and narrow-potential-window nature of ECL can be primarily preserved upon labeling DHLA-AgNCs to probe DNA and immobilizing DHLA-AgNCs onto the Au surface via sandwiched hybridization, which eventually enables a selective ECL strategy for the gene assay at +0.82 V. This gene assay strategy can sensitively determine the gene of human papillomavirus from 10 to 1000 pM with a low limit of detection of 5 pM (S/N = 3) and would open a way to improve the applied ECL bioassay.
Assuntos
Técnicas Eletroquímicas , Medições Luminescentes , Nanopartículas Metálicas , Prata , Ácido Tióctico/análogos & derivados , Prata/química , Técnicas Eletroquímicas/métodos , Nanopartículas Metálicas/química , Medições Luminescentes/métodos , Humanos , Ácido Tióctico/química , Técnicas Biossensoriais/métodos , DNA Viral/análise , DNA Viral/genética , Limite de DetecçãoRESUMO
Flexible wearable sensors recently have made significant progress in human motion detection and health monitoring. However, most sensors still face challenges in terms of single detection targets, single application environments, and non-recyclability. Lipoic acid (LA) shows a great application prospect in soft materials due to its unique properties. Herein, ionic conducting elastomers (ICEs) based on polymerizable deep eutectic solvents consisting of LA and choline chloride are prepared. In addition to the good mechanical strength, high transparency, ionic conductivity, and self-healing efficiency, the ICEs exhibit swelling-strengthening behavior and enhanced adhesion strength in underwater environments due to the moisture-induced association of poly(LA) hydrophobic chains, thus making it possible for underwater sensing applications, such as underwater communication. As a strain sensor, it exhibits highly sensitive strain response with repeatability and durability, enabling the monitoring of both large and fine human motions, including joint movements, facial expressions, and pulse waves. Furthermore, due to the enhancement of ion mobility at higher temperatures, it also possesses excellent temperature-sensing performance. Notably, the ICEs can be fully recycled and reused as a new strain/temperature sensor through heating. This study provides a novel strategy for enhancing the mechanical strength of poly(LA) and the fabrication of multifunctional sensors.
Assuntos
Ácido Tióctico , Água , Dispositivos Eletrônicos Vestíveis , Ácido Tióctico/química , Água/química , Humanos , Temperatura , Elastômeros/químicaRESUMO
Stroke poses a serious risk to the physical and mental health of patients. Endogenous compounds are widely used to treat ischemic stroke. Lipoic acid, a naturally occurring (R)-5-(1,2-dithiolan-3-yl)pentanoic acid, has therapeutic potential for the treatment of ischemic stroke. However, the direct application of lipoic acid is limited by its relatively low efficacy and instability. Therefore, there is a need to modify the structure of lipoic acid to improve its pharmaceutical capabilities. Currently, 37 lipoic acid derivatives have been synthesized, and compound AA-9 demonstrated optimal therapeutic potential in an in vitro model of induced oxidative damage using tert-butyl hydroperoxide (t-BHP). In addition, in vitro experiments have shown that compound AA-9 has an excellent safety profile. Subsequently, the therapeutic effect of AA-9 was significant in the rat MCAO ischemic stroke model, which may be attributed to the antioxidant and anti-inflammatory effects of compound AA-9 by activating PGC-1α and inhibiting NLRP3. Notably, compound AA-9 exhibited higher stability and better bioavailability properties than ALA in plasma stability and pharmacokinetic properties. In conclusion, AA-9 may be a promising neuroprotective agent for the treatment of ischemic stroke and warrants further investigation.
Assuntos
AVC Isquêmico , Fármacos Neuroprotetores , Estresse Oxidativo , Ratos Sprague-Dawley , Ácido Tióctico , Ácido Tióctico/química , Ácido Tióctico/farmacologia , Ácido Tióctico/síntese química , Animais , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Estresse Oxidativo/efeitos dos fármacos , Ratos , AVC Isquêmico/tratamento farmacológico , Estrutura Molecular , Relação Estrutura-Atividade , Masculino , Descoberta de Drogas , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Inflamação/metabolismo , HumanosRESUMO
Osteoporosis is a highly prevalent metabolic disease characterized by low systemic bone mass and deterioration of bone microarchitecture, resulting in reduced bone strength and increased fracture risk. Current treatment options for osteoporosis are limited by factors such as efficacy, cost, availability, side effects, and acceptability to patients. Gold nanoparticles show promise as an emerging osteoporosis therapy due to their osteogenic effects and ability to allow therapeutic delivery but have inherent constraints, such as low specificity and the potential for heavy metal accumulation in the body. This study reports the synthesis of ultrasmall gold particles almost reaching the Ångstrom (Ång) dimension. The antioxidant alpha-lipoic acid (LA) is used as a dispersant and stabilizer to coat Ångstrom-scale gold particles (AuÅPs). Alendronate (AL), an amino-bisphosphonate commonly used in drug therapy for osteoporosis, is conjugated through LA to the surface of AuÅPs, allowing targeted delivery to bone and enhancing antiresorptive therapeutic effects. In this study, alendronate-loaded Ångstrom-scale gold particles (AuÅPs-AL) were used for the first time to promote osteogenesis and alleviate bone loss through regulation of the WNT signaling pathway, as shown through in vitro tests. The in vivo therapeutic effects of AuÅPs-AL were demonstrated in an established osteoporosis mouse model. The results of Micro-computed Tomography, histology, and tartrate-resistant acid phosphatase staining indicated that AuÅPs-AL significantly improved bone density and prevented bone loss, with no evidence of nanoparticle-associated toxicity. These findings suggest the possible future application of AuÅPs-AL in osteoporosis therapy and point to the potential of developing new approaches for treating metabolic bone diseases using Ångstrom-scale gold particles.
Assuntos
Alendronato , Ouro , Nanopartículas Metálicas , Osteoporose , Ácido Tióctico , Animais , Alendronato/química , Alendronato/farmacologia , Ácido Tióctico/química , Ácido Tióctico/farmacologia , Ouro/química , Osteoporose/tratamento farmacológico , Camundongos , Nanopartículas Metálicas/química , Feminino , Osteogênese/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Tamanho da PartículaRESUMO
Inflammatory factors and reactive oxygen species (ROS) are risk factors for atherosclerosis. Many existing therapies use ROS-sensitive delivery systems to alleviate atherosclerosis, which achieved certain efficacy, but cannot eliminate excessive ROS. Moreover, the potential biological safety concerns of carrier materials through chemical synthesis cannot be ignored. Herein, an amphiphilic low molecular weight heparin- lipoic acid conjugate (LMWH-LA) was used as a ROS-sensitive carrier material, which consisted of injectable drug molecules used clinically, avoiding unknown side effects. LMWH-LA and curcumin (Cur) self-assembled to form LLC nanoparticles (LLC NPs) with LMWH as shell and LA/Cur as core, in which LMWH could target P-selectin on plaque endothelial cells and competitively block the migration of monocytes to endothelial cells to inhibit the origin of ROS and inflammatory factors, and LA could be oxidized to trigger hydrophilic-hydrophobic transformation and accelerate the release of Cur. Cur released within plaques further exerted anti-inflammatory and antioxidant effects, thereby suppressing ROS and inflammatory factors. We used ultrasound imaging, pathology and serum analysis to evaluate the therapeutic effect of nanoparticles on atherosclerotic plaques in apoe-/- mice, and the results showed that LLC showed significant anti-atherosclerotic effects. Our finding provided a promising therapeutic nanomedicine for the treatment of atherosclerosis.
Assuntos
Anti-Inflamatórios , Aterosclerose , Curcumina , Nanopartículas , Placa Aterosclerótica , Espécies Reativas de Oxigênio , Animais , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Curcumina/farmacologia , Curcumina/química , Aterosclerose/tratamento farmacológico , Nanopartículas/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Humanos , Placa Aterosclerótica/tratamento farmacológico , Ácido Tióctico/química , Ácido Tióctico/farmacologia , Heparina de Baixo Peso Molecular/farmacologia , Heparina de Baixo Peso Molecular/química , Heparina de Baixo Peso Molecular/uso terapêutico , Camundongos Endogâmicos C57BL , Inflamação/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Masculino , Selectina-P/metabolismo , Portadores de Fármacos/química , Antioxidantes/farmacologia , Antioxidantes/químicaRESUMO
Lipoic acid trisulfide, a sulfane sulfur-containing trisulfide of α-lipoic acid, holds promise in pharmaceuticals, yet knowledge gaps persist regarding its synthesis, properties, and stability. Here, we synthesized the lipoic acid trisulfide with a purity exceeding 99% from α-lipoic acid on a gram scale and obtained novel ß-cyclodextrin clathrates (84%-95% yield). Differential scanning calorimetry confirmed the inclusion of lipoic acid trisulfide in ß-cyclodextrins. The resulting ß-cyclodextrin clathrates exhibited significant improvements in water solubility and thermal stability. This pioneering study demonstrated a novel approach to the practical preparation of trisulfide and its ß-cyclodextrin clathrates as active ingredients, paving the way for clinical development.
Assuntos
Solubilidade , Ácido Tióctico , beta-Ciclodextrinas , Ácido Tióctico/química , beta-Ciclodextrinas/química , Sulfetos/química , Varredura Diferencial de Calorimetria , Estabilidade de Medicamentos , Água/químicaRESUMO
Polymer adhesives play an important role in many medical, consumer, and industrial products. Polymers of α-lipoic acid (αLA) have the potential to fulfill the need for versatile and environmentally friendly adhesives, but their performance is plagued by spontaneous depolymerization. We report a family of stabilized αLA polymer adhesives that can be tailored for a variety of medical or nonmedical uses and sustainably sourced and recycled in a closed-loop manner. Minor changes in monomer composition afforded a pressure-sensitive adhesive that functions well in dry and wet conditions, as well as a structural adhesive with strength equivalent to that of conventional epoxies. αLA surgical superglue successfully sealed murine amniotic sac ruptures, increasing fetal survival from 0 to 100%.
Assuntos
Ácido Tióctico , Ácido Tióctico/química , Animais , Camundongos , Polímeros/química , Reciclagem , Feminino , Adesivos/químicaRESUMO
To thoroughly understand ferroptosis's biological functions in living cells, it is crucial to investigate the polarity variations that occur during this unique Fe(II)-facilitated oxidative type of cell death. In this work, we report the development of a ratiometric probe (Po-P) to visualize the polarity changes in living cells and the inhibition effect during ferroptosis. The polarity-responsive fluorophore utilized by Po-P has a D-π-A-type structure. Based on theoretical calculations, ICT was proposed as the basis for Po-P's polarity-responsive mechanism. According to cell imaging results, Po-P had a desirable capacity for monitoring polarity fluctuations and erastin-induced ferroptosis. Furthermore, inhibition imaging revealed that dihydrolipoic acid (DHLA) could potentially prevent polarity changes that occur during erastin-induced ferroptosis, just as vitamin E (VE). We anticipate that the probe Po-P could be a valuable tool to quickly monitor polarity fluctuations and inhibition effects during ferroptosis and create new medications for treating disorders related to ferroptosis.
Assuntos
Ferroptose , Corantes Fluorescentes , Ferroptose/efeitos dos fármacos , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Ácido Tióctico/farmacologia , Ácido Tióctico/química , Ácido Tióctico/análogos & derivados , Imagem Óptica/métodos , Piperazinas/farmacologia , Piperazinas/químicaRESUMO
We have developed an innovative pathological biopsy strategy by expanding the differences of ROS levels among cancer cells, inflammatory cells and normal cells using cross-linked lipoic acid vesicles loaded with vitamin C (VC@cLAVs), combined with chemiluminescence imaging technology. By analyzing the different trends of intracellular chemiluminescence intensity, the three types of cells were quickly and accurately differentiated from diseased tissues, thus holding clinical tumor diagnostic potential.
Assuntos
Ácido Ascórbico , Espécies Reativas de Oxigênio , Ácido Tióctico , Humanos , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/análise , Ácido Tióctico/química , Ácido Ascórbico/farmacologia , Ácido Ascórbico/química , Biópsia , Neoplasias/patologia , Neoplasias/diagnóstico por imagem , Medições LuminescentesRESUMO
Lipoic acid (LA), which has good safety and oral absorption, is obtained from various plant-based food sources and needs to be supplemented through human diet. Moreover, substances with a disulfide structure can enter cells through dynamic covalent disulfide exchange with thiol groups on the cell membrane surface. Based on these factors, we constructed LA-modified nanoparticles (LA NPs). Our results showed that LA NPs can be internalized into intestinal epithelial cells through surface thiols, followed by intracellular transcytosis via the endoplasmic reticulum-Golgi pathway. Further mechanistic studies indicated that disulfide bonds within the structure of LA play a critical role in this transport process. In a type I diabetes rat model, the oral administration of insulin-loaded LA NPs exhibited a more potent hypoglycemic effect, with a pharmacokinetic bioavailability of 5.42 ± 0.53%, representing a 1.6 fold enhancement compared to unmodified PEG NPs. Furthermore, a significant upregulation of surface thiols in inflammatory macrophages was reported. Thus, we turned our direction to investigate the uptake behavior of inflammatory macrophages with increased surface thiols towards LA NPs. Inflammatory macrophages showed a 2.6 fold increased uptake of LA NPs compared to non-inflammatory macrophages. Surprisingly, we also discovered that the antioxidant resveratrol facilitates the uptake of LA NPs in a concentration-dependent manner. This is mainly attributed to an increase in glutathione, which is involved in thiol uptake. Consequently, we employed LA NPs loaded with resveratrol for the treatment of colitis and observed a significant alleviation of colitis symptoms. These results suggest that leveraging the variations of thiol expression levels on cell surfaces under both healthy and diseased states through an oral drug delivery system mediated by the small-molecule nutrient LA can be employed for the treatment of diabetes and certain inflammatory diseases.
Assuntos
Compostos de Sulfidrila , Ácido Tióctico , Ácido Tióctico/química , Animais , Compostos de Sulfidrila/química , Administração Oral , Ratos , Humanos , Nanopartículas/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/administração & dosagem , Sistemas de Liberação de Medicamentos , Masculino , Inflamação/tratamento farmacológico , Camundongos , Propriedades de Superfície , Portadores de Fármacos/química , Insulina/metabolismo , Ratos Sprague-Dawley , Tamanho da Partícula , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Células RAW 264.7RESUMO
Bacterial biofilms are notoriously problematic in applications ranging from biomedical implants to ship hulls. Cationic, amphiphilic antibacterial surface coatings delay the onset of biofilm formation by killing microbes on contact, but they lose effectiveness over time due to non-specific binding of biomass and biofilm formation. Harsh treatment methods are required to forcibly expel the biomass and regenerate a clean surface. Here, a simple, dynamically reversible method of polymer surface coating that enables both chemical killing on contact, and on-demand mechanical delamination of surface-bound biofilms, by triggered depolymerization of the underlying antimicrobial coating layer, is developed. Antimicrobial polymer derivatives based on α-lipoic acid (LA) undergo dynamic and reversible polymerization into polydisulfides functionalized with biocidal quaternary ammonium salt groups. These coatings kill >99.9% of Staphylococcus aureus cells, repeatedly for 15 cycles without loss of activity, for moderate microbial challenges (≈105 colony-forming units (CFU) mL-1, 1 h), but they ultimately foul under intense challenges (≈107 CFU mL-1, 5 days). The attached biofilms are then exfoliated from the polymer surface by UV-triggered degradation in an aqueous solution at neutral pH. This work provides a simple strategy for antimicrobial coatings that can kill bacteria on contact for extended timescales, followed by triggered biofilm removal under mild conditions.
Assuntos
Biofilmes , Materiais Revestidos Biocompatíveis , Staphylococcus aureus , Biofilmes/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Polimerização , Dissulfetos/química , Dissulfetos/farmacologia , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Polímeros/química , Polímeros/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Ácido Tióctico/química , Ácido Tióctico/farmacologia , Propriedades de SuperfícieRESUMO
Lipoic acid (LA) is a versatile antioxidant that has been used in the treatment of various oxidation-reduction diseases over the past 70 years. Owing to its large five-membered ring tension, the dynamic disulfide bond of LA is highly active, enabling the formation of poly(lipoic acid) (PLA) via ring-opening polymerization (ROP). Herein, we first summarize disulfide-mediated ROP polymerization strategies, providing basic routes for designing and preparing PLA-based materials. PLA, as a biologically derived, low toxic, and easily modified material, possesses dynamic disulfide bonds and universal non-covalent carboxyl groups. We also shed light on the biomedical applications of PLA-based materials based on their biological and structural features and further divide recent works into six categories: antibacterial, anti-inflammation, anticancer, adhesive, flexible electronics, and 3D-printed tissue scaffolds. Finally, the challenges and future prospects associated with the biomedical applications of PLA are discussed.
Assuntos
Materiais Biocompatíveis , Ácido Tióctico , Animais , Humanos , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/síntese química , Polimerização , Polímeros/química , Polímeros/farmacologia , Ácido Tióctico/química , Ácido Tióctico/farmacologia , Alicerces Teciduais/químicaRESUMO
The healing of diabetic wounds is significantly impeded due to severe oxidative stress and hindered angiogenesis, presenting a major challenge to clinical treatment. In this context, we introduces a novel hydrogel dressing strategy that uniquely combines α-lipoic acid-modified chitosan (LAMC) and melanin nanoparticles (MNPs). This innovative hydrogel, LAMC@MNPs, is formulated to gel under ultraviolet (UV) light without the need for a photoinitiator, simplifying the preparation process and potentially enhancing safety. Our experimental results demonstrate that the LAMC@MNPs hydrogel not only exhibits superior skin adhesion, with an average strength of 56.59 ± 3.16 KPa, but also effectively alleviates oxidative stress and accelerates vascular regeneration and wound healing. This is achieved by promoting cell migration and scavenging free radicals, addressing the critical barriers in diabetic wound care. The combination of these materials and their functional benefits presents a promising new approach to diabetic wound treatment.
Assuntos
Quitosana , Diabetes Mellitus Experimental , Hidrogéis , Melaninas , Ácido Tióctico , Cicatrização , Cicatrização/efeitos dos fármacos , Quitosana/química , Quitosana/farmacologia , Ácido Tióctico/química , Ácido Tióctico/farmacologia , Animais , Melaninas/química , Hidrogéis/química , Hidrogéis/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nanopartículas/química , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Masculino , Humanos , Movimento Celular/efeitos dos fármacos , Pele/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Postovulatory aging oocytes usually feature diminished potential for fertilization and poor embryonic development due to enhanced oxidative damage to the subcellular organelles and macromolecules, which stands as a formidable obstacle in assisted reproductive technologies (ART). Here, we developed lipoic acid (LA) and polyethylene glycol (PEG)-modified CeO2 nanoparticles (LA-PEG-CeNPs) with biocompatibility, enzyme-like autocatalytic activity, and free radical scavenging capacity. We further investigated the LA-PEG-CeNPs effect in mouse postovulatory oocytes during in vitro aging. The results showed that LA-PEG-CeNPs dramatically reduced the accumulation of ROS in aging oocytes, improving mitochondrial dysfunction; they also down-regulated the pro-apoptotic activity by rectifying cellular caspase-3, cleaved caspase-3, and Bcl-2 levels. Consistently, this nanoenzyme prominently alleviated the proportion of abnormalities in spindle structure, chromosome alignment, microtubule stability, and filamentous actin (F-actin) distribution in aging oocytes, furthermore decreased oocyte fragmentation, and improved its ability of fertilization and development to blastocyst. Taken together, our finding suggests that LA-PEG-CeNPs can alleviate oxidative stress damage on oocyte quality during postovulatory aging, implying their potential value for clinical practice in assisted reproduction.