RESUMEN
Chemotherapy resistance remains a significant challenge in treating ovarian cancer effectively. This study addresses this issue by utilizing a dual drug-loaded nanomicelle system comprising albendazole (ABZ) and paclitaxel (PTX), encapsulated in a novel carrier matrix of D-tocopheryl polyethylene glycol 1000 succinate vitamin E (TPGS), soluplus and folic acid. Our objective was to develop and optimize this nanoparticulate delivery system using solvent evaporation techniques to enhance the therapeutic efficacy against ovarian cancer. The formulation process involved pre-formulation, formulation, optimization, and comprehensive characterization of the micelles. Optimization was conducted through a 32 factorial design, focusing on the effects of polymer ratios on particle size, zeta potential, polydispersity index (PDI) and entrapment efficiency (%EE). The optimal formulation demonstrated improved dilution stability, as indicated by a critical micelle concentration (CMC) of 0.0015 mg/mL for the TPGS-folic acid conjugate (TPGS-FOL). Extensive characterization included differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), and Fourier-transform infrared spectroscopy (FTIR). The release profile exhibited an initial burst followed by sustained release over 90 h. The cytotoxic potential of the formulated micelles was superior to that of the drugs alone, as assessed by MTT assays on SKOV3 ovarian cell lines. Additionally, in vivo studies confirmed the presence of both drugs in plasma and tumour tissues, suggesting effective targeting and penetration. In conclusion, the developed TPGS-Fol-based nanomicelles for co-delivering ABZ and PTX show promising results in overcoming drug resistance, enhancing solubility, sustaining drug release, and improving therapeutic outcomes in ovarian cancer treatment.
Asunto(s)
Albendazol , Micelas , Neoplasias Ováricas , Paclitaxel , Femenino , Paclitaxel/farmacología , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Paclitaxel/química , Albendazol/química , Albendazol/farmacología , Albendazol/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Humanos , Animales , Línea Celular Tumoral , Portadores de Fármacos/química , Polietilenglicoles/química , Vitamina E/química , Ácido Fólico/química , Ratones , Liberación de Fármacos , Tamaño de la Partícula , Polivinilos/química , Polímeros/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Several studies have revealed that SARS-CoV-2 damages brain function and produces significant neurological disability. The SARS-CoV-2 coronavirus, which causes COVID-19, may infect the heart, kidneys, and brain. Recent research suggests that monoamine oxidase B (MAO-B) may be involved in metabolomics variations in delirium-prone individuals and severe SARS-CoV-2 infection. In light of this situation, we have employed a variety of computational to develop suitable QSAR model using PyDescriptor and genetic algorithm-multilinear regression (GA-MLR) models (R2 = 0.800-793, Q2LOO = 0.734-0.727, and so on) on the data set of 106 molecules whose anti-SARS-CoV-2 activity was empirically determined. QSAR models generated follow OECD standards and are predictive. QSAR model descriptors were also observed in x-ray-resolved structures. After developing a QSAR model, we did a QSAR-based virtual screening on an in-house database of 200 compounds and found a potential hit molecule. The new hit's docking score (-8.208 kcal/mol) and PIC50 (7.85 M) demonstrated a significant affinity for SARS-CoV-2's main protease. Based on post-covid neurodegenerative episodes in Alzheimer's and Parkinson's-like disorders and MAO-B's role in neurodegeneration, the initially disclosed hit for the SARS-CoV-2 main protease was repurposed against the MAO-B receptor using receptor-based molecular docking, which yielded a docking score of -12.0 kcal/mol. This shows that the compound that inhibits SARS-CoV-2's primary protease may bind allosterically to the MAO-B receptor. We then did molecular dynamic simulations and MMGBSA tests to confirm molecular docking analyses and quantify binding free energy. The drug-receptor complex was stable during the 150-ns MD simulation. The first computational effort to show in-silico inhibition of SARS-CoV-2 Mpro and allosteric interaction of novel inhibitors with MAO-B in post-covid neurodegenerative symptoms and other disorders. The current study seeks a novel compound that inhibits SAR's COV-2 Mpro and perhaps binds MAO-B allosterically. Thus, this study will enable scientists design a new SARS-CoV-2 Mpro that inhibits the MAO-B receptor to treat post-covid neurological illness.
Asunto(s)
COVID-19 , Enfermedades del Sistema Nervioso , Humanos , SARS-CoV-2/metabolismo , Monoaminooxidasa/metabolismo , Simulación del Acoplamiento Molecular , Descubrimiento de Drogas , Simulación de Dinámica Molecular , Péptido Hidrolasas/metabolismo , Inhibidores de Proteasas/farmacologíaRESUMEN
Drug repurposing is the finding new activity of the existing drug. Recently, Albendazole's well-known antihelmintic has got the attention of an anticancer drug. Plausible evidence of the interaction of Albendazole with one of the types of tyrosine kinase protein receptor, vascular endothelial growth factor receptor-2 (VEGFR-2) is still not well understood. Inhibition of the VEGFR-2 receptor can prevent tumor growth. The current study investigated the interaction of Albendazole with VEGFR-2.It was found that the said interaction exhibited potent binding energy ΔG = -7.12 kcal/mol, inhibitory concentration (Ki) = 6.04 µM, and as positive control comparison with standard drug (42Q1170A) showed ΔG = -12.35 kcal/mol and Ki = 881 µM. The key residue Asp1046 was formed involved hydrogen bonding with Albendazole. The molecular dynamics simulation study revealed the stable trajectory of the VEGFR-2 receptor with Albendazole bound complex having significant high free energy of binding as calculated from Molecular Mechanics Generalized Born and Surface Area study ΔG = -42.07±2.4 kcal/mol. The binding energy is significantly high for greater stability of the complex. Principal component analysis of molecular docking trajectories exhibited ordered motion at higher modes, implying a high degree of VEGFR-2 and Albendazole complex stability as seen with the standard drug 42Q. Therefore, the current work suggests the role of Albendazole as a potent angiogenesis inhibitor as ascertained by its potential interaction with VEGFR-2. The findings of research will aid in the future development of Albendazole in anticancer therapy.