Silymarin (SME)对多种癌症具有多种治疗作用，但其低水溶性和生物利用度差的问题限制了其临床使用。在本研究中，将SME加载到纳米结构脂质载体（NLCs）中，并进一步纳入粘附在原位凝胶中（SME-NLCs-Plx/CP-ISG）以局部治疗口腔癌。使用33 Box-Behnken设计（BBD），开发出了最优化的SME-NLC配方，其中固体脂肪、表面活性剂浓度和超声时间作为自变量，而粒径（PS）、聚集度指数（PDI）和%的包封效率（EE）作为因变量，导致315.5±0.1nm PS、0.341±0.01 PDI和71.05±0.05% EE的SME-NLC配方。结构研究证实了SME-NLCs的形成。SME-NLCs纳入的原位凝胶表现出对SME的持续释放，表明在颊粘膜膜上增强了保留。含有SME-NLCs的原位凝胶的IC50值（24.90±0.45 µM）比SME-NLCs（28.40±0.89 µM）和纯SME（36.60±0.26 µM）有显著下降。研究表明，由于SME-NLCs的更高渗透力，反应性氧化物（ROS）生成潜力和SME-NLCs-Plx / CP-ISG诱导Sub-G0阶段的细胞凋亡，对人KB口腔癌细胞具有较高抑制作用。因此，SME-NLCs-Plx/CP-ISG可以成为针对口腔癌患者SME的定点递送的化疗和手术替代方案。版权所有© 2023 Elsevier B.V.。保留所有权利。

Silymarin (SME) shows multiple therapeutic actions against several cancers, however, low aqueous solubility and poor bioavailability issues restrict its clinical use. In this study, SME was loaded in nanostructured lipid carriers (NLCs) and further incorporated in mucoadhesive in-situ gel (SME-NLCs-Plx/CP-ISG) for localized treatment of oral cancer. Using a 33 Box-Behnken design (BBD), an optimized SME-NLC formula was developed with the ratios of solid lipids, surfactant concentration, and sonication time as independent variables, while particle size (PS), polydispersity index (PDI), and % encapsulation efficiency (EE) as dependent variables, resulting in 315.5 ± 0.1 nm PS, 0.341 ± 0.01 PDI, and 71.05 ± 0.05 % EE. Structural studies confirmed the formation of SME-NLCs. SME-NLCs incorporated in-situ gel demonstrated a sustained release for SME, indicating enhanced retention on the buccal mucosal membrane. The in-situ gel containing SME-NLCs showed a marked decrease in IC50 value (24.90 ± 0.45 µM) than SME-NLCs (28.40 ± 0.89 µM) and plain SME (36.60 ± 0.26 µM). The studies demonstrated that Reactive oxygen species (ROS) generation potential and SME-NLCs-Plx/CP-ISG induced apoptosis at Sub-G0 phase owing to higher penetration of SME-NLCs led to higher inhibition against human KB oral cancer cells. Therefore, SME-NLCs-Plx/CP-ISG can be the alternative to chemotherapy and surgery with site-specific delivery of SME to oral cancer patients.Copyright © 2023 Elsevier B.V. All rights reserved.