Qushawy Mona, Alanazi Mansuor A, Hikal Wafaa M, Amirthalingam Palanisamy, Abu-Gharbieh Eman, Almanzalawi Wejdan Saleh, Mortagi Yasmin, Elsherbiny Nehal, Elsherbini Amira M
Department of Pharmaceutics, Faculty of Pharmacy, University of Tabuk, Tabuk, 71491, Saudi Arabia.
Department of Pharmaceutics, Faculty of Pharmacy, Sinai University, Alarish, North Sinai, 45511, Egypt.
Int J Nanomedicine. 2025 Mar 24;20:3765-3788. doi: 10.2147/IJN.S506631. eCollection 2025.
Diabetes is a chronic metabolic disease that causes serious consequences in different organs such as the heart, kidneys, pancreas, and liver. Metformin (MTF) is a common treatment for type 2 diabetes. It controls the blood glucose level by improving insulin sensitivity and glucose absorption. MTF belongs to BCS class III, which is characterized by high solubility and low permeability. Several types of nanoparticles have been developed to overcome the permeability problem of MTF.
In this study, we prepared nanostructured lipid carriers (NLCs) loaded with metformin (MTF) using hot melt homogenization-ultrasonication. To select the best formulation, the prepared MTF-NLCs were evaluated for entrapment efficiency % (EE%), particle size, zeta potential, polydispersity index (PDI), and in vitro drug release. The optimized formulation was selected based on the high EE%, small particle size, high absolute zeta potential, low polydispersity index, and high in vitro drug release. The optimized formulation was evaluated for surface morphology by transmission electron microscope (TEM) and for further biochemical and histological analyses in a high-fat diet-induced type 2 diabetes mellitus (T2DM) in vivo rat model; HFD was administered (44.3-kJ/kg total energy) for four weeks, followed by a single intraperitoneal injection of streptozotocin (STZ). Rats were allocated into four groups; Diabetic (DM), DM+MTF, DM+MTF-NLC, and control group. Serum and tissue samples were processed for inflammatory markers detection and histopathology.
The prepared MTF-NLC formulation exhibited high EE% (80.65 ± 1.95% to 99.31 ± 3.25%), small particle size (247.72±5.74nm-503.23±7.26nm), high negative zeta potential (from -31.83±0.98mV to -51.6±2.64mV), PDI value less than 0.5 for all MTF-NLCs, and controlled drug release. MTF-NLC7 appeared spherical when examined by TEM. MTF and MTF-NLC groups significantly alleviated the degenerative effects of DM in both submandibular glands (SMG) and pancreas. Additionally, treatments improved kidney and liver function reduced serum inflammatory cytokines, and tissue SMG and pancreatic immunostaining of inflammatory cytokines with favorable effects of MTF-NLCs. Moreover, the MTF-NLCs showed a significant reduction of serum inflammatory cytokines, including (TNF-α and IL-1β) and pancreatic TNF-α expression, in addition to ameliorating liver and renal functions compared to MTF alone.
The preparation of MTF as NLCs improved its permeability, enhancing its anti-inflammatory activity and providing more protection against diabetes-induced organ injury.
糖尿病是一种慢性代谢性疾病，会对心脏、肾脏、胰腺和肝脏等不同器官造成严重后果。二甲双胍（MTF）是2型糖尿病的常用治疗药物。它通过提高胰岛素敏感性和葡萄糖吸收来控制血糖水平。MTF属于BCS III类，其特点是高溶解性和低渗透性。已经开发了几种类型的纳米颗粒来克服MTF的渗透性问题。
在本研究中，我们使用热熔均质-超声法制备了负载二甲双胍（MTF）的纳米结构脂质载体（NLCs）。为了选择最佳配方，对制备的MTF-NLCs进行了包封率（EE%）、粒径、zeta电位、多分散指数（PDI）和体外药物释放评估。基于高EE%、小粒径、高绝对zeta电位、低多分散指数和高体外药物释放选择优化配方。通过透射电子显微镜（TEM）评估优化配方的表面形态，并在高脂饮食诱导的2型糖尿病（T2DM）体内大鼠模型中进行进一步的生化和组织学分析；给予高脂饮食（总能量44.3 kJ/kg）四周，然后单次腹腔注射链脲佐菌素（STZ）。将大鼠分为四组；糖尿病组（DM）、DM+MTF组、DM+MTF-NLC组和对照组。对血清和组织样本进行炎症标志物检测和组织病理学检查。
制备的MTF-NLC配方表现出高EE%（80.65±1.95%至99.31±3.25%）、小粒径（247.72±5.74nm-503.23±7.26nm）、高负zeta电位（从-31.83±0.98mV至-51.6±2.64mV），所有MTF-NLCs的PDI值均小于0.5，且药物释放得到控制。通过TEM检查时，MTF-NLC7呈球形。MTF和MTF-NLC组显著减轻了糖尿病在下颌下腺（SMG）和胰腺中的退行性影响。此外，治疗改善了肾脏和肝脏功能，降低了血清炎症细胞因子水平，以及组织SMG和胰腺中炎症细胞因子的免疫染色，MTF-NLCs具有良好效果。此外，与单独使用MTF相比，MTF-NLCs除了改善肝脏和肾脏功能外，还显著降低了血清炎症细胞因子水平，包括（TNF-α和IL-1β）以及胰腺TNF-α表达。
将MTF制备成NLCs提高了其渗透性，增强了其抗炎活性，并为糖尿病诱导的器官损伤提供了更多保护。
