Optimized Nanostructured Lipid Carriers for Metformin: Enhanced Anti-Inflammatory Activity and Protection Against Type 2 Diabetes-Induced Organ Damage.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: The preparation of MTF as NLCs improved its permeability, enhancing its anti-inflammatory activity and providing more protection against diabetes-induced organ injury.