Diabetes mellitus (DM) stands as one of the most prevalent chronic metabolic disorders globally, associated with decreased life expectancy and heightened mortality rates [1]. The escalating prevalence of DM is alarming, with a projected rise from approximately 424.9 million cases worldwide in 2019 to an anticipated 700 million cases by 2045 [2]. Notably, Type-2 DM constitutes approximately 90% of all DM cases globally [3]. Achieving glycemic control in type-2 DM involves lifestyle modifications alongside pharmacological interventions, including oral antidiabetic drugs such as biguanides (e.g., metformin)[4], sulfonylureas[4], dipeptidyl peptidase IV (DPP-4) inhibitors (gliptins)[4], glucagon-like peptide-1 (GLP-1) receptor agonists[4], sodium-glucose cotransporter (SGLT-2) inhibitors[4], alpha-glucosidase inhibitors[4], thiazolidinediones[4], and amylin analogs[4]. However, drug resistance, side effects, and individual variability responses may impede the effectiveness of these conventional therapies [1]. DM is frequently accompanied by complications such as vision, gastric, renal, and notably cardiovascular issues; with the latter being the most common even with intensive glycemic control. [5]. Recent studies indicate that DM-associated cardiovascular complications may arise from dysfunctional endothelium, observable even in early DM stages, making endothelial dysfunction a potential early biomarker and risk factor for cardiovascular diseases (CVDs) [6, 7]. Understanding the mechanisms through which DM induces endothelial cell dysfunction is crucial for preventing the onset of CVDs, such as atherosclerosis, hypertension, and stroke [8].
Despite technological advancements in DM treatments, management remains suboptimal, marked by side effects and limitations [4]. Nanomedicine applications emerge as promising solutions to address these challenges. Nanotherapies tailored for DM management offer effective blood glucose regulation and gradual release of antidiabetic drugs [1]. This extension of drug duration reduces the likelihood of acute and chronic complications associated with antidiabetic drugs [1]. The exploration of various nanoparticles (NPs) loaded with antidiabetic drugs, including liposomes, niosomes, polymers, dendrimers, micelles, and metal-based NPs, has been ongoing [9–22]. However, safety, tolerance, and stability challenges have been encountered [9–22]. To overcome these limitations, we propose the utilization of iron oxide-based NPs, known for their anti-inflammatory and hypoglycemic properties [23, 24]. They also possess antioxidant activities that can be easily detected via magnetic resonance imagining (MRI) [25]. Among these, nanoMIL-89, a metal-organic framework (MOF), demonstrates suitability as a drug carrier. NanoMIL-89 has exhibited selective uptake by endothelial cells, passage to daughter cells, and reduced inflammatory markers in dysfunctional endothelial cells [26]. Additionally, it has proven to be a suitable carrier for the drug sildenafil, used to treat pulmonary arterial hypertension (PAH) [27]. Moreover, it has been demonstrated that nanoMIL-89 exhibits non-toxic effects both in vitro and in vivo, as evidenced by studies utilizing zebrafish embryos and rodent models [24, 26].
Our selection of nanoMIL-89 as a carrier for the antidiabetic drug metformin (MET) is grounded in its cardioprotective activity and ability to carry small drugs with a molecular weight under 500 Da [27]. Moreover, MET's positive effects on blood glucose levels, insulin sensitivity, antioxidant activity, and endothelial protection align with our goal of mitigating hyperglycemia's impact on the endothelium [28, 29]. MET's association with a lower risk of CVDs in type-2 DM patients and its compatibility with nanoMIL-89 due to its size further reinforce our choice [30].
Despite MET’s low bioavailability and short half-life, loading it into nanoMIL-89 presents an opportunity to reduce dosage, improve patient compliance, and potentially minimize gastrointestinal side effects [31–33]. Therefore, our objective is to load MET into nanoMIL-89, investigate its release kinetics, and evaluate its impact on endothelial cell function and oxidative stress under both normoglycemic and hyperglycemic conditions in vitro.