Bile acid bio-nanoencapsulation improved drug targeted-delivery and pharmacological effects via cellular flux: 6-months diabetes preclinical study

Abstract

The antilipidemic drug, probucol (PB), has demonstrated potential applications in Type 2 diabetes (T2D) through its protective effects on pancreatic β-cells. pB has poor solubility and bioavailability, and despite attempts to improve its oral delivery, none has shown dramatic improvements in absorption or antidiabetic effects. Preliminary data has shown potential benefits from bile acid co-encapsulation with PB. One bile acid has shown best potential improvement of PB oral delivery (ursodeoxycholic acid, UDCA). This study aimed to examine PB and UDCA microcapsules (with UDCA microcapsules serving as control) in terms of the microcapsules' morphology, biological effects ex vivo, and their hypoglycemic and antilipidemic and anti-inflammatory effects in vivo. PBUDCA and UDCA microcapsules were examined in vitro (formulation studies), ex vivo and in vivo. PBUDCA microcapsules exerted positive effects on β-cells viability at hyperglycemic state, and brought about hypoglycemic and antiinflammatory effects on the prediabetic mice. In conclusion, PBUDCA co-encapsulation have showed beneficial therapeutic impact of dual antioxidant-bile acid effects in diabetes treatment. Understanding the link between insulin-resistance, prediabetes and Type 2 diabetes (T2) is anticipated to facilitate better ability to design new interventions in order to control the fast growing epidemic of diabetes. The link encompasses multiple physiological disturbances including obesity. In a review by Qatanani, M. and Lazar, M.A, the authors have examined specific links between insulin resistance and visceral adiposity and excess fat accumulation in blood and tissues 1. They found that there is a direct correlation between the amounts of lipid represented by biomarkers such as total cholesterol, triglycerides and noneesterified fatty acids (NEFA), and the extent of insulin-resistance and rate of prediabetes development. One of the possible underlying mechanisms to insulin-resistance and prediabetes, has been hypothesized to be oxidative stress and inflammation 2-6. Oxidative stress and local and systemic inflammation have been shown to be contributing factors in development of insulin-resistance, prediabetes and eventually T2D. Oxidative stress and inflammation have also been linked to worsening of diabetic symptoms and long-term prognosis 7,8. In addition, diabetes-inflammation has been associated with lipid dysregulation, visceral adipose tissue accumulation and insulin-resistance. Karpe, F. et al.; have shown direct association between levels of inflammatory cytokines, with development of visceral fat

Sodium alginate microencapsulation improves the short-term oral bioavailability of cannabidiol when administered with deoxycholic acid

“…Previously, our studies have demonstrated that sodium alginate microcapsules significantly increase the brain uptake and associated neuroprotective effects of probucol-the highly lipophilic, antilipidemic drug [11]. Subsequent studies of ours confirmed that microencapsulation improves therapeutic efficiency of lipophilic drugs by protecting against degradation due to low stomach pH and efflux protein activity in the intestinal epithelium [12,13].…”

“…Bile acids promote aqueous solubility and increase fluidity of phospholipid membranes, making them ideal candidates for BBB permeability experiments [ 16 ]. A report from our lab showed that co-encapsulation with a DCA variant improved the targeted-delivery effects of probucol [ 12 ]. However, there is a relative paucity of studies focusing on the permeation effects of DCA on CBD absorption.…”

Pharmacological and Advanced Cell Respiration Effects, Enhanced by Toxic Human-Bile Nano-Pharmaceuticals of Probucol Cell-Targeting Formulations

“…The reduction in IFN-γ and enhancement in IL-10 that the PB-ULCA microcapsules showed, are expected to decrease cell apoptosis and support cell function, which is supported by bioenergetics analysis [81]. Previously published data have displayed that the anti-oxidant activity of BAs enhanced β-cell viability [39,[81][82][83].…”

“…However, no significant difference was noted between the F1 and F2-treated cells in IFN-γ expression, possibly because of the different metabolic and secretory pathway compared to other cytokines [ 80 ]. The reduction in IFN-γ and enhancement in IL-10 that the PB–ULCA microcapsules showed, are expected to decrease cell apoptosis and support cell function, which is supported by bioenergetics analysis [ 81 ]. Previously published data have displayed that the anti-oxidant activity of BAs enhanced β-cell viability [ 39 , 81 , 82 , 83 ].…”

“…Different studies also showed that PB-loaded microcapsules had anti-oxidant and anti-inflammatory properties that improve mitochondrial respiration and metabolic activity [37,67,86]. In recent literature, it was shown that PB-ursodeoxycholic acid microcapsules have similar effects on cellular parameters, viability and drug release, proving that these effects were formulation dependent [81]. From these biological results, the F2 microcapsules undoubtedly showed a positive and significant protective effect on pancreatic β-cells, and improvement in bio-energetic parameters.…”