A natural lipopeptide of surfactin for oral delivery of insulin

Abstract

Surfactin, a natural lipopeptide produced by Bacillus, is gaining attention for potentially biomedical and pharmaceutical applications. Here, surfactin was assayed for oral delivery of insulin (INS) by its ability to bind to and promote protein to penetrate through the cell membrane. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, surfactin was found to form co-precipitates with INS to protect it from acidic and enzymatic attack in the gastrointestinal tract. Further analysis by non-reductive electrophoresis showed surfactin could bind to INS forming heteropolymers. Analysis with circular dichroism, we found this binding significantly influenced the INS structure with decreased rigid a-helix and b-turn, but with increased flexible b-sheet and random coil. The change with more flexible structure was favorable for INS to penetrate through the cell membrane. Fluorescence spectra analysis also showed surfactin could lead Phe and Tyr in the inner of INS exposed outside, further promoting INS permeabilization by improving the hydrophobic-lipophilic interactions between INS and cell membrane. As a result, the effective permeability (Peff) of INS plus surfactin was 4.3 times of that of INS alone. In vivo assay showed oral INS with surfactin displayed excellent hypoglycemic effects with a relative bioavailability of 12.48% and 5.97% in diabetic mice and non-diabetic dogs, respectively. Summary, surfactin is potential for oral delivery of INS by its role as an effective protease inhibitor and permeability enhancer.

Enteric-coated insulin microparticles delivered by lipopeptides of iturin and surfactin

“…Balb/C mice (5–6 weeks old, 18–20 g body weight) were purchased from the center for disease prevention and control of Hubei province (Wuhan, China) following the University Ethics Committee’s guidelines. The mice were intraperitoneally injected with streptozotocin (70 mg/kg) for induction of T1DM (Zhang et al., 2016 ).…”

“…Previously, we used the Bacillus -produced lipopeptide of surfactin (SFN) to improve INS uptake by the intestine and found the natural SFN and chemically synthesized analogs are all favorable for promoting INS uptake by the intestine (Zhang et al., 2016 , 2017 ). Addition to SFN, iturin (ITU) is another lipopeptide produced by Bacillus species with a well known anti-fungal activity (Zhao et al., 2017 ).…”

Recent Advances and Future Prospects of Non-Invasive Insulin Delivery Systems

“…Oral administration of insulin represents the most convenient route and attractive approach to developing systems that are capable of protecting insulin and enhancing its absorption [9]. Insulin is a peptide of almost negligible bioavailability (1%) when orally administered as a conventional solution, due to degradation by gastrointestinal protease enzymes, gastric acid inactivation and low intestinal membrane permeability [6]. Therefore, it has always been a challenge to establish oral formulation using different methods and technologies aiming to yield efficient and safe products.…”

“…A bacillus lipopeptide product called surfactin promotes resistance to digestion by trypsin and pepsin with amphiphilic nature that gives it a strong biosurfactant action [6]. In vivo studies showed that the combination can produce a hypoglycaemic effect with relative bioavailability 12.48% for diabetic mice and 5.97% for non-diabetic dogs.…”

“…Type 2 DM uncontrolled by oral hypoglycaemic drugs, may require having insulin added to their therapy regimen [4]. Controlling diabetes with subcutaneous (SC) insulin delivery requires multiple daily injections which are considered inconvenient for many diabetic patients since it can be accompanied by pain, lipodystrophy, tissue damage and allergic reactions at the site of injection [5,6]. Moreover, the method of the administration itself makes it inconvenient to perform in public places.…”