Coating with cationic inulin enhances the drug release profile and in vitro anticancer activity of lecithin-based nano drug delivery systems.

Core-shell structured lipidic nanoparticles (LNPs) were developed using lecithin sodium acetate (Lec-OAc) ionic complex as a core unit and quaternized inulin (QIn) as the shell part. Inulin (In) was modified using glycidyl trimethyl ammonium chloride (GTMAC) as a positively charged shell part and used for coating the negatively surface charged Lec-OAc. The critical micelle concentration (CMC) of the core was determined as 1.047 × 10-4 M, which is expected to provide high stability in blood circulation as a drug-carrying compartment. The amounts of curcumin (Cur) and paclitaxel (Ptx) loaded to LNPs (CurPtx-LNPs), and quaternized inulin-coated LNPs (Cur-Ptx-QIn-LNPs) were optimized to obtain mono-dispersed particles with maximum payload. The total amount of 2.0 mg of the drug mixture (1 mg Cur and 1 mg Ptx) was the optimized quantity for QIn-LNPs and CurPtx-QIn-LNPs due to the favorable physicochemical properties determined by dynamic light scattering (DLS) studies. This inference was confirmed by differential scanning calorimeter (DSC), and Fourier-transform infrared (FT-IR). SEM and TEM images clearly revealed the spherical shapes of LNPs and QIn-LNPs, and QIn covered the LNPs completely. The cumulative release measurements of Cur and Ptx from CurPtx-QIn-LNPs, along with the kinetic studies, showed a significant decrease in the release period of drug molecules with the effect of the coating. At the same time, Korsmeyer-Peppas was the best diffusion-controlled release model. Coating of the LNPs with QIn increased the cell-internalization of NPs to the MDA-MB-231 breast cancer cell lines, resulting in a better toxicity profile than the empty LNPs.

Levan enhanced the NF-κB suppression activity of an oral nano PLGA-curcumin formulation in breast cancer treatment.

Chemoresistance (CR) is one of the reasons why chemotherapy agents like Gemcitabine (GMC) remain insufficient in healing breast cancer. Activation of Nuclear Factor-kappa B (NF-κB) during chemotherapy is known as an important factor in the development of CR. The hydrophobic polyphenol curcumin is shown to inhibit NF-κB and hence CR. The aim of this work was to increase the poor bioavailability of curcumin by loading it into the nano-micelles made of Poly (Lactide-co-Glycolide) (PLGA) and levan, where levan as a natural fructose homopolymer makes the nano-micelle more stable and increases its uptake using the fructose moieties. In this study, a PLGA-levan-curcumin formulation (PLC) was designed and characterized. The size was measured as 154.16 ± 1.45 nm with a 67.68% encapsulation efficiency (EE%). The incorporation between the components was approved. Levan made the nano-micelles stable for at least three months, increased their uptake, and led to a 10,000-fold increase in the solubility of curcumin. The enhanced bioavailability of curcumin reduced the NF-κB levels elevated by GMC, both in vitro and in vivo. The PLC showed a complete tumor treatment, while GMC only showed a rate of 52%. These point to the great potential of the PLC to be used simultaneously with chemotherapy.

Accelerated diabetic wound healing by topical application of combination oral antidiabetic agents-loaded nanofibrous scaffolds: An in vitro and in vivo evaluation study.

The combination of oral antidiabetic drugs, pioglitazone, metformin, and glibenclamide, which also exhibit the strongest anti-inflammatory action among oral antidiabetic drugs, were loaded into chitosan/gelatin/polycaprolactone (PCL) by electrospinning and polyvinyl pyrrolidone (PVP)/PCL composite nanofibrous scaffolds by pressurized gyration to compare the diabetic wound healing effect. The combination therapies significantly accelerated diabetic wound healing in type-1 diabetic rats and organized densely packed collagen fibers in the dermis, it also showed better regeneration of the dermis and epidermis than single drug-loaded scaffolds with less inflammatory cell infiltration and edema. The formation of the hair follicles started in 14 days only in the combination therapy and lower proinflammatory cytokine levels were observed compared to single drug-loaded treatment groups. The combination therapy increased the wettability and hydrophilicity of scaffolds, demonstrated sustained drug release over 14 days, has high tensile strength and suitable cytocompatibility on L929 (mouse fibroblast) cell and created a suitable area for the proliferation of fibroblast cells. Consequently, the application of metformin and pioglitazone-loaded chitosan/gelatin/PCL nanofibrous scaffolds to a diabetic wound area offer high bioavailability, fewer systemic side effects, and reduced frequency of dosage and amount of drug.

Levan-based hydrogels for controlled release of Amphotericin B for dermal local antifungal therapy of Candidiasis.

Hydrogels from Halomonas levan polysaccharide were prepared at different crosslinking densities. Swelling results demonstrated pH dependent rather than temperature dependent swelling of the hydrogel and the highest swelling value was achieved at basic conditions with a swelling ratio of 9.1 ± 0.1 which is the highest reported for levan based hydrogels. SEM images show a porous network architecture, which indicates a large surface area of the hydrogels. Rheological analyses showed the viscoelastic behavior of the hydrogels. Biocompatibility of the hydrogels was confirmed by cell culture experiments. For drug release experiments Amphotericin B (AmB) was used. 51% of the loaded AmB was released into the PBS buffer and the released AmB had a significant antifungal activity against Candida albicans.

Development and optimization of a novel PLGA-Levan based drug delivery system for curcumin, using a quality-by-design approach.

This study aimed to develop a PLGA, Levan-based drug delivery system (DDS) of Curcumin using a quality-by-design (QbD) approach to reveal how formulation parameters affect the critical quality attributes (CQAs) of this DDS and to present an optimal design. First, a risk assessment was conducted to determine the impact of various process parameters on the CQAs of the DDS (i.e., average particle size, ZP, encapsulation efficiency and polydispersity index). Plackett-Burman design revealed that potential risk factors were Levan molecular weight, PLGA amount and acetone amount. Then, the optimization of the DDS was achieved through a Box-Behnken Design. The optimum formulation was prepared using low molecular weight Levan (134 kDa), 51.51 mg PLGA and 10 ml acetone. The model was validated and the optimized formulation was further characterized using different physic-chemical methods. The study resulted in the most stable NP with a spherical and uniform shape and physical stability tests indicated its stability for at least 60 days at room temperature. In conclusion, this study was an effort for developing a DDS which solubilizes Curcumin in clinically applicable concentrations.

Encapsulated melatonin in polycaprolactone (PCL) microparticles as a promising graft material.

Electrospraying assures many advantages with taking less time and costing less relatively to the other conventional particle production methods. In this research, we investigated the encapsulation of melatonin (MEL) hormone in polycaprolactone (PCL) microparticles by using electrospraying method. Morphology analysis of the produced particles completed with Scanning Electron Microscopy (SEM). SEM images demonstrated that micro-particles of 3 wt% PCL solution has the most suitable particle diameter size (2.3 ±â€¯0.64 µm) for melatonin encapsulation. According to the characterization of the particles, electrospraying parameters like optimal collecting distance, the flow rate of the solution and voltage of the system detected as 8 cm, 0.5 ml/h, and 10 kV respectively. For determining the chemical bonds of scaffold Fourier-Transform Infrared Spectroscopy (FTIR) were used and FTIR results showed that melatonin successfully loaded into PCL micro-particles. Drug release kinetics of the melatonin loaded particles indicated that melatonin released with a burst at the beginning and release behavior became sustainable over a period of 8 h with the encapsulation efficiency of about 73%. In addition, both in-vitro and in-vivo studies of the graft materials also completed. Primary human osteoblasts (HOB) cells and female Sprague Dawley rats were used in in-vitro and in-vivo studies. Test results demonstrate cell population, and bone volume of the rats grafted with composites has remarkably increased, this caused remodelling in bone structure. Overall, these findings indicate that encapsulation of melatonin in the PCL particles with electrospray method is optimum for new synthetic graft material.

Halomonas smyrnensis as a cell factory for co-production of PHB and levan.

Levan is a fructan type polysaccharide that has long been considered as an industrially important biopolymer however its limited availability is mainly due to the bottlenecks associated with its large-scale production. To overcome such bottlenecks in the commercialization of this very promising polysaccharide, co-production of levan with polyhydroxyalkanoates (PHAs) by halophilic Halomonas smyrnensis cultures has been proposed in this study for the first time. After in silico and in vitro assessment of PHA accumulation, fermentation profiles for levan and PHA concentrations were obtained in the presence of sucrose and glucose and the PHA granules observed by TEM were found to be poly(3-hydroxybutyrate) (PHB) after detailed structural characterization by GC-MS, DSC, FTIR and NMR. Six nutrient limitation strategies based on nitrogen (N) and phosphorus (P) were tested but highest levan and PHB yields were obtained under unlimited conditions. H. smyrnensis is proved to co-produce PHB and levan while using inexpensive carbon sources which is a commercially successful microbial cell factory system showing a great potential in lowering manufacturing costs and aiming for a zero waste policy within the biorefinery concept.