Oseltamivir phosphate released from injectable Pickering emulsions over an extended term disables human pancreatic cancer cell survival.

Pickering emulsions are colloidal dispersions stabilized by particles that either migrate to, or are formed at, the oil-water interface during emulsification. Here, we fabricated and characterized Pickering water-in-oil emulsions where molten glycerol monostearate crystallized at the surface of micron-sized water droplets and formed protective solid shells. We tested this emulsion as a reservoir delivery platform for the sustained release of low molecular weight hydrophilic molecules including sodium chloride (NaCl) and sodium citrate as model compounds, and the therapeutic oseltamivir phosphate (OP), the delivery of which was the ultimate goal of this research.

Microencapsulation of esterified krill oil, using complex coacervation.

The microencapsulation of the esterified krill oil (EKO), obtained from the transesterification of krill oil (KO) with 3,4-dihydroxyphenylacetic acid (DHPA), via complex coacervation and was investigated. The experimental findings showed that the DHPA and phenolic lipids (PLs) in the EKO affected the stability of the gelatine (GE)-EKO emulsion. To improve its stability, the effects of varying the pH of GE and the use of two emulsification devices, including the homogeniser and ultrasonic liquid processor were investigated, where the ultrasonic liquid processor was found to be a relatively more appropriate emulsification device.

Combinatorial and sequential delivery of gemcitabine and oseltamivir phosphate from implantable poly(d,l-lactic-co-glycolic acid) cylinders disables human pancreatic cancer cell survival.

Combination therapies against multiple targets are currently being developed to prevent resistance to a single chemotherapeutic agent and to extirpate pre-existing resistance in heterogeneous cancer cells in tumors due to selective pressure from the single agent. Gemcitabine (GEM), a chemotherapeutic agent, is the current standard of care for patients with pancreatic cancer. Patients with pancreatic cancer receiving GEM have a low progression-free survival.

Neuraminidase-1: a novel therapeutic target in multistage tumorigenesis.

Several of the growth factors and their receptor tyrosine kinases (RTK) such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and insulin are promising candidate targets for cancer therapy. Indeed, tyrosine kinase inhibitors (TKI) have been developed to target these growth factors and their receptors, and have demonstrated dramatic initial responses in cancer therapy. Yet, most patients ultimately develop TKI drug resistance and relapse.

Sialylation transmogrifies human breast and pancreatic cancer cells into 3D multicellular tumor spheroids using cyclic RGD-peptide induced self-assembly.

Multicellular tumor spheroids (MTS) have been at the forefront of cancer research, designed to mimic tumor-like developmental patterns in vitro. Tumor growth in vivo is highly influenced by aberrant cell surface-specific sialoglycan structures on glycoproteins. Aberrant sialoglycan patterns that facilitate MTS formation are not well defined.

Oseltamivir-conjugated polymeric micelles prepared by RAFT living radical polymerization as a new active tumor targeting drug delivery platform.

Targeted drug delivery using polymeric nanostructures has been at the forefront of cancer research, engineered for safer, more efficient and effective use of chemotherapy. Here, we designed a new polymeric micelle delivery system for active tumor targeting followed by micelle-drug internalization via receptor-induced endocytosis. We recently reported that oseltamivir phosphate targets and inhibits Neu1 sialidase activity associated with receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) which are overexpressed in cancer cells.

Release of insulin from PLGA-alginate dressing stimulates regenerative healing of burn wounds in rats.

Burn wound healing involves a complex set of overlapping processes in an environment conducive to ischaemia, inflammation and infection costing $7.5 billion/year in the U.S.

Therapeutic designed poly (lactic-co-glycolic acid) cylindrical oseltamivir phosphate-loaded implants impede tumor neovascularization, growth and metastasis in mouse model of human pancreatic carcinoma.

Poly (lactic-co-glycolic acid) (PLGA) copolymers have been extensively used in cancer research. PLGA can be chemically engineered for conjugation or encapsulation of drugs in a particle formulation. We reported that oseltamivir phosphate (OP) treatment of human pancreatic tumor-bearing mice disrupted the tumor vasculature with daily injections.

Polymerization Induced Self-Assembly of Alginate Based Amphiphilic Graft Copolymers Synthesized by Single Electron Transfer Living Radical Polymerization.

Alginate-based amphiphilic graft copolymers were synthesized by single electron transfer living radical polymerization (SET-LRP), forming stable micelles during polymerization induced self-assembly (PISA). First, alginate macroinitiator was prepared by partial depolymerization of native alginate, solubility modification and attachment of initiator. Depolymerized low molecular weight alginate (∼12 000 g/mol) was modified with tetrabutylammonium, enabling miscibility in anhydrous organic solvents, followed by initiator attachment via esterification yielding a macroinitiator with a degree of substitution of 0.

Oseltamivir phosphate monotherapy ablates tumor neovascularization, growth, and metastasis in mouse model of human triple-negative breast adenocarcinoma.

Background: Triple-negative breast cancers (TNBCs) lack the estrogen, progesterone, and epidermal growth factor (EGF) receptor-2 (HER2/neu) receptors. Patients with TNBC have typical high grading, more frequent relapses, and exhibit poorer outcomes or prognosis compared with the other subtypes of breast cancers. Currently, there are no targeted therapies that are effective for TNBC.

Transcriptional factor snail controls tumor neovascularization, growth and metastasis in mouse model of human ovarian carcinoma.

Background: Snail, a transcriptional factor and repressor of E-cadherin is well known for its role in cellular invasion. It can regulate epithelial to mesenchymal transition (EMT) during embryonic development and in epithelial cells. Snail also mediates tumor progression and metastases.

Microencapsulation by interfacial polymerisation: membrane formation and structure.

Interfacial polymerisation was mainly developed toward the end of the 1960s, leading to applications in microcapsule production by the mid-1970s. The process consists in the dispersion of one phase containing a reactive monomer, into a second immiscible phase to which is added a second monomer. Both monomers react at the droplet surface (interface), forming a polymeric membrane.

Microencapsulation of krill oil using complex coacervation.

The research work was aimed at the development of a process to yield gelatin-gum Arabic multinuclear microcapsules of krill oil (KO), via complex coacervation. On the basis of the experimental results of the screening trials, a three-level-by-three-factor Box-Behnken design was used to evaluate the effects of the ratio of the core material to the wall (RCW; x1), the stirring speed (SP; x2) and the pH (x3) on the encapsulation efficiency (EE). The experimental findings indicated that x3 has the most significant linear and quadratic effects on the EE of KO and a bilinear effect with x1, whereas x2 did not have any significant effect.

Insulin and wound healing.

Skin is a dynamic and complex organ that relies on the interaction of different cell types, biomacromolecules and signaling molecules. Injury triggers a cascade of events designed to quickly restore skin integrity. Depending on the size and severity of the wound, extensive physiological and metabolic changes can occur, resulting in impaired wound healing and increased morbidity resulting in higher rates of death.

Therapeutic targeting of Neu1 sialidase with oseltamivir phosphate (Tamiflu®) disables cancer cell survival in human pancreatic cancer with acquired chemoresistance.

Background: Resistance to drug therapy, along with high rates of metastasis, contributes to the low survival rate in patients diagnosed with pancreatic cancer. An alternate treatment for human pancreatic cancer involving targeting of Neu1 sialidase with oseltamivir phosphate (Tamiflu®) was investigated in human pancreatic cancer (PANC1) cells with acquired resistance to cisplatin and gemcitabine. Its efficacy in overcoming the intrinsic resistance of the cell to chemotherapeutics and metastasis was evaluated.

Encapsulation of protein microfiber networks supporting pancreatic islets.

Networks of discrete, genipin-crosslinked gelatin microfibers enveloping pancreatic islets were incorporated within barium alginate microcapsules. This novel technique enabled encapsulation of cellular aggregates in a spherical fibrous matrix <300 μm in diameter. Microfibers were produced by vortex-drawn extrusion within an alginate support matrix.

Alginate-PEG sponge architecture and role in the design of insulin release dressings.

Wound healing is a natural process involving several signaling molecules and cell types over a significant period of time. Although current dressings help to protect the wound from debris or infection, they do little in accelerating the healing process. Insulin has been shown to stimulate the healing of damaged skin.

Characterization of biologically active insulin-loaded alginate microparticles prepared by spray drying.

Background: Spray drying has been used as a means to encapsulate therapeutics in polymeric matrices to improve stability and alter pharmacokinetics. This research aims to characterize alginate microparticles formed by spray drying to encapsulate insulin for therapeutic delivery applications.

Methods: Particle size was characterized by laser diffraction spectroscopy, morphology by scanning electron microscopy, and protein and polymer distribution by confocal laser scanning microscopy.

Evaluation of hepatic glucose metabolism via gluconeogenesis and glycogenolysis after oral administration of insulin nanoparticles.

Nanoparticles were designed to promote insulin intestinal absorption via the oral route, to increase portal insulin levels to better mimic the physiological pathway, providing enhanced glucose control through glycogenolysis and gluconeogenesis. Nanoparticles were formulated with insulin encapsulated in the core material consisting of alginate and dextran sulfate, associated with poloxamer and subsequently coated with chitosan then albumin. A spherical and slightly rough core was observed in electron micrographs with the appearance of a concentration gradient of the polysaccharide structure toward the periphery of the nanoparticle.

Effects of an oral insulin nanoparticle administration on hepatic glucose metabolism assessed by ¹³C and ²H isotopomer analysis.

The purpose of this study was to evaluate hepatic glucose metabolism of diabetic induced rats after a daily oral load of insulin nanoparticles over 2 weeks. After the 2-week treatment, an oral glucose tolerance test was performed with [U-¹³C] glucose and ²H₂O. Plasma glucose ²H and ¹³C enrichments were quantified and the contribution of glycogenolysis and gluconeogenesis to overall glucose production were estimated.

Facilitated nanoscale delivery of insulin across intestinal membrane models.

The effect of nanoparticulate delivery system on enhancing insulin permeation through intestinal membrane was evaluated in different intestinal epithelial models using cell cultures and excised intestinal tissues. Multilayered nanoparticles were formulated by encapsulating insulin within a core consisting of alginate and dextran sulfate nucleating around calcium and binding to poloxamer, stabilized by chitosan, and subsequently coated with albumin. Insulin permeation through Caco-2 cell monolayer was enhanced 2.

Systemic and mucosal delivery of drugs within polymeric microparticles produced by spray drying.

Encapsulation of therapeutic and diagnostic materials into polymeric particles is a means to protect and control or target the release of active substances such as drugs, vaccines, and genetic material. In terms of mucosal delivery, polymeric encapsulation can be used to promote absorption of the active substance, while particles can improve the half-life of drugs administered systemically. Spray drying is an attractive technology used to produce such microparticles, because it combines both the encapsulation and drying steps in a rapid, single-step operation.

Pharmacological effect of orally delivered insulin facilitated by multilayered stable nanoparticles.

Intestinal uptake, insulinemia and hypoglycemic effect of orally delivered insulin encapsulated in polyelectrolytically stable nanoparticles were evaluated in streptozotocin-induced Wistar diabetic rats. Nanoparticles with 396nm mean diameter were formed by alginate and dextran sulfate nucleating around calcium and binding to poloxamer, stabilized by chitosan, and subsequently coated with albumin. The resulting negatively charged nanoparticles retained insulin bioactivity and enhanced pharmacological availability by shielding insulin from enzymatic degradation and through chemical and physical facilitation of permeation through the intestinal membrane.

Tuneable semi-synthetic network alginate for absorptive encapsulation and controlled release of protein therapeutics.

Stimuli-responsive hydrogels swell or contract in response to external pH, ionic strength or temperature, and are of considerable interest as pharmaceutical controlled release devices. Alginate, a mucoadhesive biopolymer, was used as building block in the semi-synthesis of a tetra-functional acetal-linked networked polymer (SNAP) with carboxylate moieties preserved as stimuli-responsive sensors and tuneable pore sizes larger than the hydrodynamic radius of model molecules ranging between 1 and 540 kDa. Based on the diffusion coefficients calculated from protein uptake experiments, the networked polymer with pre-designed pore size of 80 nm can allow vitamin B(12), lysozyme, subtilisin, insulin, albumin, and urease to diffuse freely into the hydrogel with diffusivity ratio of D(gel)/D(water) (diffusion coefficients in hydrogel to water) between 0.