Lymphatic Uptake of Liposomes after Intraperitoneal Administration Primarily Occurs via the Diaphragmatic Lymphatics and is Dependent on Liposome Surface Properties.

Drugs are commonly administered via the intraperitoneal (IP) route to treat localized infections and cancers in patients and to test drug efficacy and toxicity in preclinical studies. Despite this, there remain large gaps in our understanding of drug absorption routes (lymph vs blood) and pharmacokinetics following IP administration. This is particularly true when drugs are administered in complex delivery systems such as liposomes which are the main marketed formulation for several drugs that are administered intraperitoneally. This study investigated the impact of liposome surface properties (charge and PEGylation) on absorption into lymph and blood, and lymphatic disposition patterns, following IP administration. To achieve this, stable 3H-dipalmitoyl-phosphatidylcholine (DPPC) and 14C-sucrose-radiolabeled liposomes of 100-150 nm diameter with negative, neutral, or positive surface charge, or a PEGylated surface, were prepared and administered intraperitoneally to rats. Radiolabel concentrations were measured in lymph, blood, and lymph nodes (LNs). Lymph was collected from the thoracic lymph duct at either the abdomen (ABD) or the jugular-subclavian junction (JSJ). The lymphatic recovery of the radiolabels was substantially lower after administration in positively charged compared to the neutral, negative, or PEGylated liposomes. Radiolabel recovery was substantially greater (up to 18-fold) in the thoracic lymph collected at the JSJ when compared to that at the ABD, suggesting that liposomes entered the lymphatics at the diaphragm. Consistent with this, the concentration of the liposome labels was substantially higher (up to seven-fold) in mediastinal than in mesenteric LNs. Overall, this study shows how the peritoneal absorption and lymphatic disposition of drugs administered intraperitoneally can be manipulated through a careful selection of the drug delivery system and may thus be optimized to treat localized conditions such as cancers, infections, inflammatory diseases, and acute and critical illness.

The pathogenic mechanism of diabetes varies with the degree of overexpression and oligomerization of human amylin in the pancreatic islet ß cells.

The aggregation of human amylin (hA) to form cytotoxic structures has been closely associated with the causation of type 2 diabetes. We sought to advance understanding of how altered expression and aggregation of hA might link ß-cell degeneration with diabetes onset and progression, by comparing phenotypes between homozygous and hemizygous hA-transgenic mice. The homozygous mice displayed elevated islet hA that correlated positively with measures of oligomer formation (r=0.91; P<0.0001). They also developed hyperinsulinemia with transient insulin resistance during the prediabetes stage and then underwent rapid ß-cell loss, culminating in severe juvenile-onset diabetes. The prediabetes stage was prolonged in the hemizygous mice, wherein ß-cell dysfunction and extensive oligomer formation occurred in adulthood at a much later stage, when hA levels were lower (r=-0.60; P<0.0001). This is the first report to show that hA-evoked diabetes is associated with age, insulin resistance, progressive islet dysfunction, and ß-cell apoptosis, which interact variably to cause the different diabetes syndromes. The various levels of hA elevation cause different extents of oligomer formation in the disease stages, thus eliciting early- or adult-onset diabetes syndromes, reminiscent of type 1 and 2 diabetes, respectively. Thus, the hA-evoked diabetes phenotypes differ substantively according to degree of amylin overproduction. These findings are relevant to the understanding of the pathogenesis and the development of experimental therapeutics for diabetes.

Electrochemical Preparation of Poly(3,4-Ethylenedioxythiophene) Layers on Gold Microelectrodes for Uric Acid-Sensing Applications.

Two different methods for the synthesis of poly(3,4-ethylenedioxythiophene) (PEDOT) on gold electrodes are described, using electropolymerization of 3,4-ethylenedioxythiophene (EDOT) monomer in an aqueous and an organic solution. Cyclic voltammetry (CV) was used in the synthesis of PEDOT thin layers. Lithium perchlorate (LiClO4) was used as a dopant in both aqueous (aqueous/acetonitrile (ACN)) and organic (propylene carbonate (PC)) solvent systems. After the PEDOT layer was created in the organic system, the electrode surface was acclimatized by successive cycling in an aqueous solution for use as a sensor for aqueous samples. The use of an aqueous-based electropolymerization method has the potential benefit of removing the acclimatization step to have a shorter sensor preparation time. Although the aqueous method is more economical and environmentally friendly than the organic solvent method, superior PEDOT formation is obtained in the organic solution. The resulting PEDOT electrode surfaces were characterized by scanning electron microscopy (SEM), which showed the constant growth of PEDOT during electropolymerization from the organic PC solution, with rapid fractal-type growth on gold (Au) microelectrodes.

Sustained Release of Cx43 Antisense Oligodeoxynucleotides from Coated Collagen Scaffolds Promotes Wound Healing.

Antisense oligodeoxynucleotides targeting the mRNA of the gap junction protein Cx43 promote tissue repair in a variety of different wounds. Delivery of the antisense drug has most often been achieved by a thermoreversible hydrogel, Pluronic F-127, which is very effective in the short term but does not allow for sustained delivery over several days. For chronic wounds that take a long time to heal, repeated dosing with the drug may be desirable but is not always compatible with conventional treatments such as the weekly changing of compression bandages on venous leg ulcers. Here the coating of collagen scaffolds with antisense oligonucleotides is investigated and a way to provide protection of the oligodeoxynucleotide drug is found in conjunction with sustained release over a 7 d period. This approach significantly reduces the normal foreign body reaction to the scaffold, which induces an increase of Cx43 protein and an inhibition of healing. As a result of the antisense integration into the scaffold, inflammation is reduced with the rate of wound healing and contracture is significantly improved. This coated scaffold approach may be very useful for treating venous leg ulcers and also for providing a sustained release of any other types of oligonucleotide drugs that are being developed.

The effect of enteral nutrition on adipokines in patients with acute pancreatitis.

The mechanism behind the beneficial effects of enteral nutrition (EN) for patients with acute pancreatitis (AP) is largely unknown. Adipokines, as mediators of metabolism and inflammation, may be a possible mechanism. The study aimed to investigate the effect of EN on adipokines early in the course of AP. Patients with AP were randomised to EN or nil-by-mouth (NBM). Blood samples were taken on the first 4 d of admission and adipokine concentrations for adiponectin, leptin, omentin, resistin and visfatin were determined by ELISA assays. A linear mixed model analysis was run to determine differences in adipokine concentrations between the two study groups. A total of thirty-two patients were included in the study. Omentin concentrations were significantly higher in patients who received EN compared with NBM across the first 4 d of admission (mean difference: 11·6 (95 % CI 1·0, 22·3) ng/ml; P = 0·033). Leptin concentrations were significantly higher in patients who received EN compared with NBM after adjusting for age, sex and BMI (mean difference: 2·3 (95 % CI 0·1, 4·5) ng/ml; P = 0·037). No significant difference in adiponectin, resistin or visfatin concentrations were observed between the two study groups. EN significantly increases omentin and leptin concentrations in AP. Future research should be directed towards understanding whether these adipokines are responsible for the therapeutic benefits of EN.

Integration of scaffolds into full-thickness skin wounds: the connexin response.

Scaffolds have been reported to promote healing of hard-to-heal wounds such as burns and chronic ulcers. However, there has been little investigation into the cell biology of wound edge tissues in response to the scaffolds. Here, we assess the impact of collagen scaffolds on mouse full-thickness wound re-epithelialisation during the first 5 days of healing. We find that scaffolds impede wound re-epithelialisation, inducing a bulbous thickening of the wound edge epidermis as opposed to the thin tongue of migratory keratinocytes seen in normal wound healing. Scaffolds also increase the inflammatory response and the numbers of neutrophils in and around the wound. These effects were also produced by scaffolds made of alginate in the form of fibers and microspheres, but not as an alginate hydrogel. In addition, we find the gap junction protein connexin 43, which normally down-regulates at the wound edge during re-epithelialisation, to be up-regulated in the bulbous epidermal wound edge. Incorporation of connexin 43 antisense oligodeoxynucleotides into the scaffold can be performed to reduce inflammation whilst promoting scaffold biocompatibility.