Synthetic beta cells for fusion-mediated dynamic insulin secretion.

Generating artificial pancreatic beta cells by using synthetic materials to mimic glucose-responsive insulin secretion in a robust manner holds promise for improving clinical outcomes in people with diabetes. Here, we describe the construction of artificial beta cells (AßCs) with a multicompartmental 'vesicles-in-vesicle' superstructure equipped with a glucose-metabolism system and membrane-fusion machinery. Through a sequential cascade of glucose uptake, enzymatic oxidation and proton efflux, the AßCs can effectively distinguish between high and normal glucose levels. Under hyperglycemic conditions, high glucose uptake and oxidation generate a low pH (<5.6), which then induces steric deshielding of peptides tethered to the insulin-loaded inner small liposomal vesicles. The peptides on the small vesicles then form coiled coils with the complementary peptides anchored on the inner surfaces of large vesicles, thus bringing the membranes of the inner and outer vesicles together and triggering their fusion and insulin 'exocytosis'.

Investigation of the binding of dioxin selective pentapeptides to a polyaniline matrix.

Polyaniline in form of emeraldine salt and emeraldine base was used as a matrix to attach several labeled and non-labeled dioxin selective pentapeptides both directly to the polymer and using glutaraldehyde as a linker. The peptides have been selected as a model to study the binding process due to their smaller size, lower sensitivity to the environment and potential application as solid state extraction reagents for chlorinated toxins. The composition and the properties of the compounds were investigated by means of elemental analysis, XPS, FTIR, UV/vis, and fluorescence spectroscopy. The results have shown that 3.30-7.76% peptides were attached to the emeraldine base both with and without a linker. Glutaraldehyde and the peptides were connected to the matrix via chemical bond resulting in formation of compounds whit similar composition and stability in a broad pH range. The influence of the linker and the peptides on the electronic properties and composition of the polymer have been investigated by principal component analysis.

Inhibition of post-surgery tumour recurrence via a hydrogel releasing CAR-T cells and anti-PDL1-conjugated platelets.

The immunosuppressive microenvironment of solid tumours reduces the antitumour activity of chimeric antigen receptor T cells (CAR-T cells). Here, we show that the release-through the implantation of a hyaluronic acid hydrogel-of CAR-T cells targeting the human chondroitin sulfate proteoglycan 4, polymer nanoparticles encapsulating the cytokine interleukin-15 and platelets conjugated with the checkpoint inhibitor programmed death-ligand 1 into the tumour cavity of mice with a resected subcutaneous melanoma tumour inhibits the local recurrence of the tumour as well as the growth of distant tumours, through the abscopal effect. The hydrogel, which functions as a reservoir, facilitates the enhanced distribution of the CAR-T cells within the surgical bed, and the inflammatory microenvironment triggers platelet activation and the subsequent release of platelet-derived microparticles. The post-surgery local delivery of combination immunotherapy through a biocompatible hydrogel reservoir could represent a translational route for preventing the recurrence of cancers with resectable tumours.

N-(4-amino-7-nitrobenzaoxa-1,3-diazole)-substituted aza crown ethers: complexation with alkali, alkaline earth metal ions and ammonium.

Three novel aza-crown ether derivatives incorporating 4-amino-7-nitrobenzaoxa-1,3-diazole (NBD) chromophore were synthesized and their structure confirmed by (1)H-NMR, IR and elemental analysis. The influence of the solvent polarity and protonation on the photophysical properties of NBD-15-crown-5 was studied by UV/Vis and fluorescence methods. The influence of the investigated cations on the absorption spectra of the ligands was negligible, however emission was strongly affected. Complexation and binding stability of NBD-aza-15-crown-5 and NBD-aza-18-crown-6 were studied using fluorescence spectroscopy. NBD-aza-18-crown-6 exhibits strong selectivity toward Ca(2+) and Sr(2+) ions with formation constants about 10(3) times higher than the formation constants with the other ions included in the study.

Red blood cell-derived nanoerythrosome for antigen delivery with enhanced cancer immunotherapy.

Erythrocytes or red blood cells (RBCs) represent a promising cell-mediated drug delivery platform due to their inherent biocompatibility. Here, we developed an antigen delivery system based on the nanoerythrosomes derived from RBCs, inspired by the splenic antigen-presenting cell targeting capacity of senescent RBCs. Tumor antigens were loaded onto the nanoerythrosomes by fusing tumor cell membrane-associated antigens with nanoerythrosomes. This tumor antigen-loaded nanoerythrosomes (nano-Ag@erythrosome) elicited antigen responses in vivo and, in combination with the anti-programmed death ligand 1 (PD-L1) blockade, inhibited the tumor growth in B16F10 and 4T1 tumor models. We also generated a tumor model showing that "personalized nano-Ag@erythrosomes" could be achieved by fusing RBCs and surgically removed tumors, which effectively reduced tumor recurrence and metastasis after surgery.

In situ thermal ablation of tumors in combination with nano-adjuvant and immune checkpoint blockade to inhibit cancer metastasis and recurrence.

Tumor ablation therapies provide a minimally invasive approach to treat cancer. However, inhibition of cancer metastasis and recurrence after ablation is still a challenge in clinical trials. Here, we propose a strategy using combinatorial thermal ablation, adjuvants and immune checkpoint blockade (ICB) to inhibit metastatic tumor and recurrence via antitumor immune responses post tumor thermal ablation, which are frequently used in the clinic. Furthermore, a strong immune memory against cancer was observed 80 days after the primary tumor was ablated. Considering that all components in our design are approved by Food and Drug Administration (FDA), we provide a strategy based on clinically used cancer treatment technique that is promising in clinical translation.

A mobile phone-based approach to detection of hemolysis.

Preeclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome are pregnancy-related complications with high rates of morbidity and mortality. HELLP syndrome, in particular, can be difficult to diagnose. Recent work suggests that elevated levels of free cell hemoglobin in blood plasma can, as early as the first trimester, potentially serve as a diagnostic biomarker for impending complications. We therefore developed a point-of-care mobile phone-based platform that can quickly characterize a patient's level of hemolysis by measuring the color of blood plasma. The custom hardware and software are designed to be easy to use. A sample of the whole blood (~10µL or less) is first collected into a clear capillary tube or microtube, which is then inserted into a low-cost 3D-printed sample holder attached to the phone. A 5-10min period of quiescence allows for gravitational sedimentation of the red blood cells, leaving a layer of yellowish plasma at the top of the tube. The phone camera then photographs the capillary tube and analyzes the color components of the cell-free plasma layer. The software converts these color values to a concentration of free hemoglobin, based on a built-in calibration curve, and reports the patient's hemolysis level: non-hemolyzed, slightly hemolyzed, mildly hemolyzed, frankly hemolyzed, or grossly hemolyzed.. The accuracy of the method is ~1mgdL-1. This phone-based point-of-care system provides the potentially life-saving advantage of a turnaround time of about 10min (versus 4+hours for conventional laboratory analytical methods) and a cost of approximately one dollar USD (assuming you have the phone and the software are already available).

Leveraging H2 O2 Levels for Biomedical Applications.

Hydrogen peroxide (H2 O2 )-responsive materials have been employed as drug delivery or diagnostic systems to treat or detect diseases with abnormal oxidative stress. A number of H2 O2 -responsive systems have been developed, and they have achieved great progress in controlled drug delivery for disease treatment. However, pathological sites with elevated H2 O2 level, such as cancer and inflammation, have their own characteristics; therefore the material structures and the subsequent formulations should be reasonably designed to acquire maximized therapeutic effects. In this progress report, we overview the development of H2 O2 -responsive functional groups for constructing H2 O2 -responsive formulations, as well as the guidance for designing suitable formulations to treat each specific pathological condition. The challenges and perspectives in this field are also discussed.

Synthesis, characterization, and electrospinning of novel polyaniline-peptide polymers.

Aniline-peptide (FLDQV, FLDQVC, Dansyl-FLDQV, Dansyl-FLDQVC, and FLDQV-AMC) mixtures underwent oxidative chemical and electrochemical polymerization in excess of aniline. The products of the chemical polymerization were low molecular weight polymers containing more than 70% peptide. Electrochemically polymerized species polyaniline-FLDQV (PANI-FLDQV) consisted mainly of polyaniline units containing about 10% peptide. The solubility of the latter in 1,1,1,3,3,3-hexafluoro-2-propanol (HFP) was similar to the camphorsulfonic acid (CSA) doped emeraldine base (PANI-CSA) solubility, however the weight composition of the electrospun fibers produced from the two polymers was significantly different. 2D 1H-13C HSQC analyses were employed to analyze the binding between the aniline and peptide moieties. Binding of peptide to polyaniline is reflected by the appearance of extra cross-peaks which display line broadening between the free polyaniline and the free pentapeptide. Peptides may be chemically bonded to the polymer molecules, but they may also act as doping agents to the nitrogen atoms via hydrogen bonding.

Dansyl - Substituted Aza Crown Ethers: Complexation with Alkali, Alkaline Earth Metal Ions and Ammonium.

The present study investigates the binding properties of four dansyl substituted aza-crown ethers with alkali, alkaline earth metal ions and ammonium. The influence of the solvent polarity and protonation on the photophysical properties of the compounds was studied by UV/Vis and fluorescence methods. The host species caused only slight changes on the absorption spectra of the ligands. The fluorescence changes were more pronounced and concentration dependent thus allowing to calculate the binding constants of the process. The most stable complex under our working conditions was the one between Ba(2+) and DNS18C6.