Studies of antibacterial activity (in vitro and in vivo) and mode of action for des-acyl tridecaptins (DATs).

Tridecaptins comprise a class of linear cationic lipopeptides with an N-terminal fatty acyl moiety. These 13-mer antimicrobial peptides consist of a combination of d- and l-amino acids, conferring increased proteolytic stability. Intriguingly, they are biosynthesized by non-ribosomal peptide synthetases in the same bacterial species that also produce the cyclic polymyxins displaying similar fatty acid tails. Previously, the des-acyl analog of TriA1 (termed H-TriA1) was found to possess very weak antibacterial activity, albeit it potentiated the effect of several antibiotics. In the present study, two series of des-acyl tridecaptins were explored with the aim of improving the direct antibacterial effect. At the same time, overall physico-chemical properties were modulated by amino acid substitution(s) to diminish the risk of undesired levels of hemolysis and to avoid an impairment of mammalian cell viability, since these properties are typically associated with highly hydrophobic cationic peptides. Microbiology and biophysics tools were used to determine bacterial uptake, while circular dichroism and isothermal calorimetry were used to probe the mode of action. Several analogs had improved antibacterial activity (as compared to that of H-TriA1) against Enterobacteriaceae. Optimization enabled identification of the lead compound 29 that showed a good ADMET profile as well as in vivo efficacy in a variety of mouse models of infection.

Medical devices, smart drug delivery, wearables and technology for the treatment of Diabetes Mellitus.

Diabetes mellitus refers to a group of metabolic disorders which affect how the body uses glucose impacting approximately 9% of the population worldwide. This review covers the most recent technological advances envisioned to control and/or reverse Type 1 diabetes mellitus (T1DM), many of which will also prove effective in treating the other forms of diabetes mellitus. Current standard therapy for T1DM involves multiple daily glucose measurements and insulin injections. Advances in glucose monitors, hormone delivery systems, and control algorithms generate more autonomous and personalised treatments through hybrid and fully automated closed-loop systems, which significantly reduce hypo- and hyperglycaemic episodes and their subsequent complications. Bi-hormonal systems that co-deliver glucagon or amylin with insulin aim to reduce hypoglycaemic events or increase time spent in target glycaemic range, respectively. Stimuli responsive materials for the controlled delivery of insulin or glucagon are a promising alternative to glucose monitors and insulin pumps. By their self-regulated mechanism, these "smart" drugs modulate their potency, pharmacokinetics and dosing depending on patients' glucose levels. Islet transplantation is a potential cure for T1DM as it restores endogenous insulin and glucagon production, but its use is not yet widespread due to limited islet sources and risks of chronic immunosuppression. New encapsulation strategies that promote angiogenesis and oxygen delivery while protecting islets from recipients' immune response may overcome current limiting factors.

The Foreign Body Response to an Implantable Therapeutic Reservoir in a Diabetic Rodent Model.

Advancements in type 1 diabetes mellitus treatments have vastly improved in recent years. The move toward a bioartificial pancreas and other fully implantable systems could help restore patient's glycemic control. However, the long-term success of implantable medical devices is often hindered by the foreign body response. Fibrous encapsulation "walls off" the implant to the surrounding tissue, impairing its functionality. In this study we aim to examine how streptozotocin-induced diabetes affects fibrous capsule formation and composition surrounding implantable drug delivery devices following subcutaneous implantation in a rodent model. After 2 weeks of implantation, the fibrous capsule surrounding the devices were examined by means of Raman spectroscopy, micro-computed tomography (µCT), and histological analysis. Results revealed no change in mean fibrotic capsule thickness between diabetic and healthy animals as measured by µCT. Macrophage numbers (CCR7 and CD163 positive) remained similar across all groups. True component analysis also showed no quantitative difference in the alpha-smooth muscle actin and extracellular matrix proteins. Although principal component analysis revealed significant secondary structural difference in collagen I in the diabetic group, no evidence indicates an influence on fibrous capsule composition surrounding the device. This study confirms that diabetes did not have an effect on the fibrous capsule thickness or composition surrounding our implantable drug delivery device. Impact Statement Understanding the impact diabetes has on the foreign body response (FBR) to our implanted material is essential for developing an effective drug delivery device. We used several approaches (Raman spectroscopy and micro-computed tomography imaging) to demonstrate a well-rounded understanding of the diabetic impact on the FBR to our devices, which is imperative for its clinical translation.