An Optimized and Universal Protocol for the Synthesis of Morpholine-2,5-Diones from Natural Hydrophobic Amino Acids and Their Mixture.

Morpholine-2,5-diones (MDs) are increasingly attractive compounds that can be produced using amino acid (AA) as a starting material. These compounds can undergo polymerization to produce biodegradable materials, namely, polydepsipeptides, that hold the potential to be used in medicinal applications. In this study, a simplified yet high-yield MD synthesis procedure was developed and applied to produce a range of MDs derived from hydrophobic AAs including Leu, Ile, Val, Phe, Asp(OBzl), Lys(Z), and Ser(tBu). Moreover, using a blend of hydrophobic amino acids (Leu, Ile, Val, and Phe), mixtures of MDs could be synthesized simultaneously. Finally, the polymerization of these MD mixtures was probed and proven successful. The concept investigated herein constitutes a novel path toward the valorization of protein-rich waste by producing renewable and biodegradable materials.

Anti-aggregation effect of carbon quantum dots on diabetogenic and beta-cell cytotoxic amylin and beta amyloid heterocomplexes.

Pancreatic islet amyloid deposition is a pathological hallmark of Type 2 diabetes (T2D), contributing to reduced functional ß-cell mass. Islet amyloids result not only from the aggregation and fibrillation of human islet amyloid polypeptide (hIAPP), but also from beta-amyloid 42 (Aß42), the key amyloidogenic peptide linked to Alzheimer's disease. Importantly, Aß42 and hIAPP aggregates (IAPP:Aß42) can interact with each other and form some harmful heterocomplex fibrils. While it is well-documented that hIAPP aggregation occurs only when islets are exposed to a diabetic environment, including hyperglycemia and/or elevated concentrations of saturated fatty acids (SFAs), it remains unclear if hIAPP and IAPP:Aß42 heteromer fibrillations are directly or indirectly triggered by this environment. In this study, we show the interplay between high glucose concentrations and palmitate as the SFA in the aggregation of hIAPP. In addition, we outline that the interaction of hIAPP and Aß42 leads to the formation of complex protein aggregates, which are toxic to ß-cells. Carbon nanocolloids in the form of positively charged carbon quantum dots (CQD-pos) efficiently prevent single amyloid aggregation and the formation of IAPP:Aß42 heterocomplexes. We provide clear evidence with this study that the diabetogenic environment of islets could directly contribute to the formation of homomeric and heteromeric amyloid aggregates and fibrils in T2D. We also propose carbon nanocolloids as biocompatible nanomaterials for developing innovative therapeutic strategies that prevent the decline of functional ß-cell mass.

Heat-based transdermal delivery of a ramipril loaded cream for treating hypertension.

Angiotensin-converting enzyme (ACE) inhibitors play an important role in the development of anti-hypertension approaches, with ramipril being one of the most widely used ACE inhibitor prodrugs orally administered once or twice a day. Due to its low bioavailability, large amounts have to be administered to obtain a therapeutic effect. In this work, we propose a ramipril loaded pharmaceutical formulation in contact with an electrothermal actuator based on a gold nanohole array as an efficient approach to increase the transdermal ramipril flux. Using rats as an in vivo model, the effect on the systolic and diastolic blood pressure is evaluated, showing that under optimized conditions the blood pressure could be regulated. Heat activation resulted in total drug delivery out of a bandage loaded with 1 mg ramipril, revealing a flux of 50.9 ± 2.8 µg cm-2 h-1. Importantly, heat-based transdermal dispensing allowed efficient and rapid delivery of ramipril in spontaneously hypertensive rats, with its active form (ramiprilat) detected in blood as early as 5 minutes after delivery onset, accompanied by significant decrease in blood pressure.

Innovative transdermal delivery of insulin using gelatin methacrylate-based microneedle patches in mice and mini-pigs.

Painless and controlled on-demand drug delivery is the ultimate goal for the management of various chronic diseases, including diabetes. To achieve this purpose, microneedle patches are gaining increased attention. While degradable microneedle (MN) arrays are widely employed, the use of non-dissolving MN patches remains a challenge to overcome. In this study, we demonstrate that crosslinking gelatin methacrylate with polyethylene glycol diacrylate (PEGDA) is potent for engineering non-dissolving MN arrays. Incorporation of MoS2 nanosheets as a photothermal component into MN hydrogels results in MNs featuring on-demand release properties. An optimized MoS2-MN array patch formed using a hydrogel solution containing 500 µg mL-1 of MoS2 and photochemically crosslinked for 5 min shows required mechanical behavior under a normal compressive load to penetrate the stratum corneum of mice or pig skin and allows the delivery of macromolecular therapeutics such as insulin upon swelling. Using ex vivo and in vivo models, we show that the MoS2-MN patches can be used for loading and releasing insulin for therapeutic purposes. Indeed, transdermal administration of insulin loaded into MoS2-MN patches reduces blood glucose levels in C57BL/6 mice and mini-pigs comparably to subcutaneously injected insulin. We believe that this on-demand delivery system might alter the current insulin therapies and might be a potential approach for delivery of other proteins.

Photothermal Activatable Mucoadhesive Fiber Mats for On-Demand Delivery of Insulin via Buccal and Corneal Mucosa.

Electrospun fiber mats loaded with therapeutics have gained considerable attention as a versatile tool in the biomedical field. While these bandages are largely based on fast-dissolving polymers to release the cargo, stimuli-responsive fiber mats have the advantages of providing a timely and spatially controlled drug delivery platform, which can be refilled and reused several times. These benefits make electrospun fiber patches original platforms for painless and convenient on-demand hormone release. Because of the high need of more convenient and non-invasive methods for delivering insulin, a hormone that is currently used to treat hundred million people with diabetes worldwide, we have investigated the tremendous potential of reduced graphene oxide modified poly(acrylic acid) based fiber mats as an original platform for buccal and corneal insulin delivery on-demand. The PAA@rGO hydrogel-like fibers rendered water-insoluble by incorporating ß-cyclodextrin, followed by thermal cross-linking, which showed adequate tensile strength along with high adsorption capacity of insulin at pH 7 and good recyclability. The fiber mats maintained good fibrous morphology and high loading efficiency even after five loading-release cycles. The mucoadhesive nature of the fibers allowed their application for insulin delivery via the eye cornea and the buccal mouth lining, as evidenced in ex vivo studies. Insulin loaded PAA@rGO hydrogel-like fibers showed an insulin flux via buccal lining of pigs of 16.6 ± 2.9 µg cm-2 h-1 and 24.3 ± 3.1 µg cm-2 h-1 for porcine cornea. Testing on healthy adult volunteers confirmed the excellent, mucoadhesive nature of the bandage, with three out of six volunteers feeling completely comfortable (note 8.3) while wearing the patches in the buccal cavity.

The impact of chemical engineering and technological advances on managing diabetes: present and future concepts.

Monitoring blood glucose levels for diabetic patients is critical to achieve tight glycaemic control. As none of the current antidiabetic treatments restore lost functional ß-cell mass in diabetic patients, insulin injections and the use of insulin pumps are most widely used in the management of glycaemia. The use of advanced and intelligent chemical engineering, together with the incorporation of micro- and nanotechnological-based processes have lately revolutionized diabetic management. The start of this concept goes back to 1974 with the description of an electrode that repeatedly measures the level of blood glucose and triggers insulin release from an infusion pump to enter the blood stream from a small reservoir upon need. Next to the insulin pumps, other drug delivery routes, including nasal, transdermal and buccal, are currently investigated. These processes necessitate competences from chemists, engineers-alike and innovative views of pharmacologists and diabetologists. Engineered micro and nanostructures hold a unique potential when it comes to drug delivery applications required for the treatment of diabetic patients. As the technical aspects of chemistry, biology and informatics on medicine are expanding fast, time has come to step back and to evaluate the impact of technology-driven chemistry on diabetics and how the bridges from research laboratories to market products are established. In this review, the large variety of therapeutic approaches proposed in the last five years for diabetic patients are discussed in an applied context. A survey of the state of the art of closed-loop insulin delivery strategies in response to blood glucose level fluctuation is provided together with insights into the emerging key technologies for diagnosis and drug development. Chemical engineering strategies centered on preserving and regenerating functional pancreatic ß-cell mass are evoked in addition as they represent a permanent solution for diabetic patients.

Near-infrared light activatable hydrogels for metformin delivery.

Drug loaded hydrogels have proven to be versatile controlled-release systems. We report here on heat active hydrogel formation by mixing graphene oxide (GO) or carboxyl enriched reduced graphene oxide (rGO-COOH) with metformin hydrochloride, an insulin sensitizer drug currently used as the first line therapy to treat patients with type 2 diabetes. The driving forces of the gelation process between the graphene-based nanomaterial and metformin are hydrogen bonding and electrostatic interactions, weakened at elevated temperature. Using the excellent photothermal properties of the graphene matrixes, we demonstrate that these supramolecular drug reservoirs can be photothermally activated for transdermal metformin delivery. A sustained delivery of metformin was achieved using a laser power of 1 W cm-2. In vitro assessment of the key target Glucose-6 Phosphatase (G6P) gene expression using a human hepatocyte model confirmed that metformin activity was unaffected by photothermal activation. In vivo, metformin was detected in mice plasma at 1 h post-activation of the metformin loaded rGO-COOH gel.

Crystal structure of catena-poly[calcium-di-µ3-benzoato-κ(6) O,O':O-µ2-(dimethyl sulfoxide)-κ(2) O:O].

In the title complex, [Ca(C7H5O2)2(C2H6OS)] n , the Ca(2+) ion (site symmetry m..) is surrounded by eight O atoms, six from two bridging-chelating tridentate benzoate carboxyl groups and two from a bridging dimethyl sulfoxide mol-ecule (point group symmetry m..), giving an irregular coordination geometry [Ca-O bond length range = 2.345 (2)-2.524 (2) Å]. One-dimensional coordination complex chains extending parallel to c are generated in which the triply µ2-O-bridged Ca(2+) cations are separated by 3.6401 (5) Å. In the crystal, weak intra-chain C-H⋯π hydrogen bonds are present between the methyl H atoms of the dimethyl sulfoxide mol-ecules as donors and the aromatic rings as acceptors [C-H⋯Cg = 3.790 (4) Å].