Deep Eutectic Solvents: An Eco-friendly Design for Drug Engineering.

Invited for this month's cover, the researchers from UTCBS and CiTCoM from Université Paris Cité (Paris, France), as well as Materia Nova (Mons, Belgium). The image emphasizes the deep eutectic solvent preparation thanks to hydrogen bond acceptor and donor interactions for drugs formulation and therapeutic applications. The Review itself is available at 10.1002/cssc.202300669.

Deep Eutectic Solvents: An Eco-friendly Design for Drug Engineering.

In the spirit of circular economy and sustainable chemistry, the use of environmentally friendly chemical products in pharmacy has become a hot topic. In recent years, organic solvents have been the subject of a great range of restriction policies due to their harmful effects on the environment and toxicity to human health. In parallel, deep eutectic solvents (DESs) have emerged as suitable greener solvents with beneficial environmental impacts and a rich palette of physicochemical advantages related to their low cost and biocompatibility. Additionally, DESs can enable remarkable solubilizing effect for several active pharmaceutical ingredients (APIs), thus forming therapeutic DESs (TheDESs). In this work, special attention is paid to DESs, presenting a precise definition, classification, methods of preparation, and characterization. A description of natural DESs (NaDESs), i. e., eutectic solvents present in natural sources, is also reported. Moreover, the present review article is the first one to detail the different approaches for judiciously selecting the constituents of DESs in order to minimize the number of experiments. The role of DESs in the biomedical and pharmaceutical sectors and their impact on the development of successful therapies are also discussed.

Impact-Resistant Poly(3-Hydroxybutyrate)/Poly(ε-Caprolactone)-Based Materials, through Reactive Melt Processing, for Compression-Molding and 3D-Printing Applications.

Biobased and biocompatible polymers, such as polyhydroxyalkanoates (PHAs), are of great interest for a large range of applications in the spirit of green chemistry and upcoming reuse and recycling strategies. Polyhydroxybutyrate (PHB), as a promising biocompatible polymer belonging to PHAs, is subject to increased research concern regarding the high degree of crystallinity and brittle behavior of the resulting materials. Therefore, the improvement of PHB's physico-mechanical properties aims to decrease the Young's modulus values and to increase the ductility of samples. Here, we proposed an ambitious approach to develop melt-processed materials, while combining PHB characteristics with the ductile properties of poly(ε-caprolactone) (PCL). In order to compatibilize the poorly miscible PHB/PCL blends, dicumyl peroxide (DCP) was used as a free-radical promotor of polyester interchain reactions via the reaction extrusion process. The resulting PHB/PCL-DCP materials revealed a slight increase in the elongation at break, and significant improvement in the impact resistance (7.2 kJ.m-2) as compared to PHB. Additional decrease in the Young's modulus values was achieved by incorporating low molecular polyethylene glycol (PEG) as a plasticizer, leading to an important improvement in the impact resistance (15 kJ.m-2). Successful 3D printing using fused deposition melting (FDM) of the resulting PHB/PCL-based blends for the design of a prosthetic finger demonstrated the great potential of the proposed approach for the development of next-generation biomaterials.

Design of Thermoplastic Polyurethanes with Conferred Antibacterial, Mechanical, and Cytotoxic Properties for Catheter Application.

Thermoplastic polyurethanes (TPUs) are proposed as suitable solution for the fabrication of biocompatible catheters with appropriate mechanical parameters and confirmed antibacterial and cytocompatible properties. For this purpose, a series of quaternary ammonium salts (QASs) and quaternary phosphonium salts (QPSs) based monomers were prepared followed by the determination of their minimal inhibitory concentrations (MICs) against Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Pseudomonas aeruginosa (P. aeruginosa). A combination of the most active ammonium (QAS-C14) and phosphonium (QPS-TOP) salts led to a MIC down to 2.4 µg/mL against S. aureus and 9 µg/mL against P. aeruginosa, corroborating the existence of a synergistic effect. These quaternary onium salt (QOS) units were successfully incorporated along the polymer chain, as part of a two-step synthesis approach. The resulting TPU-QOS materials were subsequently characterized through thermal, mechanical, and surface analyses. TPU-Mix (combining the most active QAS-C14 and QPS-TOP units) showed the highest antibacterial efficiency, confirming the synergistic effect between both QOS groups. Finally, an MTT assay on the SiHa cell line revealed the low cytotoxicity level of these polymeric films, making these materials suitable for biomedical application. To go one step further in the preindustrialization approach, proof of concept regarding the catheter prototype fabrication based on TPU-QAS/QPS was validated by extrusion.

Pegylated Curcumin Derivative: Water-Soluble Conjugates with Antitumor and Antibacterial Activity.

During the past years, the synthesis of polymer prodrug structures, based on natural phytochemical compounds with a great range of valuable biological properties, has become a promising solution in cancer prevention, imaging, and detection. Curcumin (Curc) remains one of the most studied natural products, due to the impressive palette of biological properties and the possibility to be easily loaded in various micro- and nanostructures and chemically modified. In this study, pegylated curcumin derivatives were prepared by a direct esterification reaction between poly(ethylene glycol)diacid (PEG of 600 g/mol molar mass, PEG600) and Curc in the presence of N,N'-dicyclohexylcarbodiimide (PEG600-Curc). The successful reaction resulted in a water-soluble stable product that was characterized by infrared spectroscopy (Fourier transform infrared (FT-IR)) and proton (1H) and carbon (13C) NMR. The effect of the pH values of buffer solutions on PEG600-Curc spectral properties (absorption and photoluminescence) was investigated by UV-vis and fluorescence spectrophotometry. Based on the biological tests, it was confirmed that PEG600-Curc exhibits cytotoxic activity against Graffi cell lines, as a function of the Curc concentration in the conjugate and the incubation time. PEG600-Curc antibacterial activity was validated in microbiological tests against pathogenic microorganisms such as Staphylococcus aureus. Most importantly, despite the covalent attachment of Curc to PEG and the slight reduction in the therapeutic index of the conjugate, both the anticancer and antimicrobial activities remain the highest reported, thus opening the gate for further, more clinically oriented studies.

Natural Cellulose from Ziziphus jujuba Fibers: Extraction and Characterization.

Nowadays, due to their natural availability, renewability, biodegradability, nontoxicity, light weight and relatively low cost, natural fibers, especially lignocellulosic fibers, present attractive potential to substitute non-eco-friendly synthetic fibers. In this study, Ziziphus jujuba fibers were used, thanks to their low lignin content, as an alternative of renewable resource for the production of cellulosic fibers with suitable characteristics and minimal time and energy consumption. In fact, due to their valuable chemical composition, it was possible to remove the amorphous fractions and impurities from the fiber surface by applying ultrasounds coupled with alkaline treatment (80 °C, 5 wt.% NaOH), followed by a bleaching step. The efficient dissolution of the noncellulosic compounds was confirmed by Fourier Transform Infrared Spectroscopy (FTIR). The resulted increase in the crystallinity index (from 35.7% to 57.5%), occurred without impacting the crystalline structure of the fibers. The morphological analysis of the fibers evidences the higher surface area of the obtained fibers. Based on the obtained results, Ziziphus jujuba fibers were found to present a suitable sustainable source for the production of cellulosic fibers.

Valorization of Recycled Tire Rubber for 3D Printing of ABS- and TPO-Based Composites.

Vulcanized and devulcanized ground tire rubber microparticles have been used as a minor phase in acrylonitrile butadiene styrene copolymer (ABS) and thermoplastic polyolefins (TPO) for the development of materials with desired functionalities by 3D printing. These polymers have been selected because they (i) present part of the plastic waste generated by the automotive industry and (ii) have totally different properties (ABS for its stiffness and robustness and TPO for its softness and ductility). The study aims to improve the circular economy of the automotive industry by proposing a promising route for recycling the generated tire rubber waste. In this respect, emergent technology for plastic processing such as 3D printing is used, as part of the additive manufacturing technologies for the prolongated end of life of recycled plastics originated from automotive waste such as ABS and TPO. The obtained results revealed that (i) the composites are suitable for successful filament production with desired composition and diameter required for successful 3D printing by fused deposition modeling, and that (ii) the optimization of the composition of the blends allows the production of materials with interesting mechanical performances. Indeed, some of the investigated ABS-recycled rubber tire blends exhibit high impact properties as TPO-based composites do, which in addition exhibits elongation at break higher than 500% and good compression properties, accompanied with good shape recovery ratio after compression.

Potential of poly(alkylene terephthalate)s to control endothelial cell adhesion and viability.

Poly(ethylene terephthalate) (PET) is known for its various useful characteristics, including its applicability in cardiovascular applications, more precisely as synthetic bypass grafts for large diameter (≥ 6 mm) blood vessels. Although it is widely used, PET is not an optimal material as it is not interactive with endothelial cells, which is required for bypasses to form a complete endothelium. Therefore, in this study, poly(alkylene terephthalate)s (PATs) have been studied. They were synthesized via a single-step solution polycondensation reaction, which requires mild reaction conditions and avoids the use of a catalyst or additives like heat stabilizers. A homologous series was realized in which the alkyl chain length varied from 5 to 12 methylene groups (n = 5-12). Molar masses up to 28,000 g/mol were obtained, while various odd-even trends were observed with modulated differential scanning calorimetry (mDSC) and rapid heat-cool calorimetry (RHC) to access the thermal properties within the homologous series. The synthesized PATs have been subjected to in vitro cell viability assays using Human Umbilical Vein Endothelial Cells (HUVECs) and Human Dermal Microvascular Endothelial Cells (HDMECs). The results showed that HUVECs adhere and proliferate most pronounced onto PAT(n=9) surfaces, which could be attributed to the surface roughness and morphology as determined by atomic force microscopy (AFM) (i.e. Rq = 204.7 nm). HDMECs were investigated in the context of small diameter vessels and showed superior adhesion and proliferation after seeding onto PAT(n=6) substrates. These preliminary results already pave the way towards the use of PAT materials as substrates to support endothelial cell adhesion and growth. Indeed, as superior endothelial cell interactivity compared to PET was observed, time-consuming and costly surface modifications of PET grafts could be avoided by exploiting this novel material class.

Fast IR-Actuated Shape-Memory Polymers Using in Situ Silver Nanoparticle-Grafted Cellulose Nanocrystals.

In recent years, shape-memory polymers (SMPs) have gained a key position in the realm of actuating applications from daily life products to biomedical and aeronautic devices. Most of these SMPs rely mainly on shape changes upon direct heat exposure or after stimulus conversion (e.g., magnetic field and light) to heat, but this concept remains significantly limited when both remote control and fine actuation are demanded. In the present study, we propose to design plasmonic silver nanoparticles (AgNPs) grafted onto cellulose nanocrystals (CNCs) as an efficient plasmonic system for fast and remote actuation. Such CNC- g-AgNPs "nanorod-like" structures thereby allowed for a long-distance and strong coupling plasmonic effect between the AgNPs along the CNC axis, thus ensuring a fast photothermal shape-recovery effect upon IR light illumination. To demonstrate the fast and remote actuation promoted by these structures, we incorporated them at low loading (1 wt %) into poly(ε-caprolactone) (PCL)-based networks with shape-memory properties. These polymer matrix networks were practically designed from biocompatible PCL oligomers end-functionalized with maleimide and furan moieties in the melt on the basis of thermoreversible Diels-Alder reactions. The as-produced materials could find application in the realm of soft robotics for remote object transportation or as smart biomaterials such as self-tightening knots with antibacterial properties related to the presence of the AgNPs.

Poly(L-lactide) and poly(butylene succinate) immiscible blends: from electrospinning to biologically active materials.

For the first time the preparation of defect-free fibers from immiscible blends of high molar mass poly(lactic acid) (PLA) and poly(butylene succinate) (PBS) in the whole range of the polyester weight ratios is shown. Electrospinning using the solvent-nonsolvent approach proved most appropriate. Moreover, electrospinning revealed crucial for the obtaining of PLA/PBS materials maintaining integrity. DSC and XRD analyses attested for a plasticizing effect and for increased PLA crystallinity at PBS addition to PLA. The mechanical properties of the PLA/PBS mats were controlled by the alignment of the fibers and changed from plastic to brittle materials upon increasing the PBS content. Drug loading and tests against pathogenic microorganisms suggested that the obtained mats can find application as antibacterial fibrous materials.

Antibacterial fluoroquinolone antibiotic-containing fibrous materials from poly(L-lactide-co-D,L-lactide) prepared by electrospinning.

Microfibrous materials based on poly(l-lactide-co-d,l-lactide) (coPLA) and coPLA/poly(ethylene glycol) (PEG) containing a fluoroquinolone antibiotic: ciprofloxacin hydrochloride (Cipro), levofloxacin hemihydrate (Levo) or moxifloxacin hydrochloride (Moxi) were obtained by electrospinning. The presence of Moxi led to an increase in the conductivity of the coPLA and coPLA/PEG spinning solutions and to the preparation of membranes composed of fibers aligned with the collector rotation direction. The one-step incorporation of the antibiotics in the fibers was confirmed by infrared spectroscopy and fluorescence microscopy. The antibiotics were dispersed in the coPLA or coPLA/PEG polymer matrix and the XRD spectra revealed the presence of crystalline phase characteristic of PEG and of the respective antibiotic. It was found that the release profiles of the antibiotics did not depend on the antibiotic nature but were dependent on the fiber composition. The presence of PEG in the fibers allowed a more rapid antibiotic release within the first 2h of release. The performed microbiological tests with Staphylococcus aureus revealed that the coPLA/Cipro, coPLA/PEG/Cipro, coPLA/Levo, coPLA/PEG/Levo, coPLA/Moxi and coPLA/PEG/Moxi mats inhibited the bacterial growth. In addition, the presence of an antibiotic in the mats led to a substantial decrease in the adhesion of the pathogenic microorganism and in the case of the coPLA/PEG/antibiotic series - to prevention thereof.