Polyelectrolyte Complex-Covalent Interpenetrating Polymer Network Hydrogels

Polyelectrolyte complex (PEC) hydrogels possess rich microstructural diversity and tunability of the shear response, self-healing attributes, and pH- and salt-responsiveness. Yet, their utility in biotechnology and biomedicine has been limited, owing to their weak mechanical strength and uncontrolled swelling. Here, we introduce a strategy to overcome these drawbacks of PEC hydrogels by interlacing the electrostatically crosslinked PEC network with a covalently crosslinked polymer network, creating polyelectrolyte complex-covalent interpenetrating polymer network (PEC-IPN) hydrogels. Structural and material characterizations of model PEC-IPN hydrogels composed of oppositely charged ABA triblock copolymers and photocrosslinkable 4-arm poly(ethylene oxide) (PEO) highlight the key advantages of our approach. Upon initial mixing of the three constituents, the PEC network self-assembles swiftly in aqueous environs, providing structural rigidity and serving as protective scaffoldings for the covalently crosslinkable PEO precursors. Photocrosslinking of the PEO chains creates a covalent network, providing structural reinforcement to the PEC network. The resulting PEC-IPN hydrogels possess significantly improved shear and tensile strengths, swelling characteristics, and mechanical stability in saline environments while preserving the intrinsic mesoscale structure of the PEC network and its salt-responsiveness. We envision that our approach to fabricating PEC-based IPN hydrogels will pave the way for the creation of self-assembled hybrid materials that harness the unique attributes of electrostatic self-assembly pathways, with broad applications in biomedicine

Bio-instructive materials on-demand-combinatorial chemistry of peptoids, foldamers, and beyond

Combinatorial chemistry allows for the rapid synthesis of large compound libraries for high throughput screenings in biology, medicinal chemistry, or materials science. Especially compounds from a highly modular design are interesting for the proper investigation of structure-to-activity relationships. Permutations of building blocks result in many similar but unique compounds. The influence of certain structural features on the entire structure can then be monitored and serve as a starting point for the rational design of potent molecules for various applications. Peptoids, a highly diverse class of bioinspired oligomers, suit perfectly for combinatorial chemistry. Their straightforward synthesis on a solid support using repetitive reaction steps ensures easy handling and high throughput. Applying this modular approach, peptoids are readily accessible, and their interchangeable side-chains allow for various structures. Thus, peptoids can easily be tuned in their solubility, their spatial structure, and, consequently, their applicability in various fields of research. Since their discovery, peptoids have been applied as antimicrobial agents, artificial membranes, molecular transporters, and much more. Studying their three-dimensional structure, various foldamers with fascinating, unique properties were discovered. This non-comprehensive review will state the most interesting discoveries made over the past years and arouse curiosity about what may come

Cyclic Peptoid-Peptide Hybrids as Versatile Molecular Transporters

Addressing intracellular targets is a challenging task that requires potent molecular transporters capable to deliver various cargos. Herein, we report the synthesis of hydrophobic macrocycles composed of both amino acids and peptoid monomers. The cyclic tetramers and hexamers were assembled in a modular approach using solid as well as solution phase techniques. To monitor their intracellular localization, the macrocycles were attached to the fluorophore Rhodamine B. Most molecular transporters were efficiently internalized by HeLa cells and revealed a specific accumulation in mitochondria without the need for cationic charges. The data will serve as a starting point for the design of further cyclic peptoid-peptide hybrids presenting a new class of highly efficient, versatile molecular transporters

A postsynthetically 2’-“clickable” uridine with arabino configuration and its application for fluorescent labeling and imaging of DNA

The arabino-configured analog of uridine with a propargyl group at the 2’-position was synthesized and incorporated into DNA by solid-phase chemistry. The fluorescence quantum yields of DNA strands that were postsynthetically modified by blue and green emitting cyanine-styryl dyes were improved due to the arabino-configured anchor. These oligonucleotides were used as energy transfer donors in hybrids with oligonucleotides modified with acceptor dyes that emit in the yellow-red range. These combinations give energy transfer pairs with blue–yellow, blue–red and green–red emission color changes. All combinations of arabino- and ribo-configured donor strands with arabino- and ribo-configured acceptor strands were evaluated. This array of doubly modified hybrids was screened by their emission color contrast and fluorescence quantum yield. Especially mixed combinations, that means donor dyes with arabino-configured anchor with acceptor dyes with ribo-configured anchor, and vice versa, showed significantly improved fluorescence properties. Those were successfully applied for fluorescent imaging of DNA after transport into living cells

Anti-Tumor Activity of Doxorubicin-loaded Boehmite Nanocontainers

Doxorubicin-filled boehmite nanocontainers, DOX@γ-AlO(OH), with a mean diameter of 40 nm and a wall thickness of 10 nm are prepared via a microemulsion strategy and studied as drug carriers for cancer treatment. Nanocontainer structure and drug load are examined in detail based on different analytical tools. The DOX load is optimized on highest load at lowest side effects according to blood counts. Cell uptake, DOX-based fluorescence detection and systemic toxicity are evaluated based on in vitro and in vivo models. Toxicity and activity of the DOX@AlO(OH) nanocontainers are compared with non-filled AlO(OH) hollow spheres and free DOX as references and show promising results. An orthotopic breast cancer BALB/c mouse model validates the activity of DOX@AlO(OH) in vivo at lower side effects than for free DOX

Targeted micro-heterogeneity in bioinks allows for 3D printing of complex constructs with improved resolution and cell viability

Three-dimensional bioprinting is an evolving versatile technique for biomedical applications. Ideal bioinks have complex micro-environment that mimic human tissue, allow for good printing quality and provide high cell viability after printing. Here we present two strategies for enhancing gelatin-based bioinks heterogeneity on a 1–100 µm length scale resulting in superior printing quality and high cell viability. A thorough spatial and micro-mechanical characterization of swollen hydrogel heterogeneity was done using multiple particle tracking microrheology. When poly(vinyl alcohol) is added to homogeneous gelatin gels, viscous inclusions are formed due to micro-phase separation. This phenomenon leads to pronounced slip and superior printing quality of complex 3D constructs as well as high human hepatocellular carcinoma (HepG2) and normal human dermal fibroblast (NHDF) cell viability due to reduced shear damage during extrusion. Similar printability and cell viability results are obtained with gelatin/nanoclay composites. The formation of polymer/nanoclay clusters reduces the critical stress of gel fracture, which facilitates extrusion, thus enhancing printing quality and cell viability. Targeted introduction of micro-heterogeneities in bioinks through micro-phase separation is an effective technique for high resolution 3D printing of complex constructs with high cell viability. The size of the heterogeneities, however, has to be substantially smaller than the desired feature size in order to achieve good printing quality

Intriguing Heteroleptic ZnII^{II} bis(dipyrrinato) Emitters in the Far-Red Region With Large Pseudo-Stokes Shift for Bioimaging

Novel heteroleptic ZnII bis(dipyrrinato) complexes were prepared as intriguing emitters. With our tailor-made design, we achieved far-red emissive complexes with a photoluminescence quantum yield up to 45% in dimethylsulfoxide and 70% in toluene. This means that heteroleptic Zn$^{II}$ bis(dipyrrinato) complexes retain very intense emission also in polar solvents, in contrast to their homoleptic counterparts, which we prepared for comparing the photophysical properties. It is evident from the absorption and excitation spectra that heteroleptic complexes present the characteristic features of both ligands: the plain dipyrrin (L$_{p}$) and the π-extended dipyrrin (L$_{π}$). On the contrary, the emission comes exclusively from the π-extended dipyrrin L$_{π}$, suggesting an interligand nonradiative transition that causes a large pseudo-Stokes shift (up to 4,600 cm$_{-1}$). The large pseudo-Stokes shifts and the emissive spectral region of these novel heteroleptic Zn$^{II}$ bis(dipyrrinato) complexes are of great interest for bioimaging applications. Thus, their high biocompatibiliy with four different cell lines make them appealing as new fluorophores for cell imaging

Total synthesis of decarboxyaltenusin

The total synthesis of decarboxyaltenusin (5’-methoxy-6-methyl-[1,1’-biphenyl]-3,3’,4-triol), a toxin produced by various mold fungi, has been achieved in seven steps in a yield of 31% starting from 4-methylcatechol and 1-bromo-3,5-dimethoxybenzene, where the longest linear sequence consists of five steps. The key reaction was a palladium-catalyzed Suzuki coupling of an aromatic boronate with a brominated resorcin derivative

Designing Inherently Photodegradable Cell‐Adhesive Hydrogels for 3D Cell Culture

Light-based microfabrication techniques constitute an indispensable approach to fabricate tissue assemblies, benefiting from noncontact spatially and temporarily controlled manipulation of soft matter. Light-triggered degradation of soft materials, such as hydrogels, is important in tissue engineering, bioprinting, and related fields. The photoresponsiveness of hydrogels is generally not intrinsic and requires complex synthetic procedures wherein photoresponsive crosslinking groups are incorporated into the hydrogel. This paper demonstrates a novel biocompatible and inherently photodegradable poly(ethylene glycol) methacrylate (PEGMA)-based gelatin-methacryloyl (GelMA)-containing hydrogel that can be used to culture cells in 3D for at least 14 d. These gels are conveniently and quickly degraded via UV irradiation for 10 min to produce structured hydrogels of various geometries, sizes, and free-standing cell-laden hydrogel particles. These structures can be flexibly produced on demand. In particular, photodegradation can be temporarily delayed from photopolymerization, offering an alternative to hydrogel array production via photopolymerization with a photomask. The paper investigates the influences of hydrogel composition and swelling liquid on both its photodegradability and biocompatibility