Abstract This study presents the development of a hydrogel-supported perfusion platform designed for ex vivo uterine tissue graft cultivation under physiologically relevant conditions. Polyvinyl alcohol/Borax hydrogels were synthesized and systematically characterized by Fourier-transform infrared spectroscopy, rheological measurements, and swelling analyses, confirming the formation of borate–diol crosslinked hydrogel networks arising from reversible interactions characteristic of PVA/Borax systems, together with viscoelastic stability and high water retention capacity. Biocompatibility assays demonstrated that hydrogels maintained at physiological pH preserved cell viability above the ISO 10993-5 threshold, supporting their suitability as a matrix for tissue culture. A permeable nitrocellulose membrane, obtained by chemical modification of onion-derived cellulose, was incorporated into polyvinyl chloride tubing to enable controlled fluid exchange and nutrient transport. Integration of this membrane-modified tubing with the hydrogel scaffold created a perfusion system capable of sustaining uterine grafts in vitro by maintaining pH balance, supporting metabolite clearance, and enabling effective gas diffusion. The system maintained stable perfusion conditions and supported structural preservation of uterine tissue over a 5 d culture period. Preliminary trials with ovine uterine tissues confirmed the feasibility of the platform as a functional ex vivo culture environment. These findings demonstrate that the proposed system provides a physiologically relevant and scalable platform for ex vivo uterine tissue maintenance, with potential applications in reproductive biology, disease modeling, and regenerative medicine.

Characterizing drug distribution to target organs is of central importance to drug discovery, especially for compounds intended to reach the central nervous system (CNS). However, the current benchmark standard measurements, based on tissue homogenate, provide limited spatial and temporal resolution. Here, we use real-time electrochemical aptamer-based (E-AB) monitoring to determine drug concentrations across specific brain regions, blood, and liver of rats after intravenous dosing. Using vancomycin and tobramycin as models, we reveal significant regional differences in brain pharmacokinetics. Vancomycin shows distinct kinetics across cortex, hippocampus, and thalamus, crossing the blood-brain barrier (BBB) but showing limited transport across the blood-cerebrospinal fluid barrier (BCSFB). Tobramycin, despite its smaller size, fails to cross either barrier. Vancomycin's liver distribution is delayed and limited, resembling its brain kinetics more than blood. These findings challenge assumptions of uniform CNS drug distribution and fast liver uptake, highlighting the need for spatially and temporally resolved pharmacokinetic assessments. Our approach enables high-resolution, in vivo profiling of drug absorption, distribution, and clearance, offering a powerful tool to inform dosing strategies and improve translational outcomes.

The typically low, molecule-dependent permeability of antibodies across the blood-brain barrier (BBB) has driven the development of engineered constructs with optimized BBB transcytosis to facilitate efficient brain delivery. Physiologically-based pharmacokinetic (PBPK) modeling provides a framework to predict brain disposition and inform drug development; however, current models lack true a priori predictive capability and remain dependent on in-vivo data. In-vitro brain endothelial cell permeability (Papp) assays provide antibody-specific estimates of brain transport, though these assays have yet to be integrated into PBPK models. This study developed and cross-validated an integrated in-vitro-in-vivo-extrapolation (IVIVE) PBPK framework that uses Papp values to predict antibody-specific cerebrospinal fluid (CSF) concentrations a priori. Seven antibodies were evaluated, including four standard (non-FC5-fused) and three TMEM30A-binding constructs (FC5-fused). PBPK modeling was conducted using PK-Sim®/MoBi®. Papp values were used to estimate antibody-specific brain transport parameters. For comparison, a conventional modeling approach was implemented, where brain transport was inferred to be similar to a reference antibody (trastuzumab). Model performance was assessed by comparing predicted versus observed CSF exposures (area-under-the-concentration-time-curve) in rats following intravenous administration. Integration of Papp data substantially improved brain exposure predictions, reducing the absolute average percentage prediction error for CSF exposure from 296.1% (conventional approach) to 53.4% (IVIVE-PBPK). The framework accurately captured the brain disposition of both standard and FC5-fused antibodies without requiring pre-existing in-vivo CSF data. Overall, this Papp-informed PBPKmodeling approach enables a priori, mechanistic prediction of antibody brain exposure, supporting candidate selection and reducing reliance on animal studies in brain drug development.

Amino acids with β,β-carbocyclic sidechains are valuable replacements for endogenous Val, Leu, and Ile, with therapeutic benefits. When placed into ordinary peptides, these annulated variants improve metabolic stability, cell permeability, and receptor affinity and selectivity. Yet, their appearance in modern peptide drugs is often limited to β,β-cyclopentyl- and β,β-cyclohexyl-rings, one reason being the limited availability of resin- and solution-compatible β,β-carbocyclic amino acids for direct coupling. More 'exotic' rings, i.e., those with different sizes, chemical compositions, and geometric preferences, could be superior, but finding and assessing their benefits calls for more general ways to incorporate and test them. Herein, we pioneer a modular route to convert a single unsaturated residue, known as β-sulfonyldehydroamino acid (ΔSulf), in a peptide into many unique β,β-carbocycles-cyclic, polycyclic, and heteroatom-containing-in two telescoped steps. First, an unprecedented photocatalyst, Pyronin Y, in an original combination with an organodiiodide, cobalt porphyrin catalyst, sacrificial amine, and green LEDs converts ΔSulf into a Δ-amino acid with a pendant iodide. Adding Zn/Cu couple then triggers an intramolecular and stereoselective Giese cyclization. We detail the mechanism of our procedure, highlighting the interplay between aqueous metallaphotoredox catalysis, halogen-atom abstraction, and ligand-controlled cyclization using spectroscopy, cyclic voltammetry, intermediate-trapping, and radical-clock experiments.

The first bromodomain of the BET protein BRDT (BRDT-BD1) possesses a unique Arg54 residue at the terminus of the ZA channel, absent in other BET family members. We explored this structural uniqueness with 23 analogs of the BET/kinase inhibitor SG3-179, each bearing an amino acid side chain to enable potential interactions between the positively charged arginine group and the negatively charged carboxylate groups. In an AlphaScreen assay, serine analog 13 showed 35-fold selectivity for BRDT-T over BRD4-T. The BRDT-BD1 cocrystal structure with glutamic acid analog 14 showed no interaction with Arg54, suggesting that the observed preference may be related to differences in the structured water molecules. Compound 13 displayed exceptional in vitro metabolic stability but had limited cellular permeability in MDCK-MDR1 cells. Compounds 13 and 14 are among the best BRDT-BD1-preferring inhibitors reported to date and demonstrate a significant step toward identifying highly selective BRDT inhibitors for male contraception.

Novel sustainable carbon dot as dual replacements for emulsion stabilizers and Photoinitiators in macroporous polymerized high internal phase emulsion fabrication.

Exploration of the Anticancer Efficacy and In Silico Drug Screening Study of Fe(II) and Fe(III) Complexes of Schiff Base and Phenanthroline Ligand.

Traumatic brain injury (TBI) is among the most devastating condition and involves primary and secondary injury cascades. The blood-brain barrier (BBB) is a selective, semipermeable membrane that tightly controls the brain's microenvironment for proper neuronal function. Existing evidence demonstrates that TBI impairs the integrity and function of the BBB, leading to not only acute pathological changes but also long-term neuropathological consequences. Multiple BBB-related signaling molecules (e.g., Tie-2, EphB3, and Cav-1) are involved in the pathophysiological processes post-injury. These can result in microcirculatory insufficiency, neurotoxin accumulation, and cerebral edema after TBI. Together, such events synergistically cause axonal damage, neuronal cell death, and neuroinflammatory responses, which underlie the pathogenesis of TBI. In this review, we aim to summarize the pathophysiological roles of BBB breakdown in TBI, survey underlying mechanisms, and discuss therapeutic potential for this notorious disease by regulating the BBB.

Selective permeability in interdisciplinary knowledge organization: evidence from communication studies

Synthetic macrocycles offer exceptional potential as therapeutics. However, most high-throughput discovery platforms rely on genetically encoded libraries of large peptide macrocycles, which typically are not optimized for drug like properties. Fully synthetic libraries offer greater flexibility in accessing broader chemical space. Leveraging recent advances in mass spectrometry based library techniques, here we report CycloSEL (Cyclic Self-Encoded Libraries), an end-to-end workflow, that screens synthetic macrocycle libraries enriched in drug-like 'beyond rule of five' features. The workflow relies on affinity selections and hit identification by tandem mass spectrometry, eliminating the need for genetic barcodes. We construct a 16 million-member library and validate the approach against the oncology target carbonic anhydrase IX, achieving robust enrichment and accurate identification of true binders. Applying CycloSEL to the acute myeloid leukemia target WD repeat-containing protein 5 (WDR5) yields a macrocycle with subnamolar affinity, and potent inhibition of the WDR5-Mixed-Lineage Leukemia 1 (MLL1) interaction. Subsequent modifications produce a chameleonic macrocycle with passive membrane permeability, serum stability, and anti-proliferative activity in leukemia cells. Together, these results demonstrate that CycloSEL enables discovery of drug-like macrocycles from fully synthetic libraries for intracellular targets.

The glomerulus is the filtering unit of the kidney, and the glomerular filtration barrier (GFB) is responsible for filtering waste, retaining plasma protein, and maintaining fluid balance. Drug-induced nephrotoxicity is characterized by dysfunction of the GFB and is a main obstacle in the new therapeutic screening process. This paper presents the simple and robust SLAS (Society of Laboratory Automation and Society) standard format-based microfluidic GFB-on-a-chip (GFBoC). We formed and cultured the GFB by aligning human glomerular mesangial cells (gMCs), podocytes, and glomerular endothelial cells (gECs) on each side of a conventional transwell membrane as the glomerular basement membrane (GBM). This provides facile loading/unloading of the GFB transwell into the microfluidic chip, enabling its cultivation under pump-/tubing-less perfusion flow and additional off-chip bioanalysis. It also allows various and multiple experiments in parallel in a conventional incubator at moderate operation complexity. Glomerular selective permeability of the GFB was characterized by filtration and leakage of the representative macromolecule, albumin, via the GFB, while the drug doxorubicin affected the GFB during cultivation in the GFBoC. This demonstrated that the GFBoC has potential as a simple, robust, and efficient platform for the multiple testing of nephrotoxicity and kidney disease drugs in parallel.

Advances in 3D printed blood-brain barrier models.

Macrocyclic peptides (MPs) have emerged as interesting therapeutic candidates due to their ability to engage difficult protein targets with high affinity and selectivity. However, their application to intracellular targets is limited by the poor passive membrane permeability of most MPs. We previously showed that incorporation of an imidazopyridinium (IP+) moiety into an MP boosted passive membrane permeability significantly, as measured by the parallel artificial membrane permeability assay (PAMPA) (Li et al. (2024) J. Am. Chem. Soc. 146, 14633-14644). In this study, we report a detailed analysis of the entry of IP+-containing MPs into living cells. Chloroalkane penetration assay (CAPA) data show that IP+ MPs access the cytoplasm rapidly, often at rates approaching those of drug-like small molecules. Mechanistic studies, including live-cell imaging, ATP-depletion experiments, and organelle colocalization analyses, indicate that IP+ MPs traverse the plasma membrane primarily via passive diffusion, avoiding endosomal entrapment. IP+ MPs do not localize to the mitochondria, as is the case for many positively charged molecules. We show that the incorporation of an IP+ unit transforms a previously described membrane-impermeable macrocyclic antagonist of the p53-MDM2 interaction into a bioactive inhibitor of MCF-7 proliferation. Enhanced permeability is observed when the IP+ unit is positioned either within the macrocyclic backbone or on a side chain. Collectively, these results establish that IP+ incorporation is an effective strategy for the development of bioactive MPs targeting intracellular proteins.

To address the urgent requirement for antifouling reverse osmosis (RO) membranes, this work presents an innovative interfacial polymerization (IP) strategy utilizing molecularly engineered zwitterionic surfactants. Three zwitterionic surfactants with identical hydrophilic heads but distinct hydrophobic tails were synthesized, each serves a dual function: regulating IP kinetics while incorporating into the polyamide (PA) network to confer inherent antifouling properties. The surfactant combining an aromatic ring and a long alkyl chain proved most effective, enhancing integration via π-π interactions and maximizing interfacial activity to yield a polyamide layer with superior density, hydrophilicity, and permeability. The resulting membrane achieves a balance of high water permeance (2.7 LMH/bar), outstanding salt rejection (99.6%), and excellent antifouling performance. In practical tests using real coking wastewater, it consistently outperformed a leading commercial antifouling membrane (DuPont FilmTec CR100) across multiple fouling-cleaning cycles. This study establishes a new paradigm in which tailored surfactant molecular design directly governs RO membrane properties and integrated performance, offering a promising pathway to next-generation RO membranes for challenging water treatment applications.

Barriers in the human body play a crucial role in regulating the exchange of substances between compartments, with permeability alterations occurring under both physiological and pathological conditions. In vitro barrier models are essential tools for studying the mechanisms of molecular diffusion across these barriers. Traditional coculture systems or advanced organ‐on‐chip (OoC) platforms mostly utilize permeable membranes based on artificial, nonbiodegradable materials. In this study, we introduced cellulose nanofibrils (CNFs)‐based membranes to develop a new class of in vitro barrier systems. CNFs, derived from natural sources, are nontoxic, biodegradable, optically transparent, and feature a 3D fibrillar structure that mimics the cellular basement membrane. We successfully modulated the permeability of CNF‐based membranes, interposed in dual‐chamber polydimethylsiloxane devices, to small molecules through chemical and enzymatic treatments, while preserving their ability to allow cell adhesion and growth. This technology holds potential for its integration in next‐generation OoC devices, offering more realistic and complex models that closely mimic the physiological behavior of human barriers.

Cellular water content governs the concentration of all biomolecules inside a cell, thereby influencing the physical and functional properties of the cell. However, measurements of water content in physiologically relevant cell culture models remain largely unavailable, particularly in three-dimensional (3D) models such as tumor spheroids and organoids. Here, we achieve such measurements using an industrial-grade capillary steel tube. The steel tube functions as a mechanical resonator that inertially senses the buoyant mass of particles. For microgram-scale particles ≥ 400 micrometers in diameter, we achieve <1% precision error in buoyant mass with a 5-minute acquisition interval. By sequentially measuring the buoyant mass of individual, patient-derived glioblastoma tumor spheroids derived from patients with glioblastoma in media of different densities and cell permeabilities, we determine the absolute and fractional (volume/volume) water content of the spheroids, along with their dry mass, volume, and density properties. We achieve ~0.5% precision error in fractional water content with a throughput of three spheroids per hour. This enables us to detect both interspheroid heterogeneity in fractional water content and acute responses to kinase inhibition. Overall, we establish a simple and accessible technique for quantifying water content in living 3D cell culture models, opening previously unexplored avenues for studying biophysical regulation in multicellular systems.

Proteolysis-Targeting Chimeras (PROTACs) represent a novel and promising cancer treatment strategy considered a direct alternative to conventional small-molecule inhibitors. PROTACs selectively degrade disease-causing proteins (including previously 'undruggable' targets such as transcription factors and scaffolding proteins) by harnessing the cellular ubiquitin proteasome system. In this review, we look at the most recent developments in PROTAC technology and their oncology applications. Versatility, while maintaining substrate selectivity and degradation efficiency, has also been enhanced by the expanded range of E3 ligases used in PROTAC design. Improvements in the stability, bioavailability, and systemic delivery of PROTACs are being achieved through innovations in pharmacokinetics and cell permeability, enabling their clinical translations. Initial clinical trials have confirmed the potential of these agents in human patients, and early preclinical studies have shown them to be highly efficacious in models of solid tumors and hematologic malignancies. Despite these encouraging developments, crucial challenges remain, including reducing off-target effects, addressing resistance mechanisms, and clarifying the significance of PROTAC-mediated degradation pathways. Future efforts must focus on refining the selectivity and tunability of degrader compounds, enhancing treatment efficacy via combination therapies, and optimizing PROTAC design through computational and structural biology. As the field continues to evolve, PROTACs remain a highly promising strategy for addressing unmet clinical needs in oncology. In this review, recent advancements in PROTAC technology are discussed, along with its contribution to cancer therapy and ways to circumvent existing challenges to its full therapeutic potential.

Membranes offering high ion permeability with exceptional selectivity are crucial for applications ranging from sustainable water treatment to resource extraction. Inspired by "artificially constructed molecular locks" (ion imprinting) and the voltage-gated behavior of biological ion channels, we combine a carbon nanotube (CNT) conductive network with a Prussian blue (PB) ion-imprinted lattice to fabricate an electrochemically gated ion-selective membrane. Meanwhile, the anchoring of specific cations in the crystal lattice allowed for the precise tuning of subnanometer transport channel sizes. The combined action of ion-imprinted channels and redox gating enables the PB membrane to achieve an ultrahigh K+/Li+ selectivity of 481.2, far exceeding the performance (1.5-40) of previously reported electro-responsive membranes. Electrochemical characterization and DFT simulations show that applying a redox potential accelerates diffusion, improves lattice conductivity, and weakens the ion-imprinting bias. Under voltage control, the membrane preferentially transports K+, significantly increasing K+/Li+ selectivity. This work provides fundamental insights into redox-regulated transport in crystalline lattices and proposes an approach for designing next-generation ion-imprinted separation membranes with voltage-sensitive ultrahigh selectivity.

Preparation and performance regulations of ionic cellulose-based glucose semipermeable membranes.

The selective permeability of mucin hydrogels is modulated by nanoplastic contaminations.