Injectable Regenerated Silk Fibroin Micro/Nanosphere with Enhanced Permeability and Stability for Osteoarthritis Therapy.

In the therapy of early-stage osteoarthritis, to accomplish full infiltration of subchondral bone and cartilage, and to target osteoclast and chondrocyte simultaneously remain challenges in biomaterials design. Herein, a novel hierarchical drug delivery system is introduced, with micrometer-scale outer layer spheres composed of regenerated silk fibroin, characterized by connected porous structure through the n-butanol and regenerated silk fibroin combined emulsion route and freezing method. The design effectively resists clearance from the joint cavity, ensuring stable delivery and prolonged residence time within the joint space. Additionally, the system incorporates phenylboronic acid-enriched silk fibroin nanoparticles, stabilized through chemical cross-linking, which encapsulate isoliquiritin derived from Glycyrrhiza uralensis. These nanoparticles facilitate complete penetration of the cartilage extracellular matrix, exhibit pH-responsive behavior, neutralize reactive oxygen species, and enable controlled drug release, thereby enhancing therapeutic efficacy. The in vitro and in vivo experiments both demonstrate that the composite micro/nanospheres not only inhibit osteoclastogenesis with bone loss in subchondral bone and osteophyte formation, but also mitigate chondrocytes apoptosis, reduce oxidative stress associated with cartilage degeneration, and ameliorate neuropathic hyperalgesia, with the underlying mechanisms being elucidated. The study indicates that such an injectable strategy combining organic biomaterials with Chinese medicine holds substantial promise for the treatment of early osteoarthritis.

Design, synthesis and antimicrobial evaluation of propylene-tethered ciprofloxacin-isatin hybrids.

Twelve novel propylene-tethered ciprofloxacin-isatin hybrids 3a-f and 4a-f were designed, synthesized and characterized by MS, HRMS, 1H NMR and 13C NMR. All hybrids were evaluated for their in vitro antimicrobial activities against representative Gram-positive, Gram-negative and mycobacterial pathogens, cytotoxicity in VERO cell line as well as metabolic stability and in vivo pharmacokinetic (PK) properties. The preliminary results indicated that all mono-isatin-ciprofloxacin hybrids exhibited excellent antibacterial activities with MIC ranging from ≤0.03 to 0.5 µg/mL against most of the tested strains. In particular, ciprofloxacin-isatin hybrid 3d was highly potent against all tested Gram-positive and Gram-negative strains including clinically important drug-resistant pathogens, which was comparable to or more potent than the parent ciprofloxacin and reference levofloxacin. Whereas, conjugate 3b (MIC: 0.10 and 0.5 µg/mL) was 4- and 8-fold more active than ciprofloxacin (MIC: 0.78 µg/mL) and rifampicin (MIC: 0.39 µg/mL) against MTB H37Rv, and 4->256 times more potent than the three references ciprofloxacin (MIC: 2.0 µg/mL), rifampicin (MIC: 32 µg/mL) and isoniazid (>128 µg/mL) against MDR-TB. Both hybrid 3b and 3d with low cytotoxicity (CC50: 64 and 256 µg/mL) also showed acceptable metabolic stability and in vivo PK properties, could act as leads for further optimization.

Near-Infrared Fluorescent Ag2S Nanodot-Based Signal Amplification for Efficient Detection of Circulating Tumor Cells.

The level of circulating tumor cells (CTCs) plays a critical role in tumor metastasis and personalized therapy, but it is challenging for highly efficient capture and detection of CTCs because of the extremely low concentration in peripheral blood. Herein, we report near-infrared fluorescent Ag2S nanodot-based signal amplification combing with immune-magnetic spheres (IMNs) for highly efficient magnetic capture and ultrasensitive fluorescence labeling of CTCs. The near-infrared fluorescent Ag2S nanoprobe has been successfully constructed through hybridization chain reactions using aptamer-modified Ag2S nanodots, which can extremely improve the imaging sensitivity and reduce background signal of blood samples. Moreover, the antiepithelial-cell-adhesion-molecule (EpCAM) antibody-labeled magnetic nanospheres have been used for highly capture rare tumor cells in whole blood. The near-infrared nanoprobe with signal amplification and IMNs platform exhibits excellent performance in efficient capture and detection of CTCs, which shows great potential in cancer diagnostics and therapeutics.