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Enhanced drug testing efficiency has driven the prominence of high‐content and high‐throughput screening (HCHTS) in drug discovery and development. However, traditional HCHTS in well‐plates often lack complexity of in vivo conditions. 3D cell cultures, like cellular spheroids/organoids, offer a promising alternative by replicating in vivo conditions and improving the reliability of drug responses. Integrating spheroids/organoids into HCHTS requires strategies to ensure uniform formation, systemic function, and compatibility with analysis techniques. This study introduces an easy‐to‐fabricate, low‐cost, safe, and scalable approach to create a bioinert hydrogel‐based inverted colloidal crystal (BhiCC) framework for uniform and high‐yield spheroid cultivation. Highly uniform alginate microgels are fabricated and assembled into a colloidal crystal template with controllable contact area, creating engineered void spaces and interconnecting channels within agarose‐based BhiCC through the template degradation by alginate lyase and buffer. This results in a multi‐layered iCC domain, enabling the generation of in‐vitro 3D culture models with over 1000 spheroids per well in a 96‐well plate. The unique hexagonal‐close‐packed geometry of iCC structure enables HCHTS through conventional plate reader analysis and fluorescent microscopy assisted by house‐developed automated data processing algorithm. This advancement offers promising applications in tissue engineering, disease modeling, and drug development in biomedical research. 

Chirality, defined as “a mirror image,” is a universal geometry of biological and nonbiological forms of matter. This geometry of molecules determines how they interact during their assembly and transport. With the development of nanotechnology, many nanoparticles with chiral geometry or chiroptical activity have emerged for biomedical research. The mechanisms by which chirality originates and the corresponding synthesis methods have been discussed and developed in the past decade. Inspired by the chiral selectivity in life, a comprehensive and in-depth study of interactions between chiral nanomaterials and biological systems has far-reaching significance in biomedicine. Here, we investigated the effect of the chirality of nanoscale drug carriers, graphene quantum dots (GQDs), on their transport in tumor-like cellular spheroids. Chirality of GQDs (L/D-GQDs) was achieved by the surface modification of GQDs withL/D-cysteines. As anin-vitrotissue model for drug testing, cellular spheroids were derived from a human hepatoma cell line (i.e., HepG2 cells) using the Hanging-drop method. Our results reveal that theL-GQDs had a 1.7-fold higher apparent diffusion coefficient than theD-GQDs, indicating that theL-GQDs can enhance their transport into tumor-like cellular spheroids. Moreover, when loaded with a common chemotherapy drug, Doxorubicin (DOX), via π-π stacking,L-GQDs are more effective as nanocarriers for drug delivery into solid tumor-like tissue, resulting in 25% higher efficacy for cancerous cellular spheroids than free DOX. Overall, our studies indicated that the chirality of nanocarriers is essential for the design of drug delivery vehicles to enhance the transport of drugs in a cancerous tumor.