High-Throughput Screening of Surface Engineered Cyanine Nanodots for Active Transport of Therapeutic Antibodies into Solid Tumor
ADVANCED MATERIALS(2023)
摘要
The successful delivery of therapeutic biomacromolecules into solid tumor holds great challenge due to their high resistance to penetrate through the complex tumor microenvironments. Here, active-transporting nanoparticles are harnessed to efficiently deliver biomacromolecular drugs into solid tumors through cell transcytosis. A series of molecularly precise cyanine 5-cored polylysine G5 dendrimers (Cy5 nanodots) with different peripheral amino acids (G5-AA) is prepared. The capability of these positively charged nanodots to induce cell endocytosis, exocytosis, and transcytosis is evaluated via fluorescence-based high-throughput screen. The optimized nanodots (G5-R) are conjugated with alpha PD-L1 (a therapeutic monoclonal antibody binding to programmed-death ligand 1) (alpha PD-L1-G5-R) to demonstrate the nanoparticle-mediated tumor active transport. The alpha PD-L1-G5-R can greatly enhance the tumor-penetration capability through adsorption-mediated transcytosis (AMT). The effectiveness of alpha PD-L1-G5-R is tested in treating mice bearing partially resected CT26 tumors, mimicking the local immunotherapy of residual tumors post-surgery in clinic. The alpha PD-L1-G5-R embedded in fibrin gel can efficiently mediate tumor cell transcytosis, and deliver alpha PD-L1 throughout the tumor, thereby enhancing immune checkpoint blockade, reducing tumor recurrence, and significantly prolonging the survival time. The active-transporting nanodots are promising platforms for efficient tumor delivery of therapeutic biomacromolecules. High-throughput fluorescent screening of a library of single-molecule Cy5 nanodots reveals that the nanoparticle-inducing cell transcytosis is highly related to the particles' surface structures and varies significantly with cell lines. The selected Cy5 nanodots with high transcytosis-inducing capability (G5-R) can carry alpha PD-L1 to penetrate deep into solid tumor and generates potent antitumor activity through immune checkpoint blockade therapy.image
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关键词
active-transporting nanocarriers,dye-cored dendrimers,fluorescent nanodots,immune checkpoint blockade,protein drug delivery,transcytosis,tumor penetration
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