用于液体肿瘤和免疫肿瘤学模型的体内短波红外成像

In vivo imaging challenges in cancer drug discovery include imaging liquid tumors and tracking immune cell activity after checkpoint immunotherapy for solid tumors. Current methods for real-time in vivo imaging of tumor models include bioluminescence imaging (BLI), which involves using genetically modified cell lines that can confound study data due to potential changes in the cell lines' biology. This risk of potentially aberrant data is especially a concern with patient-derived xenograft (PDX) models. Our earlier work utilized targeted albumin-coated nanoparticles encapsulating rare earth-containing cores to image tumors in in vivo models of solid tumors and to image T cells in the tumor microenvironment. These biocompatible nanoparticles enable imaging without the need for genetic modification by emitting short-wave infrared (SWIR) light after excitation by a 980 nm light source. SWIR light travels through blood and tissue more efficiently than does visible bioluminescent light, providing deeper tissue illumination and sharper images. By functionalizing this technology with targeting antibodies, we were able to not only specifically image a range of solid tumors but also visualize CD8+ T cell activity around tumor sites. More recently, we have shown that our nanoparticles can be used to image and track an increase in liquid tumor burden within bone marrow and spleen over a three-week period in a lymphoma model. Briefly, U937 cells (50,000 per mouse) were injected i.v. into NSG mice on Day 0. Nanoparticles targeted to CD45 were injected on Days 10, 16, and 21, and the animals were imaged four hours post-injection using a SWIR-based imaging system. Tumor burdens were confirmed using flow cytometry. Since this initial lymphoma imaging study, we have improved our nanoparticle formulation by encapsulating the rare earth cores with a combination of biocompatible lipids and polymers, and by switching from a batch synthesis process to a microfluidics-based fabrication process. This microfluidics-based approach enables scalability and a high degree of batch-to-batch reproducibility. We tested these next-generation nanoparticles in vivo and showed that they are > 5-fold brighter than our original albumin formulation, providing researchers with a highly sensitive imaging modality to interrogate the tumor microenvironment and to visualize liquid tumors in real time , all without the risks inherent in genetic modification of the tumors and immune cells being studied.