The second phase of tumor invasion driven by immune cells: A study on doxorubicin-loaded PLG nanoparticles

Poly(lactide-co-glycolide) (PLG) nanoparticles loaded with doxorubicin have reached phase-I clinical trials for treating advanced solid tumors. This study explores cell hitchhiking, where nanoparticles associate with blood cells and investigates the impact on pharmacokinetics and tumor migration. Previous findings highlighted the early post-injection phase dominated by nonspecific nanoparticle-cell interactions and burst release. In contrast, this study examines the subsequent phase of tumor invasion, emphasizing the role of immune cells, mostly neutrophils, in redistributing the carrier to the tumor site via blood cell hitchhiking. We provide a detailed investigation of nanoparticle extravasation kinetics and mechanisms, showing qualitative and quantitative evidence of increased nanoparticle association with immune cells over time. By 30 min post-injection, approximately 15 % of monocytes and 15-19 % of neutrophils tested positive for nanoparticles, with significant differences observed between ex vivo and in vivo experiments, and between healthy and tumor-bearing animals. This study underscores the ambiguous role of immune cell-mediated tumor targeting. While the total accumulation of the carrier rises, this fraction is partially trapped in immune cells without any chance to escape.