Tumor Targeting by α_vβ₃-Integrin-Specific Lipid Nanoparticles Occurs <i>via</i> Phagocyte Hitchhiking

Abstract

Although the first nanomedicine was clinically approved more than two decades ago, nanoparticles' (NP) <i>in vivo</i> behavior is complex and the immune system's role in their application remains elusive. At present, only passive-targeting nanoformulations have been clinically approved, while more complicated active-targeting strategies typically fail to advance from the early clinical phase stage. This absence of clinical translation is, among others, due to the very limited understanding for <i>in vivo</i> targeting mechanisms. Dynamic <i>in vivo</i> phenomena such as NPs' real-time targeting kinetics and phagocytes' contribution to active NP targeting remain largely unexplored. To better understand <i>in vivo</i> targeting, monitoring NP accumulation and distribution at complementary levels of spatial and temporal resolution is imperative. Here, we integrate <i>in vivo</i> positron emission tomography/computed tomography imaging with intravital microscopy and flow cytometric analyses to study α_vβ₃-integrin-targeted cyclic arginine-glycine-aspartate decorated liposomes and oil-in-water nanoemulsions in tumor mouse models. We observed that ligand-mediated accumulation in cancerous lesions is multifaceted and identified "NP hitchhiking" with phagocytes to contribute considerably to this intricate process. We anticipate that this understanding can facilitate rational improvement of nanomedicine applications and that immune cell-NP interactions can be harnessed to develop clinically viable nanomedicine-based immunotherapies.