Inflamed Leukocyte-Mimetic Nanoparticles for Molecular Imaging of Inflammation: Application to Detection of Tumor and Acute Inflammation

Host inflammatory response of either acute or chronic in nature causes many diseases, ranging from sepsis, cardiovascular and neurodegenerative diseases, and cancer. Sensitive, specific detection of the site of inflammation will, therefore, produce a wide-ranging impact on disease diagnosis and treatment. Central to inflammation is leukocyte adhesion followed by diapedisis through inflamed endothelium, mediated by molecular interactions such as integrins activated in leukocytes and cell adhesion molecules induced in endothelium. We hypothesized that nanoparticles designed to mimic the molecular interactions occurring between inflamed leukocytes and endothelium may possess specificity toward diverse host inflammatory responses. To incorporate inflammation-sensitive molecular interactions into magnetic resonance imaging (MRI) contrast agent, superparamagnetic iron oxide (SPIO) nanoparticles were conjugated with integrin lymphocyte function-associated antigen (LFA)-1 Inserted (I) domain, engineered to mimic activated LFA-1 in leukocytes. By whole body optical imaging and MRI, I domain-coated nanoparticles were localized specifically to the tumors with high ICAM-1 expression as well as to the vasculature with ICAM-1 induction within and in the invasive front of the tumor. Furthermore, with a newly developed MRI technique, we achieved quantitative mapping of nanoparticle distribution in vivo in a mouse model of acute inflammation. This study presents the first demonstration of in vivo detection of tumor-associated vasculature by targeting inflammation with systemically injected nanoparticles, offering a possibility of tumor detection not by tumor surface antigens but by an inflamed milieu present in the tumor microenvironment.