Osteosarcoma‐Derived Exosomes as Potential PET Imaging Nanocarriers for Lung Metastasis

Abstract Lung metastases represent the most adverse clinical factor and rank as the leading cause of osteosarcoma‐related death. Nearly 80% of patients present lung micrometastasis at diagnosis not detected with current clinical tools. Herein, an exosome (EX)‐based imaging tool is developed for lung micrometastasis by positron emission tomography (PET) using osteosarcoma‐derived EXs as natural nanocarriers of the positron‐emitter copper‐64 ( 64 Cu). Exosomes are isolated from metastatic osteosarcoma cells and functionalized with the macrocyclic chelator NODAGA for complexation with 64 Cu. Surface functionalization has no effect on the physicochemical properties of EXs, or affinity for donor cells and endows them with favorable pharmacokinetics for in vivo studies. Whole‐body PET/magnetic resonance imaging (MRI) images in xenografted models show a specific accumulation of 64 Cu‐NODAGA‐EXs in metastatic lesions as small as 2–3 mm or in a primary tumor, demonstrating the exquisite tropism of EXs for homotypic donor cells. The targetability for lung metastasis is also observed by optical imaging using indocyanine green (ICG)‐labeled EXs and D‐luciferin‐loaded EXs. These findings show that tumor‐derived EXs hold great potential as targeted imaging agents for the noninvasive detection of small lung metastasis by PET. This represents a step forward in the biomedical application of EXs in imaging diagnosis with increased translational potential.