A Novel Window for Cancer Nanotheranostics: Non-invasive Ocular Assessments of Tumor Growth and Nanotherapeutics Treatment Efficacy In Vivo

A fundamental need in cancer research is animal models that allow in vivo longitudinal visualization and quantification of tumor development, nanotherapeutic delivery, response to treatment, and tumor microenvironment such as blood vessels, macrophages, fibroblasts, immune cells, and extracellular matrix. To address this need we developed a novel mouse ocular xenograft model and used it to longitudinally study tumor growth and the efficacy of nanotherapeutic treatment. Between 500 and 10,000 GFP-expressing human glioblastoma cells were implanted into the subretinal space of immunodeficient mice, and the resultant xenograft imaged in vivo non-invasively with combined fluorescence scanning laser ophthalmoscopy (SLO) and volumetric optical coherence tomography (OCT) for a period up to several months. Most xenografts exhibited a latent phase followed by a stable or rapidly increasing volume, but about 1/3 underwent spontaneous remission. After prescribed growth, a population of tumors was treated with intravenously delivered doxorubicin-containing porphyrin and cholic acid-based nanoparticles (“nanodox”). FRET emission (doxorubicin -» porphyrin) was used to localize nanodox in the xenografts, and 690 nm light exposure to activate nanodox. Treatment was highly effective in reducing tumor volume. Histopathology and flow cytometry revealed CD4+ and CD8+ immune cell infiltration of xenografts. Overall, the ocular model shows much potential for examining the relationships between neoplastic growth, neovascularization and other features of the immune microenvironment, and for evaluating treatment response longitudinally in vivo.