Nanoparticle Uptake in a Spontaneous and Immunocompetent Woodchuck Liver Cancer Model

Lewis Y Liu, Xue-Zhong Ma, Ben Ouyang, Danielle P Ings, Sagar Marwah, Jeff Liu, Annie Y Chen, Rahul Gupta, Justin Manuel, Xu-Chun Chen, Blair K Gage, Iulia Cirlan, Nicholas Khuu, Sai Chung, Damra Camat, Michael Cheng, Manmeet Sekhon, Kyryl Zagorovsky, Mohamed A Abdou Mohamed, Cornelia Thoeni, Jawairia Atif, Juan Echeverri, Dagmar Kollmann, Sandra Fischer, Gary D Bader, Warren CW Chan, Tomasz I Michalak, Ian D McGilvray, Sonya A MacParland

ACS Nano 2020, 14, 4, 4698–4715 | DOI: 10.1021/acsnano.0c00468

Abstract

There is a tremendous focus on the application of nanomaterials for the treatment of cancer. Nonprimate models are conventionally used to assess the biomedical utility of nanomaterials. However, these animals often lack an intact immunological background, and the tumors in these animals do not develop spontaneously. We introduce a preclinical woodchuck hepatitis virus-induced liver cancer model as a platform for nanoparticle (NP)-based in vivo experiments. Liver cancer development in these out-bred animals occurs as a result of persistent viral infection, mimicking human hepatitis B virus-induced HCC development. We highlight how this model addresses key gaps associated with other commonly used tumor models. We employed this model to (1) track organ biodistribution of gold NPs after intravenous administration, (2) examine their subcellular localization in the liver, (3) determine clearance kinetics, and (4) characterize the identity of hepatic macrophages that take up NPs using RNA-sequencing (RNA-seq). We found that the liver and spleen were the primary sites of NP accumulation. Subcellular analyses revealed accumulation of NPs in the lysosomes of CD14⁺ cells. Through RNA-seq, we uncovered that immunosuppressive macrophages within the woodchuck liver are the major cell type that take up injected NPs. The woodchuck-HCC model has the potential to be an invaluable tool to examine NP-based immune modifiers that promote host anti-tumor immunity.