1. Department of Biomedical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore 21218, USA.
2. Dept of Radiation Oncology and Molecular Radiation Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD 21231 USA.
3. Department of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Centre, School of Medicine, Johns Hopkins University, Baltimore, MD 21231 USA.
4. Center for Comparative Medicine, Baylor College of Medicine, Houston, TX USA.
5. Dept of Oncology, Sydney Kimmel Comprehensive Cancer Centre, School of Medicine, Johns Hopkins University, Baltimore, MD 21231 USA.
6. Department of Mechanical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore 21218, USA.
7. Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore 21218, USA.
The biological influence of physicochemical parameters of “targeted” nanoparticles on their delivery to cancer tumors remains poorly understood. A comparative analysis of nanoparticle distributions in tumors following systemic delivery across several models can provide valuable insights.
Methods: Bionized nanoferrite nanoparticles (iron oxide core coated with starch), either conjugated with a targeted anti-HER2 antibody (BH), or unconjugated (BP), were intravenously injected into athymic nude or NOD-scid gamma (NSG) female mice bearing one of five human breast cancer tumor xenografts growing in a mammary fat pad. Tumors were harvested 24 hours after nanoparticle injection, fixed, mounted, and stained. We performed detailed histopathology analysis by comparing spatial distributions of nanoparticles (Prussian blue) with various stromal cells (CD31, SMA, F4/80, CD11c, etc.) and the target antigen-expressing (HER2) tumor cells.
Results: Only BH nanoparticles were retained in tumors and generally concentrated in the tumor periphery, with nanoparticle content diminishing towards the tumor interior. Nanoparticle distribution correlated strongly with specific stromal cells within each tumor type, which varied among tumor types and between mouse strains. Weak or no correlation between nanoparticle distribution and HER2 positive cells, or CD31 cells was observed.
Conclusion: Antibody-labeled nanoparticles were retained across all tumors, irrespective of presence of the “target” antigen. Though presence of antibody on nanoparticles correlated with retention, non-cancerous host stromal cells were responsible for their retention in the tumor microenvironment. This study highlights gaps in our understanding of the complex biological interplay between disease and host immune biology, and the need to account for the influence of underlying aberrant tumor biology as factors determining nanoparticle fate in vivo.
Keywords: Immune response, nanoparticles, spatial analysis, stromal cells, targeted delivery.