Functionalized Cerium Oxide Nanoparticles Enhance Penetration into Melanoma Spheroids In Vivo through Angiogenesis

Melanoma cell spheroid engraftment is optimized in the chicken chorioallantoic membrane overcoming the complexity of other in vivo models. Using this model, greater penetration of cerium oxide nanoparticles (nanoceria) functionalized with heparin in spheroids is observed via enhancement of vascularization than nanoceria alone. This model promises a scalable, low-cost platform for early preclinical therapy screening such as for precision medicine.

Abstract

Angiogenesis is a crucial step in tumor progression, including melanoma, making anti-angiogenic strategies a widely explored treatment approach. However, both innate and acquired resistance to these therapies suggest that this approach may need re-evaluation. Nanoparticles have gained attention for their potential to enhance drug delivery and retention within tumors via the bloodstream. However, the in vitro screening of nanoparticles is limited by the inability of preclinical models to replicate the complex tumor microenvironment, especially the blood supply. Here, it is demonstrated that melanoma cells embedded in Matrigel spheroids can engraft in and be vascularized by the chorioallantoic membrane (CAM) of fertilized chicken eggs. This model allows for the assessment of nanoparticle toxicity and accumulation in tumor spheroids, as well as functional effects such as angiogenesis. Cerium oxide nanoparticles (nanoceria) and their surface functionalized derivatives are widely explored for biomedical applications due to their ability to modulate oxidative stress and angiogenesis. Here, it is observed that heparin functionalized nanoceria penetrate melanoma spheroids in the CAM and promote spheroid vascularization to a greater extent than nanoceria alone. This study aids in the development of preclinical cancer models for nanoparticle screening and provides new insight into the interplay between nanoparticle surface coatings and biological effects.