Particle-scale study on extracellular penetration of nanoparticles in tumor tissues

Nanomedicine-based cancer therapies are advancing but the efficacy are hampered by limited knowledge of drug delivery dynamics, including tumor penetration behavior. Utilizing MDA-MB-231 breast tumor spheroids in in vitro experiments and imaging techniques including two-photon microscopy and scanning electron microscopy (SEM), it is demonstrated that quasi-spherical gold nanoparticles penetrate spheroid tissues primarily through the extracellular pathway when the energy-dependent intracellular pathway is blocked. A novel self-developed 3D micro-scale CFD-DEM model integrated with a DLVO sub-model is used to simulate nanoparticle penetration behavior with the extracellular matrix (ECM) considered. The results reveal nanoparticles remain on spheroid surfaces either individually or in small aggregates, with penetration efficacy reducing at amplified concentrations due to increased collisions. Approximately 60 % of intratumoral nanoparticles attach to cells and 40 % to the ECM. Four modes at the particle-scale are identified through the DLVO force and trajectory analysis. This work offers a cost-effective and potential tool for nanoparticles tissue penetration prediction, facilitating interpret and understand the imaging data, and guiding future nanomedicine design.