Predicting diffusive transport of cationic liposomes in 3-dimensional tumor spheroids

Nanotechnology is widely used in cancer research. Models that predict nanoparticle transport and delivery in tumors (including subcellular compartments) would be useful tools. This study tested the hypothesis that diffusive transport of cationic liposomes in 3-dimensional (3D) systems can be predicted based on liposome-cell biointerface parameters (binding, uptake, retention) and liposome diffusivity. Liposomes comprising different amounts of cationic and fusogenic lipids (10-30mol% DOTAP or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1-20mol% DOPE or 1,2-dioleoyl-3-trimethylammonium-propane, +25 to +44mV zeta potential) were studied. We (a) measured liposome-cell biointerface parameters in monolayer cultures, and (b) calculated effective diffusivity based on liposome size and spheroid composition. The resulting parameters were used to simulate the liposome concentration-depth profiles in 3D spheroids. The simulated results agreed with the experimental results for liposomes comprising 10-30mol% DOTAP and ≤10mol% DOPE, but not for liposomes with higher DOPE content. For the latter, model modifications to account for time-dependent extracellular concentration decrease and liposome size increase did not improve the predictions. The difference among low- and high-DOPE liposomes suggests concentration-dependent DOPE properties in 3D systems that were not captured in monolayers. Taken together, our earlier and present studies indicate the diffusive transport of neutral, anionic and cationic nanoparticles (polystyrene beads and liposomes, 20-135nm diameter, -49 to +44mV) in 3D spheroids, with the exception of liposomes comprising >10mol% DOPE, can be predicted based on the nanoparticle-cell biointerface and nanoparticle diffusivity. Applying the model to low-DOPE liposomes showed that changes in surface charge affected the liposome localization in intratumoral subcompartments within spheroids.