Abstract 5422: Predictive models of diffusive nanoparticle transport in 3D tumor spheroids
Authors: Li Mingguang , Wientjes Michael , Yeung Bertrand , Wientjes M. Guillaume , Au Jessie L.S. 
Published: May 2015

Abstract
Nanotechnology offers a means to deliver diagnostics and therapeutics, and has emerged as an important tool in cancer translational research. We previously described a computational model that uses nanoparticle (NP)-cell biointerface data to predict diffusive NP transport in 3D tumor spheroids; the model predictions agreed with the experimental results for near-neutral liposomes and negatively-charged polystyrene beads but not for cationic liposomes that contained fusogenic lipid DOPE and underwent significant size change in the presence of tumor cells (Gao et al., AAPS J 15:816, 2013). The present study evaluated if the inferior model performance on cationic liposomes was due to fusogenic lipid, positive surface charge, and/or time-dependent NP size change. We studied eight cationic liposomes containing different levels of cationic lipid DOTAP (10-30 mol%) and fusogenic lipid DOPE (1-20 mol%), with an average initial size of ∼135 nm and 2-fold range in surface charge (+24 to +43 mV). The time-dependent NP size change was monitored by measuring NP size distribution and by live cell confocal microscopy; the results indicate the most substantial change for liposomes containing &gt;10 mol% DOPE. The required NP-cell biointerface parameters (NP association and dissociation with/from cells, NP internalization, maximum NP binding sites) were measured in monolayer cultures. Comparison of model-predicted profiles with experimental results in 3D spheroids showed good agreement (&gt;88% and &gt;95% of predicted data were within 95% and 97.5% confidence intervals of experimental results, respectively; &lt;26% average deviations) for cationic liposomes containing 10-30 mol% DOTAP and low levels DOPE (≤10 mol%), indicating the diffusive transport of these cationic NP in 3D systems could be predicted using the biointerface data. In comparison, inferior predictions were obtained for cationic liposomes with higher DOPE content (up to 88% deviations, average of 41%).In view of the substantial depletion of extracellular concentration and the substantial size increase for selected NP over the 12 hr study (e.g., &gt;8% depletion for 30 mol% DOTAPand 3-times larger size for 20 mol% DOPE), we modified the model to account for these time-dependent changes. The modified model yielded better predictions for liposomes with &lt;10 mol% DOPE, but worse predictions for liposomes containing 20 mol% DOPE (86% average deviations).This finding rules out the time-dependent changes in NP size and concentration, and suggests other DOPE properties not captured by the biointerface parameters, as potential causes of the inferior model performance. In summary, the present study, together with our earlier study, indicates the diffusive transport of NP with different sizes (20-135 nm) and varying surface charges (-49to +43mV) in 3D spheroids, with the exception of liposomes comprising &gt;10 mol% of fusogenic lipid DOPE, can be predicted based on the NP-cell biointerface parameters. RO1EB015253, DHHS.
Citation Format: Mingguang Li, Michael Wientjes, Bertrand Yeung, M. Guillaume Wientjes, Jessie L.S. Au. Predictive models of diffusive nanoparticle transport in 3D tumor spheroids. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5422. doi:10.1158/1538-7445.AM2014-5422