Predictive Models of Diffusive Nanoparticle Transport in 3-Dimensional Tumor Cell Spheroids

Abstract

Abstract. The rapidly evolving nanotechnology field highlights the need of better understanding the relationship between nanoparticle (NP) properties and NP transport in solid tumors. The present study tested the hypothesis that the diffusive transport and spatial distribution of NP can be predicted based on the following parameters: interstitial NP diffusivity, NP-cell interaction parameters (cell surface binding capacity, rate constants of association, dissociation, and internalization). We (a) established the models and equations; (b) experimentally measured, in monolayer pharynx FaDu cells, the model parameters for three NP formulations (negatively charged polystyrene beads, near-neutral liposomes, and positively charged liposomes, with respective diameter of 20, 110, and 130 nm); and (c) used the models and parameters to simulate NP diffusion in 3-dimensional (3D) systems. We next measured the NP concentration-depth profiles in tumor cell spheroids, an avascular 3D system, and found good agreement between model-simulated and experimental data in spheroids for the negative and neutral NP (>90% predicted data points at three NP concentrations and three treatment times were within the 95% confidence intervals of experimental data). Model performance was inferior for positive liposomes containing a fusogenic lipid. The present study demonstrated the possibility of using in vitro NP-cell biointerface data in monolayer cultures with in silico studies to predict the NP diffusive transport and concentration-time-depth profiles in 3D systems, as functions of NP concentrations and treatment times. Extending this approach to include convective transport may yield a cost-effective means to predict the NP delivery and residence in solid tumors.

Multiscale Tumor Spatiokinetic Model for Intraperitoneal Therapy

“…Accordingly, an investigator can predict the delivery and residence of a drug at the intended target sites based on the numerical values of model parameters that are readily measured in vitro or ex vivo (e.g., drug-cell-protein interactions can be measured using cultured tumor cells) or in vivo (e.g., whole-body pharmacokinetics). Another area of potential utility is cancer nanotechnologies, as we have shown that the three-dimensional diffusive transport of nanoparticles with different sizes and surface charges in tumor spheroids can be predicted based on biointerface parameters measured in monolayer cultures (51).…”

“…Diffusivity in tumor tissue D′ and diffusivity in tumor interstitium D int were calculated using paclitaxel diffusion coefficient in aqueous solution D aqueous , radii of paclitaxel (r s ) and interstitial matrix protein fiber (r f ), volume fraction of interstitial matrix F im , and tortuosity τ (11,34,48) (51). For tortuosity, we used the value of 2.5 established for rat cerebellum and rat peritoneal tissue (11,33).…”

Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

“…109,110 They separated parameters affecting drug transport in the MCTS into two groups: the parameters depending on liposome to cell interactions (binding constants, uptake and retention rates, termed NP-cell biointerface parameters) and the diffusivity parameters related to MCTS environment (cell and ECM density) and NP characteristics (size, shape, etc.). Gao et al 109 successfully simulated diffusion of negatively charged polystyrene beads, near-neutral liposomes and positively charged liposomes with respective diameters of 20, 110 and 130 nm in 3D pharynx FaDu tumor spheroids, while Wientjes et al 110 achieved excellent precision in the prediction of the diffusion of NPs with various sizes (20-135 nm) and surface charges (-49 to +44 mV) in MCTS. Finally, very recently, Curtis et al examined the cytotoxicity of novel two-and three-layer gold NPs in heterogeneously vascularized tumors for future in vivo evaluation.…”

Enhanced transcellular penetration and drug delivery by crosslinked polymeric micelles into pancreatic multicellular tumor spheroids

“…17,18 Recent studies have shown that modified micelles can penetrate deeper and deliver more drugs into MCTS resulting in higher toxicity to the spheroids. [15][16][17][18][19][20][21] However, one important factor that has been ignored is the micelle trafficking inside the MCTS, which revolves around how micelles pass through the peripheral cells and their surrounding extracellular matrix (ECM) networks. Due to the abnormal vascular structure of the tumor tissue, this population of cells has a typical distance of more than 100 µm from the blood vessel.…”