Elucidating the Uptake and Distribution of Nanoparticles in Solid Tumors via a Multilayered Cell Culture Model

Abstract

Multicellular layers (MCLs) have previously been used to determine the pharmacokinetics of a variety of different cancer drugs including paclitaxel, doxorubicin, methotrexate, and 5-fluorouracil across a number of cell lines. It is not known how nanoparticles (NPs) navigate through the tumor microenvironment once they leave the tumor blood vessel. In this study, we used the MCL model to study the uptake and penetration dynamics of NPs. Gold nanoparticles (GNPs) were used as a model system to map the NP distribution within tissue-like structures. Our results show that NP uptake and transport are dependent on the tumor cell type. MDA-MB-231 tissue showed deeper penetration of GNPs as compared to MCF-7 one. Intracellular and extracellular distributions of NPs were mapped using CytoViva imaging. The ability of MCLs to mimic tumor tissue characteristics makes them a useful tool in assessing the efficacy of particle distribution in solid tumors.Electronic supplementary materialThe online version of this article (doi:10.1007/s40820-014-0025-1) contains supplementary material, which is available to authorized users.

Evaluation of uptake and distribution of gold nanoparticles in solid tumors

“…As reviewed here, the uptake and distribution of NPs within avascular/hypoxic regions of solid tumors has been studied using such in vitro models [69,70,99]. However, tissue within live subjects is more complex than that formed in 3D cell culture, typically having a fully developed ECM and multiple cell types (including immune system cells) in proximity of blood and lymph vessels, which may affect the deposition patterns and uptake of NPs beyond the mere effects of diffusion in 3D space.…”

“…In particular, hyperspectral imaging has shown the feasibility of determining particle size, wavelength differentiation, spatial location, and agglomeration status of NPs in solution [152]. In [70,99], dark-field microscopy in combination with hyperspectral imaging was used to evaluate NP uptake and distribution within tissue samples harvested from mice.…”

“…Other techniques for gold NP detection in tissue have included confocal microscopy [93], atomic force microscopy (AFM) [94], fluorescence microscopy [95], dark-field microscopy [96], reflectance imaging [93], photothermal interference contrast [97], and micro computed tomography (micro-CT) [98]. Recently, hyperspectral imaging in combination with dark-field microscopy was used in [69,70,99] to assess NP uptake and distribution within histology tissue sections. In this approach, spectral libraries of known NPs are created to enable their detection in tissue.…”

“…NPs are counted in various regions of tissue ( e.g. , tumor spheroids [69,70] or multilayered cell cultures [99]) to determine concentration. However, light scattering from different components in dense tissue samples may hinder detection.…”

“…The penetration and uptake dynamics of gold NPs has very recently been studied using a Multilayered Cell Culture Model (MCL) [99], showing that NP transport and uptake are highly dependent on the tumor cell type. Gold NPs sized 20 nm were able to penetrate deeper into tissue composed of MDA-MB-231 cells than of tissue of MCF-7 cells, both human mammary carcinoma cell lines.…”