Enhanced penetration into 3D cell culture using two and three layered gold nanoparticles

Abstract

Nano-scale particles sized 10–400 nm administered systemically preferentially extravasate from tumor vasculature due to the enhanced permeability and retention effect. Therapeutic success remains elusive, however, because of inhomogeneous particle distribution within tumor tissue. Insufficient tumor vascularization limits particle transport and also results in avascular hypoxic regions with non-proliferating cells, which can regenerate tissue after nanoparticle-delivered cytotoxicity or thermal ablation. Nanoparticle surface modifications provide for increasing tumor targeting and uptake while decreasing immunogenicity and toxicity. Herein, we created novel two layer gold-nanoshell particles coated with alkanethiol and phosphatidylcholine, and three layer nanoshells additionally coated with high-density-lipoprotein. We hypothesize that these particles have enhanced penetration into 3-dimensional cell cultures modeling avascular tissue when compared to standard poly(ethylene glycol) (PEG)-coated nanoshells. Particle uptake and distribution in liver, lung, and pancreatic tumor cell cultures were evaluated using silver-enhancement staining and hyperspectral imaging with dark field microscopy. Two layer nanoshells exhibited significantly higher uptake compared to PEGylated nanoshells. This multilayer formulation may help overcome transport barriers presented by tumor vasculature, and could be further investigated in vivo as a platform for targeted cancer therapies.

Evaluation of Drug-Loaded Gold Nanoparticle Cytotoxicity as a Function of Tumor Vasculature-Induced Tissue Heterogeneity

“…Three-layered nanoparticles were previously created in 14 . Briefly, citrate-stabilized gold nanoparticles were synthesized by reducing chloroauric acid with trisodium citrate 15 .…”

“…The distribution and penetration of 2- and 3-layered gold nanoparticles were recently evaluated in vitro 14 and in vivo 12 . The purpose of these nanoparticles was to increase chemotherapy efficacy 10, 13 via enhanced distribution and penetration into heterogeneous tumor tissue.…”

“…The purpose of these nanoparticles was to increase chemotherapy efficacy 10, 13 via enhanced distribution and penetration into heterogeneous tumor tissue. The 3-layer gold nanoparticles were functionalized with phosphatidylcholine, hexadecanethiol and high-density lipoprotein 14 . Computational modeling was employed 5 to simulate the performance of these nanoparticles in vivo given measurements in vitro , with the goal to begin bridging the gap from the pre-clinical to the clinical setting.…”

“…Computational modeling was employed 5 to simulate the performance of these nanoparticles in vivo given measurements in vitro , with the goal to begin bridging the gap from the pre-clinical to the clinical setting. The model parameters were set from experimental measurements with 2D and 3D cultures of A549, H358, and PC9 Non-Small Cell Lung Cancer (NSCLC) cells 13, 14 .…”

Organ-on-a-chip platforms for studying drug delivery systems

“…Results showed considerably reduced toxicity in spheroids when compared to 2D cultures and the reduction in toxicity was attributed to change in phenotype and complex cell-cell interaction that altered the transport of nanoparticles. Spheroids of cancerous hepatocytes have also been used as a model for mimicking in vivo tumor microenvironments as shown by England et al [99]. They studied nanoparticle delivery to avascular regions in the spheroid core and used surface modification strategy to enhance nanoparticle penetration within the tumor core.…”