Three-Dimensional Tumor Spheroids as a Tool for Reliable Investigation of Combined Gold Nanoparticle and Docetaxel Treatment

SIMPLE SUMMARY: Due to the normal tissue toxicity induced by standard therapeutic options such as radiotherapy and chemotherapy, alternative solutions are being explored. Nanomaterials, such as gold nanoparticles, can help reduce side effects by increasing targeted dose to the tumor as well as act as a drug delivery system. Many nano-based systems are tested in a two-dimensional monolayer in the lab, which is not representative of the complex tumor microenvironment. Towards an accelerated translation to the clinic, use of nanomaterials, like the radio-sensitizing gold nanoparticles, were tested in three-dimensional spheroids, which exhibit many properties present in a real tumor such as the extracellular matrix, necrotic cores, and nutrient gradients. This work paves the way for more accurate experimentation in the lab that is more indicative of a real tumor response, leading to a higher chance of success in future clinical studies and clinical treatment. ABSTRACT: Radiotherapy and chemotherapy are the gold standard for treating patients with cancer in the clinic but, despite modern advances, are limited by normal tissue toxicity. The use of nanomaterials, such as gold nanoparticles (GNPs), to improve radiosensitivity and act as drug delivery systems can mitigate toxicity while increasing deposited tumor dose. To expedite a quicker clinical translation, three-dimensional (3D) tumor spheroid models that can better approximate the tumor environment compared to a two-dimensional (2D) monolayer model have been used. We tested the uptake of 15 nm GNPs and 50 nm GNPs on a monolayer and on spheroids of two cancer cell lines, CAL-27 and HeLa, to evaluate the differences between a 2D and 3D model in similar conditions. The anticancer drug docetaxel (DTX) which can act as a radiosensitizer, was also utilized, informing future potential of GNP-mediated combined therapeutics. In the 2D monolayer model, the addition of DTX induced a small, non-significant increase of uptake of GNPs of between 13% and 24%, while in the 3D spheroid model, DTX increased uptake by between 47% and 186%, with CAL-27 having a much larger increase relative to HeLa. Further, the depth of penetration of 15 nm GNPs over 50 nm GNPs increased by 33% for CAL-27 spheroids and 17% for HeLa spheroids. These results highlight the necessity to optimize GNP treatment conditions in a more realistic tumor-life environment. A 3D spheroid model can capture important details, such as different packing densities from different cancer cell lines, which are absent from a simple 2D monolayer model.