Nanoparticle-Mediated Drug Delivery of Doxorubicin Induces a Differentiated Clonogenic Inactivation in 3D Tumor Spheroids In Vitro

Abstract

Involvement of 3D tumor cell models in the in vitro biological testing of novel nanotechnology-based strategies for cancer management can provide in-depth information on the real behavior of tumor cells in complex biomimetic architectures. Here, we used polyethylene glycol-encapsulated iron oxide nanoparticles for the controlled delivery of a doxorubicin chemotherapeutic substance (IONP_DOX), and to enhance cytotoxicity of photon radiation therapy. The biological effects of nanoparticles and 150 kV X-rays were evaluated on both 2D and 3D cell models of normal human keratinocytes (HaCaT) and tumor cells-human cervical adenocarcinoma (HeLa) and human squamous carcinoma (FaDu)-through cell survival. In all 2D cell models, nanoparticles were similarly internalized in a peri-nuclear pattern, but resulted in different survival capabilities following radiation treatment. IONP on normal keratinocytes showed a protective effect, but a cytotoxic effect for cancer cells. In 3D tumor cell models, IONP_DOX were able to penetrate the cell spheroids towards the hypoxic areas. However, IONP_DOX and 150 kV X-rays led to a dose-modifying factor DMF_SF=0.1 = 1.09 ± 0.1 (200 µg/mL IONP_DOX) in HeLa spheroids, but to a radioprotective effect in FaDu spheroids. Results show that the proposed treatment is promising in the management of cervical adenocarcinoma.