Multicellular tumor spheroids: a relevant 3D model for the in vitro preclinical investigation of polymer nanomedicines

The application of nanotechnology to medicine, usually termed nanomedicine, has given a crucial impulse to the design of various drug-loaded nanocarriers driven by the aim to overcome the limits associated with traditional drug delivery modalities, in particular, in the field of cancer treatment. However, an appropriate preclinical evaluation of the real therapeutic potential of nanomedicines suffers from the lack of relevant models that are well representative of the human disease and good predictors of the therapeutic response in patients. In this context, great emphasis has been directed toward 3D tumor models aiming to surmount the insufficient predictive power of traditional 2D monolayer cultures of cancer cells. This review focuses on multicellular tumor spheroids (MCTS), which are currently the most widely employed 3D tumor model in preclinical studies. After a brief discussion on spheroid construction strategies and analytical/imaging techniques employed in experimental settings, the application of 3D MCTS to the evaluation of nanomedicines displaying various physico-chemical properties is reviewed. Finally, relevant examples of scaffold and microfluidic systems in which MCTS have been included are described.