Tumor in 3D: In Vitro Complex Cellular Models to Improve Nanodrugs Cancer Therapy

Nanodrugs represent novel solutions to reshuffle repurposed drugs for cancer therapy.They might offer different therapeutic options by combining targeted drug delivery andimaging in unique platforms. Such nanomaterials are deemed to overcome the limitations ofcurrently available treatments, ultimately improving patients’ life quality. However, despitethese promises being made for over three decades, the poor clinical translation of nanoparticle-based therapies calls for deeper in vitro and in vivo investigations. Translational issuesarise very early during the development of nanodrugs, where complex and more reliable cellmodels are often replaced by easily accessible and convenient 2D monocultures. This is particularlytrue in the field of cancer therapy. In fact, 2D monocultures provide poor informationabout the real impact of the nanodrugs in a complex living organism, especially given thepoor mimicry of the solid Tumors Microenvironment (TME). The dense and complex extracellularmatrix (ECM) of solid tumors dramatically restricts nanoparticles efficacy, impairingthe successful implementation of nanodrugs in medical applications. Herein, we propose acomprehensive guideline of the 3D cell culture models currently available, including their potentialand limitations for the evaluation of nanodrugs activity. Advanced culture techniques,more closely resembling the physiological conditions of the TME, might give a better predictionof the reciprocal interactions between cells and nanoparticles and eventually help reconsiderthe use of old drugs for new applications.