To test the efficacy of novel antitumor drugs and delivery systems, in vitro models that mimic solid tumors are necessary. Three-dimensional (3D) models such as multicellular tumor spheroids (MTS) have been deemed superior to two-dimensional (2D) cell cultures due to their ability to mimic the 3D nature of solid tumors. Although several methods exist for spheroid generation, they fail to mimic many of the intricate in vivo interactions between cancer cells as well as between cancer cells and the extracellular matrix (ECM). The issues are that these approaches make it difficult to ascertain the efficacy of drug therapies. Here, we review the importance of 3D models and the components of the tumor microenvironment (TME) and ECM that are required to recapitulate the complex interactions in clinically relevant in vitro models. We also discuss classical spheroid models as well as novel methods that attempt to recapitulate the TME to a greater extent. We focus on the use of the cyclo-RGDfK peptide and its modification with triphenyl phosphonium cation (TPP), namely cyclo-RGDfK(TPP). Within the ECM, the RGD (Arg-Gly-Asp) motif in fibronectin has been found to promote cell-to-cell and cell-to-matrix interactions. The chemically engineered cyclo-RGDfK(TPP) peptide is capable of strategically mimicking the ECM within the TME to facilitate 3D MTS formation from 2D monolayer cancer cells. Additionally, this peptide allows for a reproducible method that directly allows for the formation of tighter spheroids that can be theoretically applied to co-culturing experiments as an efficient in vitro model to study the effects of antitumor therapies.
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