Drug evaluation using 3D tissue models

Abstract

The gap between conventional in vitro 2D cultures and in vivo drug responses remains a major hurdle in drug discovery and clinical translation. To bridge the “missing link,” highly biomimetic 3D tissue models are emerging as promising platforms. These platforms are particularly critical for evaluating DDS, which must overcome significant physical barriers to reach target cells. This review first outlines cell sedimentation techniques, specifically the CAViTs and CMF methods, for simply constructing complex 3D tissues. We introduce their utility in general drug evaluation, including “patient-derived cancer avatar” models. Additionally, we briefly touch upon vascularized hepatic tissue models for assessing drug-induced vascular toxicity, and mature adipose tissue models for metabolic disease drug screening. Subsequently, we focus on how the 3D models are specifically applied to evaluate DDS, highlighting the integration of tissue engineering. The evolution of DDS evaluation models is illustrated through realistic physical barriers provided by highly hierarchical 3D tissue models. These models enable the visualization of differences in tissue penetrability depending on carrier sizes and shapes. Furthermore, we discuss the crucial role of recapitulating the 3D tumor microenvironment (TME) in evaluating next-generation DDS, such as antibody-drug conjugates (ADCs). The 3D cancer-stromal coculture models provide insights into how TME factors significantly influence ADC sensitivities, facilitating the elucidation of their TME-responsive pharmacological mechanisms. Moreover, the biomimetic systems serve as powerful platforms for screening novel combination partner compounds to synergistically enhance ADC efficacy. Finally, we discuss the future perspectives of establishing robust 3D tissue models. The fusion of tissue engineering and DDS evaluation technologies will accelerate drug development and strongly support the realization of functional precision medicine.