Culture of patient-derived multicellular clusters in suspended hydrogel capsules for pre-clinical personalized drug screening

A personalized medication regimen provides precise treatment for an individual and can be guided by pre-clinical drug screening. The economical and high-efficiency simulation of the liver tumor microenvironment (TME) in a drug-screening model has high value yet challenging to accomplish. Herein, we propose a simulation of the liver TME with suspended alginate-gelatin hydrogel capsules encapsulating patient-derived liver tumor multicellular clusters, and the culture of patient-derived tumor organoids(PDTOs) for personalized pre-clinical drug screening. The hydrogel capsule offers a 3D matrix environment with mechanical and biological properties similar to those of the liver in vivo. As a result, 18 of the 28 patient-derived multicellular clusters were successfully cultured as PDTOs. These PDTOs, along with hepatocyte growth factor (HGF) of non-cellular components, preserve stromal cells, including cancer-associated fibroblasts (CAFs) and vascular endothelial cells (VECs). They also maintain stable expression of molecular markers and tumor heterogeneity similar to those of the original liver tumors. Drugs, including cabazitaxel, oxaliplatin, and sorafenib, were tested in PDTOs. The sensitivity of PDTOs to these drugs differs between individuals. The sensitivity of one PDTO to oxaliplatin was validated using magnetic resonance imaging (MRI) and biochemical tests after oxaliplatin clinical treatment of the corresponding patient. Therefore, this approach is promising for economical, accurate, and high-throughput drug screening for personalized treatment. 1. Patient-derived liver tumor tissues were digested into multicellular clusters. 2. The hydrogel offered a 3D matrix environment that had similar mechanical and biological properties to human liver. 3. Patient-derived tumor organoids (PDTOs) were cultured by encapsulating patient-derived liver tumor multicellular clusters in suspended hydrogel capsules. 4. These PDTOs, with the hepatocyte growth factor (HGF) of non-cellular component, simulated the biomechanical characteristics of tumor microenvironment (TME), and preserved stromal cells including cancer-associated fibroblasts (CAFs) and vascular endothelial cells (VECs). Moreover, they maintained stable expression of molecular markers and tumor heterogeneity that were similar to original tumors. 5. Sensitivity of PDTOs to different drugs presented differences between individuals. 6. This personalized drug screening model has advantages including easy operatio