Biomechanically primed liver microtumor array as a high-throughput mechanopharmacological screening platform for stroma-reprogrammed combinatorial therapy
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Updated: Mar 7, 2026
3D Microtissues for Injectable Regenerative Therapy and High-throughput Drug Screening
Published on: October 4, 2017
Lu Zhu1, Xingliang Fan2, Bingjie Wang2
1Department of Biomedical Engineering, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing, 100084, China; Institute of Medical Equipment, Academy of Military Medical Sciences, Tianjin, 300161, China.
Abstract:
Recent breakthrough in stroma-reprogrammed combinatorial therapy (SRCT) for pancreatic tumor opens a new route for improving conventional chemotherapeutic efficacy, which utilizes VDR ligand to reprogram activated stromal cells in stiffened microenvironment, leading to reduced 'barrier effects' and increased tissue-infiltration of the chemotherapy drug. As a novel therapeutic strategy and mechanism of action, the progress of SRCT relies on tailored in vitro drug assessment platforms to further optimize its efficacy and extend to applications in other tumor types. Here, a high-throughput mechanopharmacological drug screening platform for SRCT was established based on biomechanically primed hepatic stromal stellate cells to recapitulate state-specific liver microtumors with barrier effects. Fifteen generic chemotherapy drugs co-administered with VDR ligand were screened to obtain optimal SRCT formulations (e.g. carboplatin + calcipotriol), which efficacy was successfully verified in xenograft tumor models. Overall, this platform provides a powerful tool for discovery and optimization of tissue-specific SRCT and realizes 'mechanopharmacology' to translate insights of stromal mechanobiology to pharmaceutical applications.
Insights
A new stroma-reprogrammed combinatorial therapy (SRCT) approach improves chemotherapy by reprogramming tumor stroma. This study developed a screening platform to optimize SRCT formulations for enhanced drug delivery and efficacy.
Area of Science:
- Biomedical Engineering
- Cancer Therapy
- Mechanobiology
Background:
- Pancreatic tumors possess a stiff microenvironment that creates barrier effects, hindering chemotherapy drug infiltration.
- Stroma-reprogrammed combinatorial therapy (SRCT) offers a novel strategy to overcome these barriers by reprogramming activated stromal cells.
- Optimizing SRCT requires effective in vitro drug assessment platforms to tailor treatments for specific tumor types.
Purpose of the Study:
- To establish a high-throughput mechanopharmacological drug screening platform for SRCT.
- To identify optimal SRCT formulations by screening chemotherapy drugs combined with a VDR ligand.
- To validate the efficacy of optimized SRCT in preclinical tumor models.
Main Methods:
- Development of a screening platform using biomechanically primed hepatic stellate cells to mimic liver microtumors.
- Screening of 15 generic chemotherapy drugs co-administered with a VDR ligand.
- In vivo validation of optimal SRCT formulations in xenograft tumor models.
Main Results:
- An optimal SRCT formulation, such as carboplatin + calcipotriol, was identified.
- The developed platform successfully recapitulated microtumor barrier effects.
- The efficacy of the optimized SRCT was confirmed in preclinical xenograft models.
Conclusions:
- The established platform enables the discovery and optimization of tissue-specific SRCT.
- This work translates mechanobiology insights into pharmaceutical applications via 'mechanopharmacology'.
- SRCT holds promise for enhancing chemotherapeutic efficacy by overcoming tumor microenvironment barriers.
