Increasing the tumour targeting of antitumour drugs through anlotinib-mediated modulation of the extracellular matrix and the RhoA/ROCK signalling pathway

Xuedan Han; Jialei Liu; Yidong Zhang; Eric Tse; Qiyi Yu; Yu Lu; Yi Ma; Lufeng Zheng

doi:10.1016/j.jpha.2024.100984

Volume 14 Issue 8

Aug. 2024

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Xuedan Han, Jialei Liu, Yidong Zhang, Eric Tse, Qiyi Yu, Yu Lu, Yi Ma, Lufeng Zheng. Increasing the tumour targeting of antitumour drugs through anlotinib-mediated modulation of the extracellular matrix and the RhoA/ROCK signalling pathway[J]. Journal of Pharmaceutical Analysis, 2024, 14(8): 100984. doi: 10.1016/j.jpha.2024.100984

Citation:

Xuedan Han, Jialei Liu, Yidong Zhang, Eric Tse, Qiyi Yu, Yu Lu, Yi Ma, Lufeng Zheng. Increasing the tumour targeting of antitumour drugs through anlotinib-mediated modulation of the extracellular matrix and the RhoA/ROCK signalling pathway[J]. Journal of Pharmaceutical Analysis, 2024, 14(8): 100984. doi: 10.1016/j.jpha.2024.100984

Citation:

Xuedan Han, Jialei Liu, Yidong Zhang, Eric Tse, Qiyi Yu, Yu Lu, Yi Ma, Lufeng Zheng. Increasing the tumour targeting of antitumour drugs through anlotinib-mediated modulation of the extracellular matrix and the RhoA/ROCK signalling pathway[J]. Journal of Pharmaceutical Analysis, 2024, 14(8): 100984. doi: 10.1016/j.jpha.2024.100984

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Increasing the tumour targeting of antitumour drugs through anlotinib-mediated modulation of the extracellular matrix and the RhoA/ROCK signalling pathway

doi: 10.1016/j.jpha.2024.100984

Xuedan Han^a,
Jialei Liu^b,
Yidong Zhang^a,
Eric Tse^c,
Qiyi Yu^a,
Yu Lu^a,
Yi Ma^{b
,
,},
Lufeng Zheng^{a
,
,}

a. School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China;
b. Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, Nanjing, 211198, China;
c. Sino Biopharmaceutical Group Limited, Beijing, 100026, China

Funds:

This work was supported by the National Natural Science Foundation of China (Grant No.: 82173842) and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions, China. We thank Chia Tai Tianqing Pharmaceutical Group Co., Ltd. for providing anlotinib, penpulimab, and TQB2450.

Received Date: Nov. 11, 2023
Accepted Date: Apr. 23, 2024
Rev Recd Date: Apr. 19, 2024
Publish Date: Apr. 25, 2024

Abstract

Abstract

Anlotinib has strong antiangiogenic effects and leads to vessel normalization. However, the “window period” characteristic in regulating vessel normalization by anlotinib cannot fully explain the long-term survival benefits achieved through combining it with other drugs. In this study, through RNA sequencing (RNA-seq) and label-free quantitative proteomics analysis, we discovered that anlotinib regulated the expression of components of the extracellular matrix (ECM), leading to a significant reduction in ECM stiffness. Our bioinformatic analysis revealed a potential positive relationship between the ECM pathway and gefitinib resistance, poor treatment outcomes for programmed death 1 (PD-1) targeting, and unfavourable prognosis following chemotherapy in lung cancer patients. We administered anlotinib in combination with these antitumour drugs and visualized their distribution using fluorescent labelling in various tumour types. Notably, our results demonstrated that anlotinib prolonged the retention time and distribution of antitumour drugs at the tumour site. Moreover, the combination therapy induced notable loosening of the tumour tissue structure. This reduction was associated with decreased interstitial fluid pressure and tumour solid pressure. Additionally, we observed that anlotinib effectively suppressed the Ras homologue family member A (RhoA)/Rho-associated protein kinase (ROCK) signalling pathway. These findings suggest that, in addition to its antiangiogenic and vessel normalization effects, anlotinib can increase the distribution and retention of antitumour drugs in tumours by modulating ECM expression and physical properties through the RhoA/ROCK signalling pathway. These valuable insights contribute to the development of combination therapies aimed at improving tumour targeting in cancer treatment.
- Anlotinib,
- Extracellular matrix,
- Interstitial fluid pressures,
- Tumour solid pressure,
- RhoA/ROCK

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References(45)

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