Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth

Ke Wang; Pei-Yin Liao; Wei-Chun Chang; Cian-Ru Yang; Yu-Ting Su; Ping-Ching Wu; Yang-Chang Wu; Yao-Ching Hung; Najim Akhtar; Hsueh-Chou Lai; Wen-Lung Ma

doi:10.3389/fphar.2023.1281067

Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth

Front Pharmacol. 2024 Jan 16:14:1281067. doi: 10.3389/fphar.2023.1281067. eCollection 2023.

Authors

Ke Wang^{1

2}, Pei-Yin Liao¹, Wei-Chun Chang², Cian-Ru Yang¹, Yu-Ting Su¹, Ping-Ching Wu^{3

4

5

6}, Yang-Chang Wu⁷, Yao-Ching Hung^{2

8}, Najim Akhtar¹, Hsueh-Chou Lai^{2

9}, Wen-Lung Ma^{1

2}

Affiliations

¹ Graduate Institute of Biomedical Sciences, and Ph.D. Program for Health Science and Industry, School of Medicine, China Medical University, Taichung, Taiwan.
² Department of Medical Research, Chinese Medicine Research and Development Center, and Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan.
³ Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.
⁴ Institute of Oral Medicine and Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁵ Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan.
⁶ Medical Device Innovation Center, Taiwan Innovation Center of Medical Devices and Technology, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.
⁷ Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan.
⁸ Department of Obstetrics and Gynecology, Asia University Hospital, Taichung, Taiwan.
⁹ Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.

Abstract

Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective response rate. Lipid conjugates have been used to improve delivery efficacy or pharmaceutical benefits for decades. However, the feasibility of utilizing lipid-drug conjugates (LDCs) in HCC regimens remains untested. In this study, oral feeding of linoleate-fluorescein isothiocyanate conjugates showed that the compound was well distributed in a spontaneous HCC mouse model. Therefore, a rationale design was developed for chemically synthesizing a linoleate-pazopanib conjugate (LAPC). The LAPC showed a significantly improved cytotoxicity compared to the parental drug pazopanib. Pazopanib's angiogenic suppressing signals were not observed in LAPC-treated HCC cells, potentially suggesting an altered mechanism of action (MOA). In an efficacy trial comparing placebo, oral pazopanib, and LAPC treatments in the hepatitis B virus transgene-related spontaneous HCC mouse model (HBVtg-HCC), the LAPC treatment demonstrated superior tumor ablating capacity in comparison to both placebo and pazopanib treatments, without any discernible systemic toxicity. The LAPC exposure is associated with an apoptosis marker (Terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) and an enhanced ferroptosis (glutathione peroxidase 4 [GPX4]) potential in HBVtg-HCC tumors. Therefore, the LAPC showed excellent HCC ablative efficacy with altered MOA. The molecular mechanisms of the LAPC and LDCs for HCC therapeutics are of great academic interest. Further comprehensive preclinical trials (e.g., chemical-manufacture-control, toxicity, distribution, and pharmacokinetics/pharmacodynamics) are expected.

Keywords: LAPC; LDC; hepatocellular carcinoma; linoleate; pazopanib.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by National Science and Technology Council (NSTC111-2320-B-039-011; NSTC111-2314-B-039-062-MY3; NSTC110-2314-B-039-046; NSTC111-2622-B-039-004-), National Health Research Institute (NHRI-EX111-11110BI), China Medical University/Hospital (CMU109-MF-26; DMR-111-118; DMR-110-025; DMR-111-204; DMR-111-238), and Asia University Hospital (AUH-11151021). This study also been supported by the Center of Applied Nanomedicine, the Medical Device Innovation Center (MDIC) National Cheng Kung University, Taiwan. The authors thank the support provided by the Ministry of Science and Technology in Taiwan under MOST 110-2221-E−006-013-MY3, and Academia Sinica Healthy Longevity Grand Challenge Competition (AS-HLGC-110-07).