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Linoleate-pazopanib conjugation as active pharmacological ingredient to abolish hepatocellular carcinoma growth.
Wang, Ke; Liao, Pei-Yin; Chang, Wei-Chun; Yang, Cian-Ru; Su, Yu-Ting; Wu, Ping-Ching; Wu, Yang-Chang; Hung, Yao-Ching; Akhtar, Najim; Lai, Hsueh-Chou; Ma, Wen-Lung.
Afiliación
  • Wang K; Graduate Institute of Biomedical Sciences, and Ph.D. Program for Health Science and Industry, School of Medicine, China Medical University, Taichung, Taiwan.
  • Liao PY; Department of Medical Research, Chinese Medicine Research and Development Center, and Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan.
  • Chang WC; Graduate Institute of Biomedical Sciences, and Ph.D. Program for Health Science and Industry, School of Medicine, China Medical University, Taichung, Taiwan.
  • Yang CR; Department of Medical Research, Chinese Medicine Research and Development Center, and Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan.
  • Su YT; Graduate Institute of Biomedical Sciences, and Ph.D. Program for Health Science and Industry, School of Medicine, China Medical University, Taichung, Taiwan.
  • Wu PC; Graduate Institute of Biomedical Sciences, and Ph.D. Program for Health Science and Industry, School of Medicine, China Medical University, Taichung, Taiwan.
  • Wu YC; Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.
  • Hung YC; Institute of Oral Medicine and Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • Akhtar N; Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan.
  • Lai HC; Medical Device Innovation Center, Taiwan Innovation Center of Medical Devices and Technology, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan.
  • Ma WL; Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan.
Front Pharmacol ; 14: 1281067, 2023.
Article en En | MEDLINE | ID: mdl-38293667
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Clinical_trials Idioma: En Revista: Front Pharmacol Año: 2023 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Clinical_trials Idioma: En Revista: Front Pharmacol Año: 2023 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Suiza