PDF(Pubmed)
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.
摘要：
靶向参与新血管生成的多种激酶的小分子化合物在不可切除的肝细胞癌（HCC）患者中显示出生存益处。尽管如此，尽管多激酶抑制剂（MKIs）的有益作用，缺乏增强佐剂限制了其客观反应率.数十年来,脂质缀合物已经用于改善递送功效或药物益处。然而,在HCC方案中使用脂质-药物缀合物(LDC)的可行性仍未测试.在这项研究中,口服亚油酸酯-异硫氰酸荧光素结合物显示,该化合物在自发性HCC小鼠模型中分布良好.因此,开发了用于化学合成亚油酸酯-帕唑帕尼缀合物(LAPC)的基本原理设计。与亲本药物帕唑帕尼相比,LAPC显示出显著改善的细胞毒性。在LAPC处理的HCC细胞中未观察到帕唑帕尼的血管生成抑制信号，可能提示作用机制(MOA)改变。在一项比较安慰剂的疗效试验中，口服帕唑帕尼,和LAPC治疗在乙型肝炎病毒转基因相关的自发性HCC小鼠模型（HBVtg-HCC），与安慰剂和帕唑帕尼治疗相比，LAPC治疗表现出优异的肿瘤消融能力，没有任何明显的全身毒性。LAPC暴露与HBVtg-HCC肿瘤中的凋亡标志物（末端脱氧核苷酸转移酶dUTP缺口末端标记[TUNEL]）和铁凋亡增强（谷胱甘肽过氧化物酶4[GPX4]）潜力相关。因此,LAPC显示出优异的肝癌消融疗效，MOA改变。LAPC和LDC用于HCC治疗的分子机制具有极大的学术兴趣。进一步的综合临床前试验(例如，化学制造控制，毒性,分布，和药代动力学/药效学）预期。
