Multicomponent thermosensitive lipid complexes enhance desmoplastic tumor therapy through boosting anti-angiogenesis and synergistic strategy
Multicomponent thermosensitive lipid complexes enhance desmoplastic tumor therapy through boosting anti-angiogenesis and synergistic strategy
复制标题
多组分热敏脂质复合物通过促进抗血管生成和协同策略增强促结缔组织肿瘤治疗
DOI：
10.1016/j.ijpharm.2021.120533
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发表时间：
2021-04-10
影响因子：
5.8
通讯作者：
Chen, Yan
中科院分区：
文献类型：
--
作者：
Guo, Jian;Zeng, Huating;Chen, Yan
目前，与临床前试验相比，载化疗药物的热敏脂质体尚未显示出超过标准的临床效果。除了临床试验设计和加热装置的限制因素外，促结缔组织增生性肿瘤中的异常血管生成是导致临床疗效出乎意料的关键因素。畸形的肿瘤血管系统可导致血管运输减少和热敏脂质体在肿瘤中的不均匀分布。在这里，我们报告了一种通过缺氧诱导因子（HIF）-1 α-血管内皮生长因子（VEGF）轴的基础上淫羊藿苷和薏苡仁油双负载多组分热敏脂质复合物（IC-ML）的抗血管生成的策略。IC-ML可下调HepG 2细胞中HIF-1 α的表达，具有协同抗肿瘤作用。此外，给予IC-ML的共培养3D肿瘤球的HepG 2 + LX-2细胞显示出最强的渗透和生长抑制。因此，IC-ML在轻度高温下体内显示出改善的肿瘤渗透和与HIF-1 α-VEGF下调的上级协同抗肿瘤功效。IC-ML的抗肿瘤疗效的提高来自于抗血管生成策略和全面的肿瘤微环境重塑，包括清除促纤维增生肿瘤中的癌相关成纤维细胞以及抑制M2型肿瘤相关巨噬细胞浸润。本研究提出了一种新的多组分协同抗肿瘤策略，以提高热敏脂质复合物对肝细胞癌的治疗潜力。
Currently, the chemotherapy drugs-loaded thermosensitive liposomes have not shown an over standard of clinical effects compared to preclinical trials. In addition to the limiting factors of clinical trial design and heating device, abnormal angiogenesis in desmoplastic tumor is a key factor for unexpected clinical efficacy. Malformed tumor vasculature may result in reduced vascular transport and the heterogeneous distribution of thermosensitive liposomes in tumor. Here, we report an anti-angiogenesis strategy through hypoxia-inducible factors (HIF)-1 alpha-vascular endothelial growth factor (VEGF) axis based on icaritin and coix seed oil dual loaded multicomponent thermosensitive lipid complexes (IC-ML). IC-ML could downregulate the HIF-1 alpha expression in HepG2 cells with a synergetic antitumor effect. In addition, HepG2 + LX-2 cells co-cultured 3D tumor spheres administered IC-ML showed the strongest penetration and inhibition of growth. Accordingly, IC-ML displayed improved tumor penetration and superior synergistic antitumor efficacy with HIF-1 alpha-VEGF downregulation in vivo under mild hyperthermia. The improvement of antitumor efficacy of IC-ML comes from the antiangiogenesis strategy and comprehensive tumor microenvironment remodeling, including depletion of cancerassociated fibroblasts as well as inhibition of M2-type tumor associated macrophage infiltration in desmoplastic tumor. This study proposes a novel multicomponent synergistic antitumor strategy to improve the therapeutic potential of thermosensitive lipid complexes for hepatocellular carcinoma.