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Tumor Progression of Non-Small Cell Lung Cancer Controlled by Albumin and Micellar Nanoparticles of Itraconazole, a Multitarget Angiogenesis Inhibitor
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2017-11-07 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00855 Ling Zhang 1 , Zhengsheng Liu 1 , Kuan Yang 1 , Chao Kong 1 , Chun Liu 1 , Huijun Chen 1 , Jinfeng Huang 2 , Feng Qian 1
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2017-11-07 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00855 Ling Zhang 1 , Zhengsheng Liu 1 , Kuan Yang 1 , Chao Kong 1 , Chun Liu 1 , Huijun Chen 1 , Jinfeng Huang 2 , Feng Qian 1
Affiliation
Itraconazole (ITA), an old and widely prescribed antifungal drug with excellent safety profile, has more recently been demonstrated to be a multitarget antiangiogenesis agent affecting multiple angiogenic stimulatory signals and pathways, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, and mammalian target of rapamycin (mTOR). In this study, we developed two nanoparticle formulations, i.e., polymer micelles (IP2K) and albumin nanoparticles (IBSA), to solubilize the extremely hydrophobic and insoluble ITA to allow intravenous administration and pharmacokinetics (PK)/pharmacodynamics (PD) comparisons. Although none of the formulations showed strong antiproliferation potency against non-small cell lung cancer (NSCLC) cells in vitro, when administrated at the equivalent ITA dose to a NSCLC patient-derived xenograft (PDX) model, IBSA retarded while IP2K accelerated the tumor growth. We attributed the cause of this paradox to formulation-dependent PK and vascular manipulation: IBSA demonstrated a more sustained PK with a Cmax of 60–70% and an AUC ∼2 times of those of IP2K, and alleviated the tumor hypoxia presumably through vascular normalization. In contrast, the high Cmax of IP2K elevated tumor hypoxia through a strong angiogenesis inhibition, which could have aggravated cancer aggressiveness and accelerated tumor growth. Furthermore, IBSA induced minimal hepatic and hematologic toxicities compared to IP2K and significantly enhanced the in vivo tumor inhibition activity of paclitaxel albumin nanoparticles when used in combination. These findings suggest that formulation and pharmacokinetics are critical aspects to be considered when designing the ITA angiogenesis therapy, and IBSA could potentially be assessed as a novel and safe multitarget angiogenesis therapy to be used in combination with other anticancer agents.
中文翻译:
白蛋白和伊曲康唑的胶束纳米颗粒控制的非小细胞肺癌的肿瘤进展,伊曲康唑是一种多靶点血管生成抑制剂。
伊曲康唑(ITA)是一种具有广泛安全性的古老且处方广泛的抗真菌药物,最近被证明是一种多靶点抗血管生成剂,可影响多种血管生成刺激信号和途径,包括血管内皮生长因子(VEGF),碱性成纤维细胞生长因子( bFGF),血管内皮生长因子受体2(VEGFR2)糖基化和雷帕霉素(mTOR)的哺乳动物靶标。在这项研究中,我们开发了两种纳米颗粒制剂,即聚合物胶束(IP2K)和白蛋白纳米颗粒(IBSA),以溶解极疏水和不溶的ITA,从而可以进行静脉内给药和药代动力学(PK)/药效学(PD)比较。尽管没有一种制剂对非小细胞肺癌(NSCLC)细胞显示出强大的抗增殖能力在体外,当以相同的ITA剂量对NSCLC患者衍生的异种移植(PDX)模型给药时,IBSA会延迟,而IP2K会加速肿瘤的生长。我们将这种悖论的原因归因于依赖制剂的PK和血管操纵:IBSA表现出更持久的PK,C max为IP2K的60%至70%,AUC约为IP2K的2倍,并缓解了肿瘤的缺氧。正常化。与此相反,高Ç最大IP2K的通过强大的血管生成抑制作用,这可能加剧癌症侵袭性和加速肿瘤生长升高肿瘤缺氧。此外,与IP2K相比,IBSA诱导的肝脏和血液学毒性最小,并显着增强了体内当联合使用时,紫杉醇白蛋白纳米颗粒具有抑制肿瘤的活性。这些发现表明,配方和药代动力学是设计ITA血管生成疗法时应考虑的关键方面,IBSA可能被评估为可与其他抗癌药物联合使用的新型安全多靶血管生成疗法。
更新日期:2017-11-07
中文翻译:
白蛋白和伊曲康唑的胶束纳米颗粒控制的非小细胞肺癌的肿瘤进展,伊曲康唑是一种多靶点血管生成抑制剂。
伊曲康唑(ITA)是一种具有广泛安全性的古老且处方广泛的抗真菌药物,最近被证明是一种多靶点抗血管生成剂,可影响多种血管生成刺激信号和途径,包括血管内皮生长因子(VEGF),碱性成纤维细胞生长因子( bFGF),血管内皮生长因子受体2(VEGFR2)糖基化和雷帕霉素(mTOR)的哺乳动物靶标。在这项研究中,我们开发了两种纳米颗粒制剂,即聚合物胶束(IP2K)和白蛋白纳米颗粒(IBSA),以溶解极疏水和不溶的ITA,从而可以进行静脉内给药和药代动力学(PK)/药效学(PD)比较。尽管没有一种制剂对非小细胞肺癌(NSCLC)细胞显示出强大的抗增殖能力在体外,当以相同的ITA剂量对NSCLC患者衍生的异种移植(PDX)模型给药时,IBSA会延迟,而IP2K会加速肿瘤的生长。我们将这种悖论的原因归因于依赖制剂的PK和血管操纵:IBSA表现出更持久的PK,C max为IP2K的60%至70%,AUC约为IP2K的2倍,并缓解了肿瘤的缺氧。正常化。与此相反,高Ç最大IP2K的通过强大的血管生成抑制作用,这可能加剧癌症侵袭性和加速肿瘤生长升高肿瘤缺氧。此外,与IP2K相比,IBSA诱导的肝脏和血液学毒性最小,并显着增强了体内当联合使用时,紫杉醇白蛋白纳米颗粒具有抑制肿瘤的活性。这些发现表明,配方和药代动力学是设计ITA血管生成疗法时应考虑的关键方面,IBSA可能被评估为可与其他抗癌药物联合使用的新型安全多靶血管生成疗法。