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Abstract：
Gemcitabine (Gem) has been a standard first-line drug for pancreatic cancer (PCa) treatment; however, Gem\'s rapid metabolism and systemic instability (short half-life) limit its clinical outcome. The objective of this study was to modify Gem into a more stable form called 4-(N)-stearoyl-gemcitabine (4NSG) and evaluate its therapeutic efficacy in patient-derived xenograft (PDX) models from PCa of Black and White patients.Methods 4NSG was synthesized and characterized using nuclear magnetic resonance (NMR), elemental analysis, and high-performance liquid chromatography (HPLC). 4NSG-loaded solid lipid nanoparticles (4NSG-SLN) were developed using the cold homogenization technique and characterized. Patient-derived pancreatic cancer cell lines labeled Black (PPCL-192, PPCL-135) and White (PPCL-46, PPCL-68) were used to assess the in vitro anticancer activity of 4NSG-SLN. Pharmacokinetics (PK) and tumor efficacy studies were conducted using PDX mouse models bearing tumors from Black and White PCa patients.Results 4NSG was significantly stable in liver microsomal solution. The effective mean particle size (hydrodynamic diameter) of 4NSG-SLN was 82 ± 6.7 nm, and the half maximal inhibitory concentration (IC50) values of 4NSG-SLN treated PPCL-192 cells (9 ± 1.1 µM); PPCL-135 (11 ± 1.3 µM); PPCL-46 (12 ± 2.1) and PPCL-68 equaled to 22 ± 2.6 were found to be significantly lower compared to Gem treated PPCL-192 (57 ± 1.5 µM); PPCL-135 (56 ± 1.5 µM); PPCL-46 (56 ± 1.8 µM) and PPCL-68 (57 ± 2.4 µM) cells. The area under the curve (AUC), half-life, and pharmacokinetic clearance parameters for 4NSG-SLN were 3-fourfold higher than that of GemHCl. For in-vivo studies, 4NSG-SLN exhibited a two-fold decrease in tumor growth compared with GemHCl in PDX mice bearing Black and White PCa tumors.Conclusion 4NSG-SLN significantly improved the Gem\'s pharmacokinetic profile, enhanced Gem\'s systemic stability increased its antitumor efficacy in PCa PDX mice bearing Black and White patient tumors.
摘要：
吉西他滨（Gem）一直是胰腺癌（PCa）治疗的标准一线药物；然而，宝石的快速代谢和全身不稳定（半衰期短）限制了其临床结果。这项研究的目的是将Gem修饰成更稳定的形式，称为4-（N）-硬脂酰-吉西他滨（4NSG），并评估其在来自黑白PCa的患者来源的异种移植（PDX）模型中的疗效患者患者患者。方法合成4NSG并用核磁共振(NMR)对其进行表征,元素分析,和高效液相色谱（HPLC）。使用冷均质化技术开发了4NSG负载的固体脂质纳米颗粒（4NSG-SLN）并进行了表征。标记为黑色(PPCL-192,PPCL-135)和白色(PPCL-46,PPCL-68)的患者来源的胰腺癌细胞系用于评估4NSG-SLN的体外抗癌活性。使用携带来自黑色和白色PCa患者的肿瘤的PDX小鼠模型进行药代动力学(PK)和肿瘤功效研究。结果4NSG在肝微粒体溶液中显著稳定。4NSG-SLN的有效平均粒径（流体动力学直径）为82±6.7nm，4NSG-SLN处理的PPCL-192细胞的半数最大抑制浓度（IC50）值（9±1.1µM）；PPCL-135（11±1.3µM）；PPCL-46（12±2.1）和PPCL-68与Gem处理的PPCL-192µ（57µ1.5M）相比显着降低。PL-135（P46±PCM-2.4）曲线下面积（AUC），半衰期,4NSG-SLN的药代动力学清除参数比GemHCl高3-4倍。对于体内研究，在携带黑色和白色PCa肿瘤的PDX小鼠中,与GemHCl相比,4NSG-SLN表现出肿瘤生长降低两倍。结论4NSG-SLN能显著改善Gem的药代动力学,增强Gem的系统稳定性增加了其在携带黑白患者肿瘤的PCaPDX小鼠中的抗肿瘤功效。
