新型 5-氟尿嘧啶碳酸酯负载脂质体：作为抗肿瘤剂的制备、体外和体内评价,Molecular Pharmaceutics

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新型 5-氟尿嘧啶碳酸酯负载脂质体：作为抗肿瘤剂的制备、体外和体内评价
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2022-06-22 , DOI: 10.1021/acs.molpharmaceut.1c00820
Xuelei Wang ₁ , Apeng Wang ₁ , Wenkai Feng ₁ , Dan Wang ₁ , Xiaoru Guo ₁ , Xiaowei Wang ₁ , Qingfang Miao ₁ , Mingliang Liu ₁ , Guimin Xia ₁

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5-氟尿嘧啶 (5-FU) 是一种针对多种癌症，尤其是结直肠癌的化疗药物。但其血浆半衰期短，不良反应严重，限制了其广泛的临床应用。为了克服这些缺点，一种新型的亲脂性 5-FU 碳酸盐 [XL-01, (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2 H)-yl)甲基十四烷基碳酸酯]通过配方筛选和优化，采用薄膜分散法设计、合成并封装成脂质体(LipoXL-01)。LipoXL-01的特点是粒径约为100 nm，多分散指数为0.200，ζ-电位值为-41 mV，封装效率为93.9%，载药效率为11.6%。LipoXL-01 的细胞摄取在 HCT15 细胞上以浓度依赖性方式增加。LipoXL-01比5-FU更能增强HCT15细胞诱导细胞凋亡和抑制细胞迁移和阻滞S期细胞周期的能力。此外，LipoXL-01 表现出缓慢的药物释放曲线，在 8 小时内累积释放率为 12%。药代动力学和生物分布研究结果表明，LipoXL-01 具有较长的血浆半衰期（7.21 小时）和较高的肿瘤蓄积量（8 小时时为 733 nmol/g）。这体内抗肿瘤作用研究还表明，LipoXL-01 比 5-FU 具有更有效的功效（65% vs 48% 的肿瘤抑制率）。同时，通过分析受试小鼠的体重以及血液学和病理学参数，观察到可忽略不计的全身毒性。目前的研究表明，LipoXL-01 可能是用于结直肠癌化疗的有前途的纳米候选物。

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Novel 5-Fluorouracil Carbonate-Loaded Liposome: Preparation, In Vitro, and In Vivo Evaluation as an Antitumor Agent

5-Fluorouracil (5-FU) is a chemotherapeutic drug against many types of cancers, especially colorectal cancer. However, its short plasma half-life and serious adverse reactions limit its wide clinical applications. To overcome these shortcomings, a novel lipophilic 5-FU carbonate [XL-01, (5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) methyl tetradecyl carbonate] was designed, synthesized, and encapsulated into liposome (LipoXL-01) by a thin-film dispersion method through formulation screening and optimization. LipoXL-01 was characterized by a particle size of around 100 nm, polydispersity index of 0.200, ζ-potential value of −41 mV, encapsulation efficiency of 93.9%, and drug-loading efficiency of 11.6%. The cellular uptake of LipoXL-01 was increased in a concentration-dependent manner on HCT15 cells. LipoXL-01 could enhance the induction of cell apoptosis and the inhibition of cell migration and arrest the ability of the cell cycle at the S-phase on HCT15 cells better than 5-FU. Additionally, LipoXL-01 exhibited a slow drug release profile with a cumulative release rate of 12% in 8 h. The results of pharmacokinetic and biodistribution studies revealed that LipoXL-01 had a long plasma half-life (7.21 h) and a high tumor accumulation (733 nmol/g at 8 h). The in vivo antitumor effect study also showed that LipoXL-01 had more potent efficacy than 5-FU (65 vs 48% of the tumor-inhibition rate). Simultaneously, negligible systemic toxicity was observed via analyzing the body weight as well as hematological and pathological parameters in the tested mice. The current study suggested that LipoXL-01 might be a promising nanocandidate for chemotherapy of colorectal cancer.

更新日期：2022-06-22

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