Oral 4-(N)-stearoyl gemcitabine nanoparticles inhibit tumor growth in mouse models.
Oral 4-(N)-stearoyl gemcitabine nanoparticles inhibit tumor growth in mouse models.
复制标题
口服 4-(N)-硬脂酰吉西他滨纳米颗粒抑制小鼠模型中的肿瘤生长
DOI：
10.18632/oncotarget.21264
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发表时间：
2017-10-27
期刊：
影响因子：
--
通讯作者：
Cui Z
中科院分区：
文献类型：
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作者：
Wang C;Zheng Y;Sand Oval MA;Valdes SA;Chen Z;Lansakara-P DS;Du M;Shi Y;Cui Z
尽管最近靶向肿瘤治疗取得了进展，但使用细胞毒药物的全身化疗仍然是一种重要的癌症治疗方式。吉西他滨是一种核苷类似物，通常用于治疗各种实体肿瘤，但口服吉西他滨剂型仍未推出。此前，我们通过将吉西他滨的酰胺前体药物4-(N)-硬脂酰吉西他滨(GemC18)掺入到固体脂质纳米粒中，开发了4-(N)-硬脂酰吉西他滨固体脂质纳米粒(GemC18-SLNS)。静脉给药时，GemC18-SLNS对多种人和小鼠肿瘤模型显示出很强的抗肿瘤活性。在本研究中，我们确定了健康小鼠口服GemC18-SLNS时吉西他滨的血浆药代动力学，并评价了GemC18-SLNS在小鼠肺癌模型中的抗肿瘤活性。在口服GemC18-SLNS的小鼠中，吉西他滨的血药浓度经历了一个吸收阶段和清除阶段，Tmax为~2小时，吉西他滨在GemC18-SLNS中的绝对口服生物利用度为~70%(以AUC0-24 h为基础)。在预先建立肿瘤的小鼠(即小鼠TC-1或LLC肺癌细胞)中，口服GemC18-SLNS显著抑制肿瘤生长并延长小鼠的存活时间，与同等摩尔剂量的GemC18或GemC18在植物油或吐温20中的作用相比。免疫组织化学染色显示，口服GemC18-SLNS对LLC肿瘤也具有显著的抗增殖、抗血管生成和促凋亡活性。将吉西他滨的亲脂酰胺前药制成固体脂质纳米粒可能是开发安全有效的吉西他滨口服制剂的一种可行的方法。
In spite of recent advances in targeted tumor therapy, systemic chemotherapy with cytotoxic agents remains a vital cancer treatment modality. Gemcitabine is a nucleoside analog commonly used in the treatment of various solid tumors, but an oral gemcitabine dosage form remain unavailable. Previously, we developed the 4-(N)-stearoyl gemcitabine solid lipid nanoparticles (GemC18-SLNs) by incorporating 4-(N)-stearoyl gemcitabine (GemC18), an amide prodrug of gemcitabine, into solid lipid nanoparticles. GemC18-SLNs, when administered intravenously, showed strong antitumor activity against various human and mouse tumors in mouse models. In the present study, we defined the plasma pharmacokinetics of gemcitabine when GemC18-SLNs were given orally to healthy mice and evaluated the antitumor activity of GemC18-SLNs when given orally in mouse models of lung cancer. In mice orally gavaged with GemC18-SLNs, plasma gemcitabine concentration followed an absorption phase and then clearance phase, with a Tmax of ~2 h. The absolute oral bioavailability of gemcitabine in the GemC18-SLNs was ~70% (based on AUC0-24 h values). In mice with pre-established tumors (i.e. mouse TC-1 or LLC lung cancer cells), oral GemC18-SLNs significantly inhibited the tumor growth and increased mouse survival time, as compared to the molar equivalent dose of gemcitabine hydrochloride or GemC18 in vegetable oil or in Tween 20. Immunohistostaining revealed that oral GemC18-SLNs also have significant antiproliferative, antiangiogenic, and proapoptotic activity in LLC tumors. Formulating a lipophilic amide prodrug of gemcitabine into solid lipid nanoparticles may represent a viable approach toward developing a safe and efficacious gemcitabine oral dosage form.