通过pH触发的超弹性纳米颗粒将塞来昔布重新用于结直肠癌靶向治疗:在DMH诱导的肿瘤发生过程中通过上调Wnt/β-catenin通路提高疗效

IF 5.2 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Shahira F. El Menshawe , Khaled Shalaby , Mohammed H. Elkomy , Heba M. Aboud , Yasmin M. Ahmed , Abdelmeged A. Abdelmeged , Marwa Elkarmalawy , Mahmoud A. Abou Alazayem , Amani M. El Sisi
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引用次数: 0

摘要

塞来昔布(CLX)是一种环氧化酶 2(COX-2)的选择性抑制剂,对多种癌症具有潜在活性。然而,低生物利用度和心血管副作用仍然是限制其应用的主要挑战。在这项工作中,我们开发了具有 pH 触发表面电荷反转特性的超弹性纳米颗粒(UENVs),可将 CLX 有效地输送到结直肠部位,实现滚雪球式肿瘤靶向。CLX-UENV是通过薄膜水合方法制成的。采用方框-贝肯设计法评估了配方因素(Span 80、Tween 80和超声时间)对纳米囊泡特征的影响,并计算出了最佳配方。最佳配方是正包覆聚乙烯亚胺(CLX-PEI-UENVs),然后包覆 Eudragit S100(CLX-ES-PEI-UENVs)。在 1,2-二甲基肼诱导的 Wistar 大鼠结直肠癌中,对优化后的纳米货物的活性进行了探索。评估了大鼠结肠中 COX-2、Wnt-2 和 β-catenin 的水平。优化后的 CLX-ES-PEI-UENVs 制剂直径为 253.62 nm,zeta 电位为 -23.24 mV,夹带率为 85.64%,累积释放率为 87.20%(24 h)。ES 包衣阻碍了 CLX 在酸性环境(胃和早期小肠)中的快速释放,并显示出在结肠部分的释放时间延长。在结肠环境中,由于 pH 值较高,ES 涂层被去除,纳米囊冠上的电荷从负电荷转变为正电荷。此外,药代动力学研究表明,CLX-ES-PEI-UENVs 的口服生物利用度比 CLX 悬浮液高 2.13 倍。总之,这些研究结果表明,CLX-ES-PEI-UENVs可以通过上调Wnt/β-catenin通路,成为一种很有前景的结直肠靶向纳米平台,从而有效治疗肿瘤。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Repurposing celecoxib for colorectal cancer targeting via pH-triggered ultra-elastic nanovesicles: Pronounced efficacy through up-regulation of Wnt/β-catenin pathway in DMH-induced tumorigenesis

Repurposing celecoxib for colorectal cancer targeting via pH-triggered ultra-elastic nanovesicles: Pronounced efficacy through up-regulation of Wnt/β-catenin pathway in DMH-induced tumorigenesis

Celecoxib (CLX), a selective inhibitor for cyclooxygenase 2 (COX-2), has manifested potential activity against diverse types of cancer. However, low bioavailability and cardiovascular side effects remain the major challenges that limit its exploitation. In this work, we developed ultra-elastic nanovesicles (UENVs) with pH-triggered surface charge reversal traits that could efficiently deliver CLX to colorectal segments for snowballed tumor targeting. CLX-UENVs were fabricated via a thin-film hydration approach. The impact of formulation factors (Span 80, Tween 80, and sonication time) on the nanovesicular features was evaluated using Box–Behnken design, and the optimal formulation was computed. The optimum formulation was positively coated with polyethyleneimine (CLX-PEI-UENVs) and then coated with Eudragit S100 (CLX-ES-PEI-UENVs). The activity of the optimized nano-cargo was explored in 1,2-dimethylhydrazine-induced colorectal cancer in Wistar rats. Levels of COX-2, Wnt-2 and β-catenin were assessed in rats' colon. The diameter of the optimized CLX-ES-PEI-UENVs formulation was 253.62 nm, with a zeta potential of −23.24 mV, 85.64% entrapment, and 87.20% cumulative release (24 h). ES coating hindered the rapid release of CLX under acidic milieu (stomach and early small intestine) and showed extended release in the colon section. In colonic environments, the ES coating layer was removed due to high pH, and the charge on the nanovesicular corona was shifted from negative to positive. Besides, a pharmacokinetics study revealed that CLX-ES-PEI-UENVs had superior oral bioavailability by 2.13-fold compared with CLX suspension. Collectively, these findings implied that CLX-ES-PEI-UENVs could be a promising colorectal-targeted nanoplatform for effective tumor management through up-regulation of the Wnt/β-catenin pathway.

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来源期刊
International Journal of Pharmaceutics: X
International Journal of Pharmaceutics: X Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
6.60
自引率
0.00%
发文量
32
审稿时长
24 days
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