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
{"title":"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","authors":"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","doi":"10.1016/j.ijpx.2023.100225","DOIUrl":null,"url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":null,"pages":null},"PeriodicalIF":5.2000,"publicationDate":"2023-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590156723000695/pdfft?md5=3b125d769dd69d3e0eed17cee103de1e&pid=1-s2.0-S2590156723000695-main.pdf","citationCount":"0","resultStr":"{\"title\":\"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\",\"authors\":\"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\",\"doi\":\"10.1016/j.ijpx.2023.100225\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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.</p></div>\",\"PeriodicalId\":14280,\"journal\":{\"name\":\"International Journal of Pharmaceutics: X\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.2000,\"publicationDate\":\"2023-12-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2590156723000695/pdfft?md5=3b125d769dd69d3e0eed17cee103de1e&pid=1-s2.0-S2590156723000695-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Pharmaceutics: X\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2590156723000695\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Pharmaceutics: X","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2590156723000695","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
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.