低能量自发制备用于诱导结直肠癌癌症细胞凋亡的槲皮素负载橙油纳米乳液

摘要(中文译文)

植物化学物作为抗癌剂具有潜在应用价值。本研究考察了槲皮素、冷压橙皮油及其混合物在天然状态、胶束分散体和纳米乳液中诱导HCT116和Caco-2结直肠癌细胞凋亡的活性。采用气相色谱分析表征橙油组成。开发了不同的增溶系统，以将这些植物化学物载入自乳化浓缩液中，该浓缩液滴加入水后可自发形成胶束分散体和纳米乳液。进行了多项评价以表征纳米乳液，并开展了一些生物学评价，包括细胞毒性、细胞凋亡、蛋白表达和活性氧检测。气相色谱分析显示，d-柠檬烯是橙油中的主要成分（占89%）。由单一表面活性剂以及两种表面活性剂与助表面活性剂混合物组成的系统能够将500 mg槲皮素和5%橙油载入100 ml纳米乳液中。纳米乳液的粒径范围为12 ± 0.09 nm至27 ± 0.1 nm，取决于所载入的植物化学物，z电位值在-0.9 mV范围内。槲皮素和橙油的包封率均>93%，且两种成分从制剂中的释放均呈现可控的时间依赖性特征。天然状态的槲皮素和橙油对受试结直肠癌细胞表现出细胞毒性和促凋亡活性，而将这两种植物化学物联合后该活性增强。与未配制的天然状态相比，这些植物化学物的胶束分散体和纳米乳液形式显示出增强的细胞毒性、促凋亡活性和活性氧水平，表明纳米颗粒具有强大效应。此外，与使用单一表面活性剂制备的纳米乳液相比，使用两种表面活性剂混合物制备的纳米乳液通过下调CDC25A、PI3k和Bcl-2表达水平并上调Bax表达，表现出最佳的细胞毒性和晚期凋亡活性。将槲皮素和橙油联合制备于共配制纳米乳液中可被视为一种有前景的配方，可作为处方规定药物的佐剂加以研究，以增强其抗结直肠癌细胞的活性。

Abstract

Phytochemicals showed potential application as anticancer agents. In the current investigation, quercetin, cold-pressed orange peel oil, and their mixture in their natural state and in micellar dispersion and nanoemulsions were examined for their activity to induce HCT116 and Caco-2 colorectal cancer cells to apoptosis. Gas chromatographic analysis was used to characterize orange oil composition. Different solubilization systems were developed in order to incorporate these phytochemicals into a self emulsifyable concentrate that spontaneously forms micellar dispersions and nanoemulsions upon titration into water. Different evaluations were performed to characterize the nanoemulsions. Some biological evaluations including cytotoxicity, apoptosis, protein expression, and reactive oxygen species were also performed. Gas chromatographic analysis showed that d-limonene is the major constituent contained (89%) of orange oil. Systems composed of a single surfactant and a mixture of two surfactants and a cosurfactant were able to incorporate 500 mg quercetin and 5% orange oil in 100 ml nanoemulsions. The particle size of the nanoemulsions ranges between 12 ± 0.09 nm and 27 ± 0.1 nm, depending on the incorporated phytochemical, with z-potential value in the range of -0.9 mV. Encapsulation efficiency for both quercetin and orange oil was > 93% and the release from the formulations exhibited a controlled, time-dependent profile for both quercetin and orange oil. Quercetin and orange oil in their natural state showed cytotoxic and apoptotic activity against the tested colorectal cancer cells, which is enhanced upon combining these phytochemicals. The micellar dispersions and nanoemulsion form of these phytochemicals showed enhanced cytotoxicity, apoptotic activity, and ROS levels compared to their unformulated natural states indicating the powerful effect of nanoparticles. Moreover, nanoemulsion fabricated with a mixture of two surfactants showed the best cytotoxic and late apoptotic activity through downregulation of CDC25A, PI3k, and Bcl-2 expression levels and upregulation of Bax expression compared to nanoemulsion made using a single surfactant. Combining quercetin and orange oil in a co-fabricated nanoemulsion could be considered a promising formula that could be examined as an adjuvant to the protocol-prescribed drugs to enhance their activity against colorectal cancer cells.

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