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Self-Nanoemulsifying Drug Delivery System of Genkwanin: A Novel Approach for Anti-Colitis-Associated Colorectal Cancer
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2021-02-12 , DOI: 10.2147/dddt.s292417 Hua-Feng Yin 1, 2 , Chun-Ming Yin 3 , Ting Ouyang 4 , Shu-Ding Sun 1 , Wei-Guo Chen 1 , Xiao-Lin Yang 5 , Xin He 6 , Chun-Feng Zhang 1
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2021-02-12 , DOI: 10.2147/dddt.s292417 Hua-Feng Yin 1, 2 , Chun-Ming Yin 3 , Ting Ouyang 4 , Shu-Ding Sun 1 , Wei-Guo Chen 1 , Xiao-Lin Yang 5 , Xin He 6 , Chun-Feng Zhang 1
Affiliation
Purpose: The aim of the present study was to develop an optimized Genkwanin (GKA)-loaded self-nanoemulsifying drug delivery system (SNEDDS) formulation to enhance the solubility, intestinal permeability, oral bioavailability and anti-colitis-associated colorectal cancer (CAC) activity of GKA.
Methods: We designed a SNEDDS comprised oil phase, surfactants and co-surfactants for oral administration of GKA, the best of which were selected by investigating the saturation solubility, constructing pseudo-ternary phase diagrams, followed by optimizing thermodynamic stability, emulsification efficacy, self-nanoemulsification time, droplet size, transmission electron microscopy (TEM), drug release and intestinal permeability. In addition, the physicochemical properties and pharmacokinetics of GKA-SNEDDS were characterized, and its anti-colitis-associated colorectal cancer (CAC) activity and potential mechanisms were evaluated in AOM/DSS-induced C57BL/6J mice model.
Results: The optimized nanoemulsion formula (OF) consists of Maisine CC, Labrasol ALF and Transcutol HP in a weight ratio of 20:60:20 (w/w/w), in which ratio the OF shows multiple improvements, specifically small mean droplet size, excellent stability, fast release properties as well as enhanced solubility and permeability. Pharmacokinetic studies demonstrated that compared with GKA suspension, the relative bioavailability of GKA-SNEDDS was increased by 353.28%. Moreover, GKA-SNEDDS not only significantly prevents weight loss and improves disease activity index (DAI) but also reduces the histological scores of inflammatory cytokine levels as well as inhibiting the formation of colon tumors via inducing tumor cell apoptosis in the AOM/DSS-induced CAC mice model.
Conclusion: Our results show that the developed GKA-SNEDDS exhibited enhanced oral bioavailability and excellent anti-CAC efficacy. In summary, GKA-SNEDDS, using lipid nanoparticles as the drug delivery carrier, can be applied as a potential drug delivery system for improving the clinical application of GKA.
Keywords: insoluble herbal drug, nanoparticle-based drug delivery system, intestinal permeability, pharmacokinetics, anticancer efficacy
中文翻译：
芩宽宁自纳米乳化给药系统：抗结肠炎相关结直肠癌的新方法
目的：本研究的目的是开发一种优化的芫花素（GKA）负载自纳米乳化药物递送系统（SNEDDS）制剂，以提高溶解度、肠道通透性、口服生物利用度和抗结肠炎相关结直肠癌（CAC） GKA 的活性。
方法：我们设计了一种由油相、表面活性剂和助表面活性剂组成的口服 GKA SNEDDS，通过研究饱和溶解度、构建伪三元相图来选择最佳的 SNEDDS，然后优化热力学稳定性、乳化功效、自-纳米乳化时间、液滴大小、透射电子显微镜（TEM）、药物释放和肠道渗透性。此外，还对 GKA-SNEDDS 的理化性质和药代动力学进行了表征，并在 AOM/DSS 诱导的 C57BL/6J 小鼠模型中评估了其抗结肠炎相关结直肠癌 (CAC) 活性和潜在机制。
结果：优化后的纳米乳液配方（OF）由Maisine CC、Labrasol ALF和Transcutol HP组成，重量比为20:60:20（w/w/w），其中OF显示出多项改进，特别是平均液滴小尺寸、优异的稳定性、快速释放特性以及增强的溶解度和渗透性。药代动力学研究表明，与GKA混悬液相比，GKA-SNEDDS的相对生物利用度提高了353.28%。此外，GKA-SNEDDS不仅显着防止体重减轻和改善疾病活动指数（DAI），而且还降低炎症细胞因子水平的组织学评分，并通过诱导AOM/DSS诱导的肿瘤细胞凋亡来抑制结肠肿瘤的形成CAC小鼠模型。
结论：我们的结果表明，开发的 GKA-SNEDDS 具有增强的口服生物利用度和优异的抗 CAC 功效。综上所述，以脂质纳米粒为药物递送载体的GKA-SNEDDS可以作为一种潜在的药物递送系统，提高GKA的临床应用。
关键词:难溶性草药, 纳米颗粒给药系统, 肠道通透性, 药代动力学, 抗癌功效
更新日期：2021-04-20
Methods: We designed a SNEDDS comprised oil phase, surfactants and co-surfactants for oral administration of GKA, the best of which were selected by investigating the saturation solubility, constructing pseudo-ternary phase diagrams, followed by optimizing thermodynamic stability, emulsification efficacy, self-nanoemulsification time, droplet size, transmission electron microscopy (TEM), drug release and intestinal permeability. In addition, the physicochemical properties and pharmacokinetics of GKA-SNEDDS were characterized, and its anti-colitis-associated colorectal cancer (CAC) activity and potential mechanisms were evaluated in AOM/DSS-induced C57BL/6J mice model.
Results: The optimized nanoemulsion formula (OF) consists of Maisine CC, Labrasol ALF and Transcutol HP in a weight ratio of 20:60:20 (w/w/w), in which ratio the OF shows multiple improvements, specifically small mean droplet size, excellent stability, fast release properties as well as enhanced solubility and permeability. Pharmacokinetic studies demonstrated that compared with GKA suspension, the relative bioavailability of GKA-SNEDDS was increased by 353.28%. Moreover, GKA-SNEDDS not only significantly prevents weight loss and improves disease activity index (DAI) but also reduces the histological scores of inflammatory cytokine levels as well as inhibiting the formation of colon tumors via inducing tumor cell apoptosis in the AOM/DSS-induced CAC mice model.
Conclusion: Our results show that the developed GKA-SNEDDS exhibited enhanced oral bioavailability and excellent anti-CAC efficacy. In summary, GKA-SNEDDS, using lipid nanoparticles as the drug delivery carrier, can be applied as a potential drug delivery system for improving the clinical application of GKA.
Keywords: insoluble herbal drug, nanoparticle-based drug delivery system, intestinal permeability, pharmacokinetics, anticancer efficacy
中文翻译：
芩宽宁自纳米乳化给药系统：抗结肠炎相关结直肠癌的新方法
目的：本研究的目的是开发一种优化的芫花素（GKA）负载自纳米乳化药物递送系统（SNEDDS）制剂，以提高溶解度、肠道通透性、口服生物利用度和抗结肠炎相关结直肠癌（CAC） GKA 的活性。
方法：我们设计了一种由油相、表面活性剂和助表面活性剂组成的口服 GKA SNEDDS，通过研究饱和溶解度、构建伪三元相图来选择最佳的 SNEDDS，然后优化热力学稳定性、乳化功效、自-纳米乳化时间、液滴大小、透射电子显微镜（TEM）、药物释放和肠道渗透性。此外，还对 GKA-SNEDDS 的理化性质和药代动力学进行了表征，并在 AOM/DSS 诱导的 C57BL/6J 小鼠模型中评估了其抗结肠炎相关结直肠癌 (CAC) 活性和潜在机制。
结果：优化后的纳米乳液配方（OF）由Maisine CC、Labrasol ALF和Transcutol HP组成，重量比为20:60:20（w/w/w），其中OF显示出多项改进，特别是平均液滴小尺寸、优异的稳定性、快速释放特性以及增强的溶解度和渗透性。药代动力学研究表明，与GKA混悬液相比，GKA-SNEDDS的相对生物利用度提高了353.28%。此外，GKA-SNEDDS不仅显着防止体重减轻和改善疾病活动指数（DAI），而且还降低炎症细胞因子水平的组织学评分，并通过诱导AOM/DSS诱导的肿瘤细胞凋亡来抑制结肠肿瘤的形成CAC小鼠模型。
结论：我们的结果表明，开发的 GKA-SNEDDS 具有增强的口服生物利用度和优异的抗 CAC 功效。综上所述，以脂质纳米粒为药物递送载体的GKA-SNEDDS可以作为一种潜在的药物递送系统，提高GKA的临床应用。
关键词:难溶性草药, 纳米颗粒给药系统, 肠道通透性, 药代动力学, 抗癌功效
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