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      Self-Nanoemulsifying Drug Delivery System of Genkwanin: A Novel Approach for Anti-Colitis-Associated Colorectal Cancer

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          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.


          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.


          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.


          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.

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          Most cited references 76

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          Inflammasomes and Cancer.

          Inflammation affects all stages of tumorigenesis. A key signaling pathway leading to acute and chronic inflammation is through activation of the caspase-1 inflammasome. Inflammasome complexes are assembled on activation of certain nucleotide-binding domain, leucine-rich repeat-containing proteins (NLR), AIM2-like receptors, or pyrin. Of these, NLRP1, NLRP3, NLRC4, NLRP6, and AIM2 influence the pathogenesis of cancer by modulating innate and adaptive immune responses, cell death, proliferation, and/or the gut microbiota. Activation of the inflammasome and IL18 signaling pathways is largely protective in colitis-associated colorectal cancer, whereas excessive inflammation driven by the inflammasome or the IL1 signaling pathways promotes breast cancer, fibrosarcoma, gastric carcinoma, and lung metastasis in a context-dependent manner. The clinical relevance of inflammasomes in multiple forms of cancer highlights their therapeutic promise as molecular targets. In this review, we explore the crossroads between inflammasomes and the development of various tumors and discuss possible therapeutic values in targeting the inflammasome for the prevention and treatment of cancer. Cancer Immunol Res; 5(2); 94-99. ©2017 AACR.
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            Intestinal barrier in inflammatory bowel disease.

            A complex mucosal barrier protects as the first line of defense the surface of the healthy intestinal tract from adhesion and invasion by luminal microorganisms. In this review, we provide an overview about the major components of this protective system as for example an intact epithelium, the synthesis of various antimicrobial peptides (AMPs) and the formation of the mucus layer. We highlight the crucial importance of their correct functioning for the maintenance of a proper intestinal function and the prevention of dysbiosis and disease. Barrier disturbances including a defective production of AMPs, alterations in thickness or composition of the intestinal mucus layer, alterations of pattern-recognition receptors, defects in the process of autophagy as well as unresolved endoplasmic reticulum stress result in an inadequate host protection and are thought to play a crucial role in the pathogenesis of the inflammatory bowel diseases Crohn's disease and ulcerative colitis.
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              Development and bioavailability assessment of ramipril nanoemulsion formulation.

              The objective of our investigation was to design a thermodynamically stable and dilutable nanoemulsion formulation of Ramipril, with minimum surfactant concentration that could improve its solubility, stability and oral bioavailability. Formulations were taken from the o/w nanoemulsion region of phase diagrams, which were subjected to thermodynamic stability and dispersibility tests. The composition of optimized formulation was Sefsol 218 (20% w/w), Tween 80 (18% w/w), Carbitol (18% w/w) and standard buffer solution pH 5 (44% w/w) as oil, surfactant, cosurfactant and aqueous phase, respectively, containing 5 mg of ramipril showing drug release (95%), droplet size (80.9 nm), polydispersity (0.271), viscosity (10.68 cP), and infinite dilution capability. In vitro drug release of the nanoemulsion formulations was highly significant (p<0.01) as compared to marketed capsule formulation and drug suspension. The relative bioavailability of ramipril nanoemulsion to that of conventional capsule form was found to be 229.62% whereas to that of drug suspension was 539.49%. The present study revealed that ramipril nanoemulsion could be used as a liquid formulation for pediatric and geriatric patients and can be formulated as self-nanoemulsifying drug delivery system (SNEDDS) as a unit dosage form.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                12 February 2021
                : 15
                : 557-576
                [1 ]School of Traditional Chinese Pharmacy, China Pharmaceutical University , Nanjing, 210009, Jiangsu, People’s Republic of China
                [2 ]Jiangxi QingFeng Pharmaceutical Co., Ltd , Ganzhou, 341000, Jiangxi, People’s Republic of China
                [3 ]Emergency Department, The First Affiliated Hospital of Gannan Medical University , Ganzhou, 341000, Jiangxi, People’s Republic of China
                [4 ]School of Chinese Materia Medical, Beijing University of Chinese Medicine , Beijing, People’s Republic of China
                [5 ]Shanghai University of Traditional Chinese Medicine , Shanghai, 201203, People’s Republic of China
                [6 ]School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Hong Kong SAR, People’s Republic of China
                Author notes
                Correspondence: Xin He School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong , Shatin, Hong Kong SAR, People’s Republic of ChinaTel +852-54445989 Email xhe06@qub.ac.uk
                Chun-Feng Zhang School of Traditional Chinese Pharmacy, China Pharmaceutical University , Nanjing, 210009, People’s Republic of ChinaTel +86-25-86185129 Email zhangchunfeng67@163.com
                © 2021 Yin et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 6, Tables: 9, References: 76, Pages: 20
                Original Research


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