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      Development of Triptolide Self-Microemulsifying Drug Delivery System and Its Anti-tumor Effect on Gastric Cancer Xenografts

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          Abstract

          Purpose: To develop a triptolide (TP) self-microemulsifying drug delivery system and to investigate its anti-tumor effect on human gastric cancer line MGC80-3 xenografts in nude mice.

          Methods: The medium chain triglyceride (MCT) was selected as oil phase; polyoxyethylene castor oil (EL) was selected as surfactant, and PEG-400 was selected as cosurfactant. The mass ratio of each phase was optimized by central composite design and response surface methodology to prepare TP-SMEDDS (self-microemulsifying drug delivery system). The quality of TP-SMEDDS was evaluated, and its inhibitory effect on tumor growth investigated in nude mice transplanted with MGC80-3 cells.

          Results: The final prescription process was defined as follows: MCT mass ratio: 25.3%; EL mass ratio: 49.6%; PEG-400 mass ratio: 25.1%. The prepared TP-SMEDDS was a transparent liquid with a clear appearance (the theoretical particle size: 31.168 nm). On transmission electron microscopy, the microemulsion particles were spherical in size and uniformly distributed without adhesions. The in vitro release experiment showed complete release of the prepared TP-SMEDDS in PBS solution in 6 h. In vivo antitumor activity showed its inhibitory effect in the xenograft model.

          Conclusion: The self-microemulsifying delivery system improved the oral bioavailability and the in vivo antitumor effect of TP.

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          Most cited references 36

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          Triptolide inhibits the growth and metastasis of solid tumors.

          Triptolide (TPL), a diterpenoid triepoxide purified from the Chinese herb Tripterygium wilfordii Hook F, was tested for its antitumor properties in several model systems. In vitro, TPL inhibited the proliferation and colony formation of tumor cells at extremely low concentrations (2-10 ng/ml) and was more potent than Taxol. Likewise, in vivo, treatment of mice with TPL for 2-3 weeks inhibited the growth of xenografts formed by four different tumor cell lines (B16 melanoma, MDA-435 breast cancer, TSU bladder cancer, and MGC80-3 gastric carcinoma), indicating that TPL has a broad spectrum of activity against tumors that contain both wild-type and mutant forms of p53. In addition, TPL inhibited experimental metastasis of B16F10 cells to the lungs and spleens of mice. The antitumor effect of TPL was comparable or superior with that of conventional antitumor drugs, such as Adriamycin, mitomycin, and cisplatin. Importantly, tumor cells that were resistant to Taxol attributable to the overexpression of the multidrug resistant gene 1 were still sensitive to the effects of TPL. Studies on cultured tumor cells revealed that TPL induced apoptosis and reduced the expression of several molecules that regulate the cell cycle. Taken together, these results suggest that TPL has several attractive features as a new antitumor agent.
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            Self-microemulsifying drug delivery system (SMEDDS)--challenges and road ahead.

            Self-microemulsifying drug delivery system (SMEDDS) has emerged as a vital strategy to formulate poor water soluble compounds for bioavailability enhancement. However, certain limitations are associated with SMEDDS formulations which include in vivo drug precipitation, formulation handling issues, limited lymphatic uptake, lack of predictive in vitro tests and oxidation of unsaturated fatty acids. These limitations restrict their potential usage. Inclusion of polymers or precipitation inhibitors within lipid based formulations helps to maintain drug supersaturation after dispersion. This, thereby, improves the bioavailability and reduces the variability on exposure. Also, formulating solid SMEDDS helps to overcome liquid handling and stability problems. Usage of medium chain triglycerides (MCT) and suitable antioxidants to minimize oxidation of unsaturated fatty acids are few of the steps to overcome the limitations associated with SMEDDS. The review discussed here, in detail, the limitations of SMEDDS and suitable measures that can be taken to overcome them.
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              Triptolide Inhibits Lung Cancer Cell Migration, Invasion, and Metastasis.

              Triptolide is an extract from Tripterygium wilfordii used in traditional Chinese medicine to treat autoimmune disorders. Triptolide has anticancer effects in vitro and is reported to impair cancer cell migration. We studied whether triptolide inhibits lung cancer cell migration and metastasis.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                03 October 2019
                2019
                : 9
                Affiliations
                1Department of Pharmacy, First People's Hospital of Yuhang District , Hangzhou, China
                2Department of Pharmacy, Zhejiang Integrated Traditional Chinese and Western Medicine Hospital , Hangzhou, China
                Author notes

                Edited by: Bo Zhang, West China Hospital, Sichuan University, China

                Reviewed by: Mariangela Garofalo, University of Padova, Italy; Hoi Huen Chan, Hong Kong Polytechnic University, Hong Kong; Chi Chun Wong, The Chinese University of Hong Kong, China

                *Correspondence: Min Ge gm682013@ 123456sina.com

                This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2019.00978
                6788343
                Copyright © 2019 Xie, Wu, Ji, Jiang, Zhang, Ge and Cai.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 5, Tables: 4, Equations: 0, References: 39, Pages: 10, Words: 6058
                Funding
                Funded by: Chinese Medicine Research Program of Zhejiang Province 10.13039/501100005199
                Award ID: 2016ZA170
                Funded by: Hangzhou Science and Technology Bureau 10.13039/501100003786
                Funded by: Beijing Medical and Health Foundation 10.13039/501100011930
                Categories
                Oncology
                Original Research

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