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

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.

SUBMITTER: Xie M

PROVIDER: S-EPMC6788343 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Xie Minghua M Wu Jia J Ji Liqaing L Jiang Xiaorui X Zhang Jin J Ge Min M Cai Xinjun X

Frontiers in oncology 20191003

<b>Purpose:</b> 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. <b>Methods:</b> 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 (se ...[more]

PMID: 31637212

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Project description:The development of HIV protease inhibitors (PIs) has been one of the most significant advances of the past decade in controlling HIV infection. Unfortunately, the benefits of HIV PIs are compromised by serious side effects. One of the most frequent and deleterious side effects of HIV PIs is severe gastrointestinal (GI) disorders including mucosal erosions, epithelial barrier dysfunction, and leak-flux diarrhea, which occurs in 16-62% of patients on HIV PIs. Although the underlying mechanisms behind HIV PI-associated serious adverse side effects remain to be identified, our recent studies have shown that activation of endoplasmic reticulum (ER) stress response plays a critical role in HIV PI-induced GI complications. The objective of this study was to develop a novel self-microemulsifying drug delivery system (SMEDDS) using various antioxidants as surfactants and cosurfactants to reduce the GI side effects of the most commonly used HIV PI, ritonavir. The biological activities of this SMSDDS of ritonavir were compared with that of Norvir, which is currently used in the clinic. Rat normal intestinal epithelial cells (IEC-6) and mouse Raw 264.7 macrophages were used to examine the effect of new SMEDDS of ritonavir on activation of ER stress and oxidative stress. Sprague-Dawley rats and C57/BL6 mice were used for pharmacokinetic studies and in vivo studies. The intracellular and plasma drug concentrations were determined by HPLC analysis. Activation of ER stress was detected by Western blot analysis and secreted alkaline phosphatase (SEAP) reporter assay. Reactive oxygen species (ROS) was measured using dichlorodihydrofluorescein diacetate as a probe. Cell viability was determined by Roche's cell proliferation reagent WST-1. Protein levels of inflammatory cytokines (TNF-alpha and IL-6) were determined by enzyme-linked immunosorbent assays (ELISA). The intestinal permeability was assessed by luminal enteral administration of fluorescein isothiocyanate conjugated dextran (FITC-dextran, 4 kDa). The pathologic changes in intestine were determined by histological examination. The results indicated that incorporation of antioxidants in this new SMEDDS not only significantly reduced ritonavir-induced ER stress activation, ROS production and apoptosis in intestinal epithelial cells and macrophages, but also improved the solubility, stability and bioavailability of ritonavir, and significantly reduced ritonavir-induced disruption of intestinal barrier function in vivo. In conclusion, this new SMEDDS of ritonavir has less GI side effects compared to Norvir. This new SMEDDS can be used for other HIV PIs and any insoluble antiviral drug with serious GI side effects.

Dataset Information

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

Publications

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

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