Tissue Distribution, Excretion, and Interaction With Human Serum Albumin of Total Bioflavonoid Extract From Selaginella doederleinii.

Selaginella doederleinii Hieron is a traditional Chinese medicinal herb widely used to treat different cancers. Previously, we showed that the total bioflavonoid extract of S. doederleinii (TBESD) exhibits anti-carcinogenic activities both in vitro and in vivo. However, the plasma protein binding and pharmacokinetics parameters of TBESD remain unclear. To investigate plasma protein binding, tissue distribution, and excretion of TBESD, rats were administered a single dose of TBESD (600 mg/kg) intragastrically and tissue distribution and excretion of TBESD components were determined by rapid high-performance liquid chromatography and tandem mass spectrometry. TBESD binding to human serum albumin (HSA) was assessed by fluorescence spectroscopy. TBESD components amentoflavone, delicaflavone, robustaflavone, 2″,3″-dihydro-3',3‴-biapigenin, and 3',3‴-binaringenin were rapidly absorbed and distributed in various tissues, mostly in the lungs, kidneys, and ovaries, without long-term accumulation. The excretion of bioflavonoids occurred mostly via the intestinal tract and constituted 30% of the administered dose up to 48 h. Spectral analysis indicated that TBESD had a dynamic quenching effect on HSA by binding to one HSA site through hydrophobic interactions and hydrogen bond formation. This is the first comprehensive report on the tissue distribution, excretion, and plasma protein binding of TBESD. This study provides important information on TBESD pharmacokinetics necessary for its further development into a therapeutic form for clinical applications.

Disclosing targets and pharmacological mechanisms of total bioflavonoids extracted from Selaginella doederleinii against non-small cell lung cancer by combination of network pharmacology and proteomics.

ETHNOPHARMACOLOGICAL RELEVANCE: Previously, the total bioflavonoids extract from Selaginella doederleinii (SDTBE) presented favorable in vitro and in vivo activities against non-small cell lung cancer (NSCLC), hinting at its medicinal potential. However, up to nowadays, targets and integrative action mechanisms of SDTBE are still not very clear, which presents an obstacle to the development of herbal medicine. AIM OF THE STUDY: The present study aimed to disclose the potential targets and integrative action mechanism of SDTBE against NSCLC. MATERIALS AND METHODS: A system pharmacology-based strategy including target fishing, network pharmacology analysis and molecular docking were applied to predict the potential targets and pathways for the seven main active ingredients in SDTBE. A proteomics study was subsequently performed for validating the affected pathways and possible targets. Western blot assay, mouse xenograft tumor model and immunofluorescence assays were used to further confirm the key targets and integrative action mechanisms of SDTBE against NSCLC. RESULTS: By system pharmacology, it was inferred that SDTBE could mainly act on mitogen-activated protein kinase (MAPK) and PI3K-AKT signaling pathways by targeting epidermal growth factor receptor (EGFR), protein kinase B (AKT) and mitogen-activated or extracellular signal-regulated protein kinase (MEK), which was validated by proteomics results, and further confirmed in vitro and in vivo by Western blot and immunofluorescence assays. CONCLUSION: SDTBE targeting multi-targets including EGFR, AKT and MEK could exert its anti-NSCLC effect mainly via MAPK and PI3K-AKT signaling pathways.

Improved solubility, dissolution rate, and oral bioavailability of main biflavonoids from Selaginella doederleinii extract by amorphous solid dispersion.

Amentoflavone, robustaflavone, 2″,3″-dihydro-3',3‴-biapigenin, 3',3‴-binaringenin, and delicaflavone are five major hydrophobic components in the total biflavonoids extract from Selaginella doederleinii (TBESD) that display favorable anticancer properties. The purpose of this study was to develop a new oral delivery formulation to improve the solubilities, dissolution rates, and oral bioavailabilities of the main ingredients in TBESD by the solid dispersion technique. Solid dispersions of TBESD with various hydrophilic polymers were prepared, and different technologies were applied to select the suitable carrier and method. TBESD amorphous solid dispersion (TBESD-ASD) with polyvinylpyrrolidone K-30 was successfully prepared by the solvent evaporation method. The physicochemical properties of TBESD-ASD were investigated by scanning electron microscopy, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. As a result, TBESD was found to be molecularly dispersed in the amorphous carrier. The solubilities and dissolution rates of all five ingredients in the TBESD-ASD were significantly increased (nearly 100% release), compared with raw TBESD. Meanwhile, TBESD-ASD showed good preservation stability for 3 months under accelerated conditions of 40 °C and 75% relative humidity. A subsequent pharmacokinetic study in rats revealed that Cmax and AUC0-t of all five components were significantly increased by the solid dispersion preparation. An in vivo study clearly revealed that compared to raw TBESD, a significant reduction in tumor size and microvascular density occurred after oral administration of TBESD-ASD to xenograft-bearing tumor mice. Collectively, the developed TBESD-ASD with the improved solubility, dissolution rates and oral bio-availabilities of the main ingredients could be a promising chemotherapeutic agent for cancer treatment.

Proliposomes for oral delivery of total biflavonoids extract from Selaginella doederleinii: formulation development, optimization, and in vitro-in vivo characterization.

PURPOSE: Amentoflavone, robustaflavone, 2'',3''-dihydro-3',3'''-biapigenin, 3',3'''-binaringenin and delicaflavone are five major active ingredients in the total biflavonoids extract from Selaginella doederleinii (TBESD) with favorable anticancer properties. However, the natural-derived potent antitumor agent of TBESD is undesirable due to its poor solubility. The present study was to develop and optimize a proliposomal formulation of TBESD (P-TBESD) to improve its solubility, oral bioavailability and efficacy. MATERIALS AND METHODS: P-TBESD containing a bile salt, a protective hydrophilic isomalto-oligosaccharides (IMOs) coating, were successfully prepared by thin film dispersion-sonication method. The physicochemical and pharmacokinetic properties of P-TBESD were characterized, and the antitumor effect was evaluated using the HT-29 xenograft-bearing mice models in rats. RESULTS: Compared with TBESD, the relative bioavailability of amentoflavone, robustaflavone, 2'',3''-dihydro-3',3'''-biapigenin, 3',3'''-binaringenin and delicaflavone from P-TBESD were 669%, 523%, 761%, 955% and 191%, respectively. The results of pharmacodynamics demonstrated that both TBESD and P-TBESD groups afforded antitumor effect without systemic toxicity, and the antitumor effect of P-TBESD was significantly superior to that of raw TBESD, based on the tumor growth inhibition and histopathological examination. CONCLUSION: Hence, IMOs-modified proliposomes have promising potential for TBESD solving the problem of its poor solubility and oral bioavailability, which can serve as a practical oral preparation for TBESD in the future cancer therapy.