Enhancing the Oral Bioavailability of the Poorly Soluble Drug Dicumarol with a Bioadhesive Polymer

Thanos, Christopher D.; Li, Zhi; Goddard, Moses; Reineke, Joshua; Bailey, Nicola; Cross, Matthew E.; Burrill, Roxanne; Mathiowitz, Edith

doi:10.1002/jps.10446

Cited by 20 publications

(11 citation statements)

References 21 publications

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“…However this enhancement in cytotoxicity may also be due to the interaction of docetaxel with BCL-2. BCL-2 is a multidomain antiapoptotic protein that sequesters BAX and BAK proteins, two pro-apoptotic proteins that play a major role in mitochondrial outer membrane permeabilization, a pivotal event in the intrinsic apoptosis pathway (Thanos et al, 2003) DTX and paclitaxel both induce phosphorylation of BCL-2 leading to the release of BAX and BAK, however DTX does so at a concentration 100-fold less than paclitaxel (Sadurni et al, 2005). Clinically there is incomplete cross-resistance, specifically with paclitaxel-resistant breast, lung and ovarian tumors potentially due to different mechanisms of uptake, efflux, or stimulation of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Formulation development of a novel targeted theranostic nanoemulsion of docetaxel to overcome multidrug resistance in ovarian cancer

et al. 2014

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Objective Ovarian cancer is a highly lethal disease in which the majority of patients eventually demonstrate multidrug resistance. Develop a novel active targeted theranostic nanomedicine designed to overcome drug efflux mechanisms, using a Generally Regarded As Safe (GRAS) grade nanoemulsion (NE) as a clinically relevant platform. Materials and methods The NEs surface-functionalized with folate and gadolinium, were made using GRAS grade excipients and a high-shear microfluidization process. Efficacy was evaluated in ovarian cancer cells, SKOV3 and SKOV3TR. The NE accumulation in tumors was evaluated in SKOV3 tumor-bearing mice by magnetic resonance imaging (MRI). Results and discussion The NE with particle size <150nm were stable in plasma and parenteral fluids for 24 h. Ovarian cancer cells in vitro efficiently took up the non-targeted and folate-targeted NEs; improved cytotoxicity was observed for the folate-targeted NEs showing a 270- fold drop in the IC50 in SKOV3TR cells as compared to docetaxel alone. The addition of gadolinium did not affect cell viability in vitro, but showed relaxation times comparable to Magnevist®. Folate-targeted NEs accumulated in tumors for prolonged period of time compared to Magnevist® and showed enhanced contrast compared to non-targeted NEs with MRI in SKOV3 tumor-bearing mice suggesting active targeting of NEs due to folate modification. Conclusions A folate-targeted, theranostic NE delivers docetaxel by receptor mediated endocytosis that shows enhanced cytotoxicity capable of overcoming ABC transporter mediated taxane resistance. The diagnostic capability of the targeted nanomedicine showed enhanced contrast in tumors compared to clinically relevant MRI contrast agent Magnevist®.

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Section: Discussionmentioning

confidence: 99%

Formulation development of a novel targeted theranostic nanoemulsion of docetaxel to overcome multidrug resistance in ovarian cancer

et al. 2014

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“…Various studies have been reported in attempt to improve solubilities of poorly water-soluble drugs. Increasing the available surface area for dissolution via particle size reduction is one of the oldest methods for improving the dissolution rates of poorly water-soluble drugs (1). Solid dispersion systems have been widely studied and repeatedly shown to improve the dissolution properties of poorly water-soluble drugs (2,3).…”

Section: Introductionmentioning

confidence: 99%

Improvement of Dissolution Behavior for Poorly Water-Soluble Drug by Application of Cyclodextrin in Extrusion Process: Comparison between Melt Extrusion and Wet Extrusion

Yano

Kleinebudde

2010

AAPS PharmSciTech

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The purpose of this study was to improve dissolution behavior of poorly water-soluble drugs by application of cyclodextrin in extrusion processes, which were melt extrusion process and wet extrusion process. Indomethacin (IM) was employed as a model drug. Extrudates containing IM and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) in 1:1 w/w ratio were manufactured by both melt extrusion process and wet extrusion process. In vitro drug release properties of IM from extrudates and physiochemical properties of extrudates were investigated. The dissolution rates of IM from extrudates manufactured by melt extrusion and wet extrusion with HP-beta-CyD were significantly higher than that of the physical mixture of IM and HP-beta-CyD. In extrudate manufactured by melt extrusion, gamma-form of IM changed to amorphous completely during melt extrusion due to heating above melting point of IM. On the other hand, in extrudate manufactured by wet extrusion, gamma-form of IM changed to amorphous partially due to interaction between IM and HP-beta-CyD and mechanical agitating force during process. Application of HP-beta-CyD in extrusion process is useful for the enhancement of dissolution rate for poorly water-soluble drugs.

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“…After this discovery, researchers began engineering microspheres (MSs) to deliver drugs with poor water solubility (8-10), poor gastrointestinal permeability (11), or poor oral bioavailability (8,9,(12)(13)(14)(15) to the small intestine. MS-based oral drug delivery systems (ODDSs) can be made from biodegradable polymers (12,(16)(17)(18), nondegradable polymers (19-21), and polysaccharides (22, 23) and can be engineered to carry polypeptides (18,24,25) and other molecules (26, 27).…”

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confidence: 99%

Unique insights into the intestinal absorption, transit, and subsequent biodistribution of polymer-derived microspheres

Reineke

Cho

Dingle

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Polymeric microspheres (MSs) have received attention for their potential to improve the delivery of drugs with poor oral bioavailability. Although MSs can be absorbed into the absorptive epithelium of the small intestine, little is known about the physiologic mechanisms that are responsible for their cellular trafficking. In these experiments, nonbiodegradable polystyrene MSs (diameter range: 500 nm to 5 μm) were delivered locally to the jejunum or ileum or by oral administration to young male rats. Following administration, MSs were taken up rapidly (≤5 min) by the small intestine and were detected by transmission electron microscopy and confocal laser scanning microscopy. Gel permeation chromatography confirmed that polymer was present in all tissue samples, including the brain. These results confirm that MSs (diameter range: 500 nm to 5 μm) were absorbed by the small intestine and distributed throughout the rat. After delivering MSs to the jejunum or ileum, high concentrations of polystyrene were detected in the liver, kidneys, and lungs. The pharmacologic inhibitors chlorpromazine, phorbol 12-myristate 13-acetate, and cytochalasin D caused a reduction in the total number of MSs absorbed in the jejunum and ileum, demonstrating that nonphagocytic processes (including endocytosis) direct the uptake of MSs in the small intestine. These results challenge the convention that phagocytic cells such as the microfold cells solely facilitate MS absorption in the small intestine.oral delivery | uptake mechanism B eginning in the 1960s, several groups (1-7) demonstrated that the small intestine could absorb microparticles with a diameter >1 μm, challenging dogma that the small intestine could only absorb small macromolecules. After this discovery, researchers began engineering microspheres (MSs) to deliver drugs with poor water solubility (8-10), poor gastrointestinal permeability (11), or poor oral bioavailability (8,9,(12)(13)(14)(15) to the small intestine. MS-based oral drug delivery systems (ODDSs) can be made from biodegradable polymers (12,(16)(17)(18), nondegradable polymers (19-21), and polysaccharides (22, 23) and can be engineered to carry polypeptides (18,24,25) and other molecules (26, 27). The motivation for using microparticulate-based ODDSs is to improve the oral bioavailability of drugs by enhancing their delivery and transit through the absorptive epithelium of the small intestine. This work may ultimately enable patients to take medications orally instead of relying on daily or weekly injections or other, less convenient routes of administration (28).More than five decades after Sanders and Ashworth discovered that the small intestine can engulf large particles (1), little is known today about the cellular mechanisms or physiologic pathways that facilitate the absorption, transit, and biodistribution of microparticles that are delivered to the small intestine. Nonetheless, the diverse physiology and multitude of cell types in the small intestine likely play a central role in these processes. The absorp...

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Enhancing the Oral Bioavailability of the Poorly Soluble Drug Dicumarol with a Bioadhesive Polymer

Cited by 20 publications

References 21 publications

Formulation development of a novel targeted theranostic nanoemulsion of docetaxel to overcome multidrug resistance in ovarian cancer

Formulation development of a novel targeted theranostic nanoemulsion of docetaxel to overcome multidrug resistance in ovarian cancer

Improvement of Dissolution Behavior for Poorly Water-Soluble Drug by Application of Cyclodextrin in Extrusion Process: Comparison between Melt Extrusion and Wet Extrusion

Unique insights into the intestinal absorption, transit, and subsequent biodistribution of polymer-derived microspheres

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