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Perorally active nanomicellar formulation of quercetin in the treatment of lung cancer.

Tan BJ, Liu Y, Chang KL, Lim BK, Chiu GN - Int J Nanomedicine (2012)

Bottom Line: Realizing the therapeutic benefits of quercetin is mostly hampered by its low water solubility and poor absorption.The quercetin nanomicelles were stable when tested in simulated gastric (pH 1.2) and intestinal (pH 7.4) fluids, and were non-toxic to the Caco-2 cells as reflected by reversible reduction in transepithelial electrical resistance and ≤25% lactose dehydrogenase release.The nanomicellar quercetin formulation was well tolerated by the tumor-bearing animals, with no significant weight loss observed at the end of the 10-week study period.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.

ABSTRACT

Background: Realizing the therapeutic benefits of quercetin is mostly hampered by its low water solubility and poor absorption. In light of the advantages of nanovehicles in the delivery of flavanoids, we aimed to deliver quercetin perorally with nanomicelles made from the diblock copolymer, polyethylene glycol (PEG)-derivatized phosphatidylethanolamine (PE).

Methods: Quercetin-loaded nanomicelles were prepared by using the film casting method, and were evaluated in terms of drug incorporation efficiency, micelle size, interaction with Caco-2 cells, and anticancer activity in the A549 lung cancer cell line and murine xenograft model.

Results: The incorporation efficiency into the nanomicelles was ≥88.9% when the content of quercetin was up to 4% w/w, with sizes of 15.4-18.5 nm and polydispersity indices of <0.250. Solubilization of quercetin by the nanomicelles increased its aqueous concentration by 110-fold. The quercetin nanomicelles were stable when tested in simulated gastric (pH 1.2) and intestinal (pH 7.4) fluids, and were non-toxic to the Caco-2 cells as reflected by reversible reduction in transepithelial electrical resistance and ≤25% lactose dehydrogenase release. The anticancer activity of quercetin could be significantly improved over the free drug through the nanomicellar formulation when tested using the A549 cancer cell line and murine xenograft model. The nanomicellar quercetin formulation was well tolerated by the tumor-bearing animals, with no significant weight loss observed at the end of the 10-week study period.

Conclusion: A stable PEG-PE nanomicellar formulation of quercetin was developed with enhanced peroral anticancer activity and no apparent toxicity to the intestinal epithelium.

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Interaction of quercetin nanomicelles with Caco-2 cells. (Panel A)Cellular accumulation of FITC-labeled nanomicelles over 24 hours of incubation at 37°C Representative images from fluoresence confocal microscopy are shown. (Panel B) Change in TEER upon treatment with quercetin in free (green) and nanomicellar (orange) forms, as well as empty nanomicelles (blue) and 1% triton-X (red), with the arrow indicating treatment duration of 24 hours.Notes:+, #, *, and ‡ represent P < 0.05 compared to values at t = 0 hours.
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f3-ijn-7-651: Interaction of quercetin nanomicelles with Caco-2 cells. (Panel A)Cellular accumulation of FITC-labeled nanomicelles over 24 hours of incubation at 37°C Representative images from fluoresence confocal microscopy are shown. (Panel B) Change in TEER upon treatment with quercetin in free (green) and nanomicellar (orange) forms, as well as empty nanomicelles (blue) and 1% triton-X (red), with the arrow indicating treatment duration of 24 hours.Notes:+, #, *, and ‡ represent P < 0.05 compared to values at t = 0 hours.

Mentions: The well-established Caco-2 cell monolayer was employed as the in vitro model for gastrointestinal epithelium, and the cellular accumulation of the PEG-lipid nanomicelles was assessed by confocal microscopy. To facilitate visualization, the nanomicelles were spiked with 1 mol% DSPE-PEG2000-N-carboxyfluorescein. The Caco-2 cells were exposed to the fluorescence-labeled nanomicelles for up to 24 hours at 37°C, and cellular accumulation of the nanomicelles increased over time (Figure 3A). Furthermore, the accumulation of the nanomicelles was independent of P-gp activity and endocytic processes, which was supported by results summarized in Suppl Data Figure 2. Cellular accumulation of the carboxyfluorescein-tagged nanomicelles occurred even in the presence of the P-gp inhibitor cyclosporine A or in the presence of endocytic inhibitors (hyperosmotic sucrose of 0.45 M or Brefeldin A) or a change of incubation temperature from 37°C to 4°C. Collectively, these data suggest that the nanomicelles are likely to accumulate inside Caco-2 cells by passive diffusion.


Perorally active nanomicellar formulation of quercetin in the treatment of lung cancer.

Tan BJ, Liu Y, Chang KL, Lim BK, Chiu GN - Int J Nanomedicine (2012)

Interaction of quercetin nanomicelles with Caco-2 cells. (Panel A)Cellular accumulation of FITC-labeled nanomicelles over 24 hours of incubation at 37°C Representative images from fluoresence confocal microscopy are shown. (Panel B) Change in TEER upon treatment with quercetin in free (green) and nanomicellar (orange) forms, as well as empty nanomicelles (blue) and 1% triton-X (red), with the arrow indicating treatment duration of 24 hours.Notes:+, #, *, and ‡ represent P < 0.05 compared to values at t = 0 hours.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3278229&req=5

f3-ijn-7-651: Interaction of quercetin nanomicelles with Caco-2 cells. (Panel A)Cellular accumulation of FITC-labeled nanomicelles over 24 hours of incubation at 37°C Representative images from fluoresence confocal microscopy are shown. (Panel B) Change in TEER upon treatment with quercetin in free (green) and nanomicellar (orange) forms, as well as empty nanomicelles (blue) and 1% triton-X (red), with the arrow indicating treatment duration of 24 hours.Notes:+, #, *, and ‡ represent P < 0.05 compared to values at t = 0 hours.
Mentions: The well-established Caco-2 cell monolayer was employed as the in vitro model for gastrointestinal epithelium, and the cellular accumulation of the PEG-lipid nanomicelles was assessed by confocal microscopy. To facilitate visualization, the nanomicelles were spiked with 1 mol% DSPE-PEG2000-N-carboxyfluorescein. The Caco-2 cells were exposed to the fluorescence-labeled nanomicelles for up to 24 hours at 37°C, and cellular accumulation of the nanomicelles increased over time (Figure 3A). Furthermore, the accumulation of the nanomicelles was independent of P-gp activity and endocytic processes, which was supported by results summarized in Suppl Data Figure 2. Cellular accumulation of the carboxyfluorescein-tagged nanomicelles occurred even in the presence of the P-gp inhibitor cyclosporine A or in the presence of endocytic inhibitors (hyperosmotic sucrose of 0.45 M or Brefeldin A) or a change of incubation temperature from 37°C to 4°C. Collectively, these data suggest that the nanomicelles are likely to accumulate inside Caco-2 cells by passive diffusion.

Bottom Line: Realizing the therapeutic benefits of quercetin is mostly hampered by its low water solubility and poor absorption.The quercetin nanomicelles were stable when tested in simulated gastric (pH 1.2) and intestinal (pH 7.4) fluids, and were non-toxic to the Caco-2 cells as reflected by reversible reduction in transepithelial electrical resistance and ≤25% lactose dehydrogenase release.The nanomicellar quercetin formulation was well tolerated by the tumor-bearing animals, with no significant weight loss observed at the end of the 10-week study period.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.

ABSTRACT

Background: Realizing the therapeutic benefits of quercetin is mostly hampered by its low water solubility and poor absorption. In light of the advantages of nanovehicles in the delivery of flavanoids, we aimed to deliver quercetin perorally with nanomicelles made from the diblock copolymer, polyethylene glycol (PEG)-derivatized phosphatidylethanolamine (PE).

Methods: Quercetin-loaded nanomicelles were prepared by using the film casting method, and were evaluated in terms of drug incorporation efficiency, micelle size, interaction with Caco-2 cells, and anticancer activity in the A549 lung cancer cell line and murine xenograft model.

Results: The incorporation efficiency into the nanomicelles was ≥88.9% when the content of quercetin was up to 4% w/w, with sizes of 15.4-18.5 nm and polydispersity indices of <0.250. Solubilization of quercetin by the nanomicelles increased its aqueous concentration by 110-fold. The quercetin nanomicelles were stable when tested in simulated gastric (pH 1.2) and intestinal (pH 7.4) fluids, and were non-toxic to the Caco-2 cells as reflected by reversible reduction in transepithelial electrical resistance and ≤25% lactose dehydrogenase release. The anticancer activity of quercetin could be significantly improved over the free drug through the nanomicellar formulation when tested using the A549 cancer cell line and murine xenograft model. The nanomicellar quercetin formulation was well tolerated by the tumor-bearing animals, with no significant weight loss observed at the end of the 10-week study period.

Conclusion: A stable PEG-PE nanomicellar formulation of quercetin was developed with enhanced peroral anticancer activity and no apparent toxicity to the intestinal epithelium.

Show MeSH
Related in: MedlinePlus