Abstract
Aim:
Ergosterol is a plant sterol with anti-tumor and anti-angiogenic activities, but is poorly soluble. In this study, we attempted to enhance its anti-tumor action and oral bioavailability via poly(lactide-co-glycolide) (PLGA) nanoparticle encapsulation.
Methods:
Ergosterol-loaded PLGA nanoparticles (NPs/Erg) were prepared using the emulsion/solvent evaporation technique. Their physicochemical properties were characterized, and their cytotoxicity against human cancer cell lines was evaluated with MTT assay. The pharmacokinetics and tissue distribution of NPs/Erg were investigated in rats and mice, respectively.
Results:
NPs/Erg were spherical in shape with a particle size of 156.9±4.8 nm and a Zeta potential of -19.27±1.13 mV, and had acceptable encapsulation efficiency and loading capacity. NPs/Erg exerted much stronger cytotoxicity against human cancer cells than the free ergosterol, and showed significantly reduced IC50 values (14.69±0.48 μg/mL in glioma U251 cells; 9.43±0.52 μg/mL in breast cancer MCF-7 cells; 4.70±0.41 μg/mL in hepatoma HepG2 cells). After oral administration of a single dose in rats, NPs/Erg displayed a prolonged plasma circulation with a 4.9-fold increase of oral bioavailability compared with the free ergosterol. After mice received NPs/Erg, the ergosterol in NPs/Erg was rapidly distributed in stomach, kidneys, liver, brain, spleen, and virtually non-existent in heart and lungs. The presence of NPs/Erg in brain was particularly improved compared with the free ergosterol.
Conclusion:
The PLGA nanoparticles serve as a promising carrier for the poorly soluble ergosterol and significantly improve its bioavailability, biodistribution and in vitro anti-tumor activities.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant 30973677), the Doctoral Fund of Ministry of Education of China (Grant 20113227110012), and the Industry-University-Research Institution Cooperation (Grants BY2009141 and CY2010023) in the Jiangsu Province and Zhenjiang City. The authors also thank the Jiangsu University Ethics Committee for their kind guidance in the animal experiments.
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Supplementary information is available at the Acta Pharmacologica Sinica's website.
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Supplementary Information Figure S1
Chromatograms of ergosterol and internal standard in rat plasma, heart, liver, spleen, lung, kidney, stomach, brain and excrement homogenate: (A1) blank rat plasma, (A2)∼(A9): blank heart, liver, spleen, lung, kidney, stomach, brain and excrement homogenate; (B1) blank plasma spiked with ergosterol, and internal standard, (B2)∼(B9): blank heart, liver, spleen, lung, kidney, stomach, brain and excrement homogenate spiked with ergosterol and internal standard; (C1) a rat plasma sample after oral administration, (C2)∼(C9): heart, liver, spleen, lung, kidney, stomach, brain and excrement homogenate samples after oral administration (1, internal standard; 2, ergosterol). (DOC 477 kb)
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Zhang, Hy., Firempong, C., Wang, Yw. et al. Ergosterol-loaded poly(lactide-co-glycolide) nanoparticles with enhanced in vitro antitumor activity and oral bioavailability. Acta Pharmacol Sin 37, 834–844 (2016). https://doi.org/10.1038/aps.2016.37
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DOI: https://doi.org/10.1038/aps.2016.37
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