ABSTRACT
Purpose
To investigate the potential of thermosensitive and biadhesive nanomicelles in improving the bioavailability of docetaxel (DCT) and its chemotherapeutic effect.
Method
DCT-loaded nanomicelles were prepared by emulsufication and characterized in terms of physico-chemical and visco-elastic parameters. The optimzed formulation was evaluated for in vivo localization, pharmacokinetic and anti-tumor efficacy.
Results
The hydrodynamic size of DCT-loaded nanomicelles was approximately 13 nm and the nanomicelles exhibited a sufficient gelation strength (9250 mPa·s) and bioadhesive force (2100 dyn/cm2) to be retained in the upper part of rectum. We observed a high rectal bioavailability of 29% DCT compared to that following oral administration in rats, as it successfully evaded the multidrug efflux transporters and hepatic first-pass metabolism. Plasma concentration around ∼50 ng/mL was maintained throughout the study period (12 h) while Taxotere® attained subtherapeutic range within 4 h of drug administration. Results also revealed that the rectally administered DCT-loaded nanomicelles exhibited a significant anti-tumor effect (200 mm3) with a reduced toxicity profile when compared to orally administered DCT (950 mm3). Furthermore, histological study showed that the rectal mucosa was completely intact with no signs of irritation upon treatment with DCT-loaded nanomicelles.
Conclusions
Taken together, our novel thermosensitive and biadhesive nanomicelles demonstrated the ability to improve the bioavailability and chemotherapeutic potential of DCT in vivo. To the best of our knowledge, this is the first report describing the rectal delivery of DCT-loaded nanomicelles.
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ACKNOWLEDGMENTS AND DISCLOSURES
Youn Gee Seo and Dong-Wuk Kim contributed equally to this work. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2012R1A2A2A01045658) in South Korea.
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Seo, Y.G., Kim, DW., Yeo, W.H. et al. Docetaxel-Loaded Thermosensitive and Bioadhesive Nanomicelles as a Rectal Drug Delivery System for Enhanced Chemotherapeutic Effect. Pharm Res 30, 1860–1870 (2013). https://doi.org/10.1007/s11095-013-1029-0
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DOI: https://doi.org/10.1007/s11095-013-1029-0