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Docetaxel-Loaded Thermosensitive and Bioadhesive Nanomicelles as a Rectal Drug Delivery System for Enhanced Chemotherapeutic Effect

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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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REFERENCES

  1. Kintzel PE, Michaud LB, Lange MK. Docetaxel-associated epiphora. Pharmacotherapy. 2006;26:853–67.

    Article  PubMed  CAS  Google Scholar 

  2. Cho HJ, Yoon HY, Koo H, Ko SH, Shim JS, Lee JH, et al. Self-assembled nanoparticles based on hyaluronic acid-ceramide (HA-CE) and Pluronic for tumor-targeted delivery of docetaxel. Biomaterials. 2011;32:7181–90.

    Article  PubMed  CAS  Google Scholar 

  3. Lavelle F, Bissery MC, Combeau C, Riou JF, Vrignaud P, André S. Preclinical evaluation of docetaxel (Taxotere). Semin Oncol. 1995;22:3–16.

    CAS  Google Scholar 

  4. Engels FK, Mathot RA, Verweij J. Alternative drug formulations of docetaxel: a review. Anticancer Drugs. 2007;18:95–103.

    Article  PubMed  CAS  Google Scholar 

  5. Gelderblom H, Loos WJ, Verweij J, van der Burg ME, de Jonge MJ, Brouwer E, et al. Modulation of cisplatin pharmacodynamics by Cremophor EL: experimental and clinical studies. Eur J Cancer. 2002;38:205–13.

    Article  PubMed  CAS  Google Scholar 

  6. Yan YD, Kim DH, Sung JH, Yong CS, Choi HG. Enhanced oral bioavailability of docetaxel in rats by four consecutive days of pre-treatment with curcumin. Int J Pharm. 2010;399:116–20.

    Article  PubMed  CAS  Google Scholar 

  7. Yin YM, Cui FD, Mu CF, Choi MK, Kim JS, Chung SJ, et al. Docetaxel microemulsion for enhanced oral bioavailability: preparation and in vitro and in vivo evaluation. J Control Rel. 2009;140:86–94.

    Article  CAS  Google Scholar 

  8. Gao K, Sun J, Liu K, Liu X, He Z. Preparation and characterization of a submi-cron lipid emulsion of docetaxel: submicron lipid emulsion of docetaxel. Drug Dev Ind Pharm. 2008;34:1227–37.

    Article  PubMed  CAS  Google Scholar 

  9. McDonald SL, Stevenson DA, Moir SE, Hutcheon AW, Haites NE, et al. Genomic changes identified by comparative genomic hybridisation in docetaxel-resistant breast cancer cell lines. Eur J Cancer. 2005;41:1086–94.

    Article  PubMed  CAS  Google Scholar 

  10. Elsabahy M, Perron ME, Bertrand N, Yu GE, Leroux JC. Solubilization of docetaxel in poly(ethylene oxide)-block-poly(butylene/styrene oxide) micelles. Biomacromolecules. 2007;8:2250–7.

    Article  PubMed  CAS  Google Scholar 

  11. Du W, Hong L, Yao T, Yang X, He Q, Yang B, et al. Synthesis and evaluation of water-soluble docetaxel prodrugs-docetaxel esters of malic acid. Bioorg Med Chem. 2007;15:6323–30.

    Article  PubMed  CAS  Google Scholar 

  12. Esmaeili F, Dinarvand R, Ghahremani MH, Amini M, Rouhani H, Sepehri N, et al. Docetaxel-albumin conjugates: preparation, in vitro evaluation and biodistribution studies. J Pharm Sci. 2009;98:2718–30.

    Article  PubMed  CAS  Google Scholar 

  13. Straubinger RM, Balasubramanian SV. Preparation and characterization of taxane-containing liposomes. Methods Enzymol. 2005;391:97–117.

    Article  PubMed  CAS  Google Scholar 

  14. Chen J, Qiu L, Hu M, Jin Y, Han J. Preparation, characterization and in vitro evaluation of solid dispersions containing docetaxel. Drug Dev Ind Pharm. 2008;34:588–94.

    Article  PubMed  CAS  Google Scholar 

  15. Esmaeili F, Dinarvand R, Ghahremani MH, Ostad SN, Esmaily H, Atyabi F. Cellular cytotoxicity and in-vivo biodistribution of docetaxel poly(lactide-co-glycolide) nanoparticles. Anticancer Drugs. 2010;21:43–52.

    Article  PubMed  CAS  Google Scholar 

  16. Malingré MM, Richel DJ, Beijnen JH, Rosing H, Koopman FJ, Huinink WW, et al. Coadministration of cyclosporine strongly enhances the oral bioavailability of docetaxel. J Clin Oncol. 2001;19:1160–6.

    PubMed  Google Scholar 

  17. Engels FK, Mathot RA, Loos WJ, van Schaik RH, Verweij J. Influence of high-dose ketoconazole on the pharmacokinetics of docetaxel. Cancer Biol Ther. 2006;5:833–9.

    PubMed  CAS  Google Scholar 

  18. Ben Reguiga M, Bonhomme-Faivre L, Farinotti R. Bioavailability and tissular distribution of docetaxel, a P-glycoprotein substrate, are modified by interferon-alpha in rats. J Pharm Pharmacol. 2007;59:401–8.

    Article  PubMed  CAS  Google Scholar 

  19. Yuan Y, Ying C, Li Z, Ping ZH, Sha GY, Bo Z, et al. Thermosensitive and mucoadhesive in situ gel based on poloxamer as new carrier for rectal administration of nimesulide. Int J Pharm. 2012;430:114–9.

    Article  PubMed  CAS  Google Scholar 

  20. Choi HG, Kim MH, Lee MK, Kim CK. Effect of additives on the physicochemical properties of liquid suppository. Int J Pharm. 1999;190:13–9.

    Article  PubMed  CAS  Google Scholar 

  21. Yong CS, Choi JS, Quan QZ, Rhee JD, Kim CK, Lim SJ, et al. Effect of sodium chloride on the gelation temperature, gel strength and bioadhesive force of poloxamer gels containing diclofenac sodium. Int J Pharm. 2001;226:195–205.

    Article  PubMed  CAS  Google Scholar 

  22. Choi HG, Jung JH, Ryu JM, Yoon SJ, Sung Oh YK, et al. Development of in situ-gelling and mucoadhesive acetaminophen liquid suppository. Int J Pharm. 1998;165:33–44.

    Article  CAS  Google Scholar 

  23. Xuan JJ, Balakrishnan P, Oh DH, Yeo WH, Park SM, Yong CS, et al. Rheological characterization and in vivo evaluation of thermosensitive poloxamer-based hydrogel for intramuscular injection of piroxicam. Int J Pharm. 2010;395:317–23.

    Article  PubMed  CAS  Google Scholar 

  24. Mu CF, Balakrishnan P, Cui FD, Yin YM, Lee YB, Choi HG, et al. The effects of mixed MPEG-PLA/Pluronic copolymer micelles on the bioavailability and multidrug resistance of docetaxel. Biomaterials. 2010;31:2371–9.

    Article  PubMed  CAS  Google Scholar 

  25. Yun MO, Choi HG, Jung JH, Kim CK. Development of thermoreversible insulin liquid suppository with sodium salicylate. Int J Pharm. 1999;189:137–45.

    Article  PubMed  CAS  Google Scholar 

  26. Yong CS, Yang CH, Rhee JD, Lee BJ, Kim DC, Kim DD, et al. Enhanced rectal bioavailability of ibuprofen in rats by poloxamer 188 and menthol. Int J Pharm. 2004;269:169–76.

    Article  PubMed  CAS  Google Scholar 

  27. Ray A, Larson N, Pike DB, Greuner M, Naik A, Bauer H, et al. Comparison of active and passive targeting of docetaxel for prostate cancer therapy by HPMA copolymer RGDfK conjugates. Mol Pharm. 2011;8:1090–9.

    Article  PubMed  CAS  Google Scholar 

  28. Sakai M, Hobara N, Hokama N, Kameya H, Ohshiro S, Sakanashi M, et al. Increased bioavailability of tacrolimus after rectal administration in rats. Biol Pharm Bull. 2004;27:1480–2.

    Article  PubMed  CAS  Google Scholar 

  29. Chen MJ, Cheng YM, Lai PH, Wu JF, Hsu YC. In vitro biocompatibility of thermally gelling liquid mucoadhesive loaded curcuminoids in colorectal cancer chemoprevention. Int J Colorectal Dis. 2012;27:869–78.

    Article  PubMed  Google Scholar 

  30. Barakat NS. In vitro and in vivo characteristics of a thermogelling rectal delivery system of etodolac. APPS Pharm Sci Tech. 2009;10:724–31.

    Article  CAS  Google Scholar 

  31. Mayol L, Biondi M, Quaglia F, Fusco S, Borzacchiello A, La AL, et al. Injectable thermally responsive mucoadhesive gel for sustained protein delivery. Biomacromolecules. 2011;12:28–33.

    Article  PubMed  CAS  Google Scholar 

  32. Yang Y, Wang J, Zhang X, Lu W, Zhang Q. A novel mixed micelle gel with thermo-sensitive property for the local delivery of docetaxel. J Control Rel. 2009;135:175–82.

    Article  CAS  Google Scholar 

  33. Hu K, Cao S, Hu F, Feng J. Enhanced oral bioavailability of docetaxel by lecithin nanoparticles: preparation, in vitro, and in vivo evaluation. Int J Nanomed. 2012;7:3537–45.

    Article  CAS  Google Scholar 

  34. Kim JK, Kim MS, Park JS, Kim CK. Thermo-reversible flurbiprofen liquid suppository with HP-b-CD as a solubility enhancer: improvement of rectal bioavailability. J Incl Phenom Macrocycl Chem. 2009;64:265–72.

    Article  CAS  Google Scholar 

  35. Wang L, Li M, Zhang N. Folate-targeted docetaxel-lipid-based-nanosuspensions for active-targeted cancer therapy. Int J Nanomed. 2012;7:3281–94.

    CAS  Google Scholar 

  36. Xu Z, Chen L, Gu W, Gao Y, Lin L, Zhang Z, et al. The performance of docetaxel-loaded solid lipid nanoparticles targeted to hepatocellular carcinoma. Biomaterials. 2009;30:226–32.

    Article  PubMed  Google Scholar 

  37. Koo AN, Min KH, Lee HJ, Lee SU, Kim K, Kwon IC, et al. Tumor accumulation and antitumor efficacy of docetaxel-loaded core-shell-corona micelles with shell-specific redox-responsive cross-links. Biomaterials. 2012;33:1489–99.

    Article  PubMed  CAS  Google Scholar 

  38. Varma RK, Kaushal R, Junnarkar AY, Thomas GP, Naidu MU, Singh PP, et al. Polysorbate 80: a pharmacological study. Arzneimittelforschung. 1985;35:804–8.

    PubMed  CAS  Google Scholar 

Download references

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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Authors and Affiliations

  1. College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan, 712-749, South Korea

    Youn Gee Seo, Woo Hyun Yeo, Thiruganesh Ramasamy, Jung-Ae Kim, Dong Hoon Oh, Chul Soon Yong, Jong Oh Kim & Han-Gon Choi

  2. College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 1271, Sa-3-Dong, Ansan, 426-791, South Korea

    Dong-Wuk Kim, Jin Ki Kim & Han-Gon Choi

  3. College of Pharmacy, Seoul National University, San 56-1 Shinlim-Dong, Kwanak-Ku, Seoul, 151-742, South Korea

    Yu-Kyoung Oh

  4. Research Centre, Samil Pharmaceutical Co. Ltd., Anyang Megavalley 799, Gwanyang-Dong, Anyang, Gyeonggi-Do, 431-060, South Korea

    Young-Joon Park

  5. College of Oriental Medicine, Daegu Haany University, Gyongsan, 712-715, South Korea

    Sae Kwang Ku

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  1. Youn Gee Seo
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  2. Dong-Wuk Kim
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  11. Chul Soon Yong
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  12. Jong Oh Kim
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  13. Han-Gon Choi
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Corresponding authors

Correspondence to Chul Soon Yong, Jong Oh Kim or Han-Gon Choi.

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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

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