Skip to main content
Log in

Development of a Nanocrystalline Paclitaxel Formulation for Hipec Treatment

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To develop a nanocrystalline paclitaxel formulation with a high paclitaxel-to-stabilizer ratio which can be used for hyperthermic intraperitoneal chemotherapy (HIPEC).

Methods

Paclitaxel (PTX) nanocrystals were prepared via wet milling using Pluronic F127® as stabilizer. The suitability of paclitaxel nanosuspensions for HIPEC treatment was evaluated by analyzing the cytotoxicity of both stabilizer and formulation, and by determining the maximum tolerated dose (MTD) and bioavailability. The effect on tumor growth was evaluated by magnetic resonance imaging (MRI) at day 7 and 14 after HIPEC treatment in rats with peritoneal carcinomatosis of ovarian origin.

Results

Monodisperse nanosuspensions (±400 nm) were developed using Pluronic F127® as single additive. The cytotoxicity and MTD of this nanocrystalline formulation was similar compared to Taxol®, while its bioavailability was higher. MRI data after HIPEC treatment with a PTX nanocrystalline suspension showed a significant reduction of tumor volume compared to the non-treated group. Although no significant differences on tumor volume were observed between Taxol® and the nanosuspension, the rats treated with the nanosuspension recovered faster following the HIPEC procedure.

Conclusion

Nanosuspensions with a high paclitaxel-to-stabilizer ratio are of interest for the treatment of peritoneal carcinomatosis of ovarian origin via HIPEC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

HIPEC:

hyperthermic intraperitoneal chemotherapy

MTD:

maximum tolerated dose

PEO:

polyethylene oxide

Plu F127:

Pluronic F127®

Plu F68:

Pluronic F68®

PPO:

polypropylene oxide

PTX:

paclitaxel

TGD:

tumor growth delay

References

  1. Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010;46(4):765–81.

    Article  PubMed  CAS  Google Scholar 

  2. Sugarbaker PH. Comprehensive management of peritoneal surface malignancy using cytoreductive surgery and perioperative intraperitoneal chemotherapy: the Washington Cancer Institute approach. Expert Opin Pharmacother. 2009;10(12):1965–77.

    Article  PubMed  CAS  Google Scholar 

  3. Mohamed F, Cecil T, Moran B, Sugarbaker P. A new standard of care for the management of peritoneal surface malignancy. Curr Oncol. 2011;18(2):E84–96.

    Article  PubMed  CAS  Google Scholar 

  4. Bristow RE, Puri I, Chi DS. Cytoreductive surgery for recurrent ovarian cancer: A meta-analysis. Gynecol Oncol. 2009;112(1):265–74.

    Article  PubMed  Google Scholar 

  5. Dovern E, de Hingh I, Verwaal VJ, van Driel WJ, Nienhuijs SW. Hyperthermic intraperitoneal chemotherapy added to the treatment of ovarian cancer. A review of achieved results and complications. Eur J Gynaecol Oncol. 2010;31(3):256–61.

    PubMed  CAS  Google Scholar 

  6. Markman M. Intraperitoneal antineoplastic drug delivery: rationale and results. Lancet Oncol. 2003;4(5):277–83.

    Article  PubMed  CAS  Google Scholar 

  7. Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37(13):1590–8.

    Article  PubMed  CAS  Google Scholar 

  8. Colson YL, Liu R, Southard EB, Schulz MD, Wade JE, Griset AP, et al. The performance of expansile nanoparticles in a murine model of peritoneal carcinomatosis. Biomaterials. 2011;32(3):832–40.

    Article  PubMed  CAS  Google Scholar 

  9. Peltonen L, Hirvonen J. Pharmaceutical nanocrystals by nanomilling: critical process parameters, particle fracturing and stabilization methods. J Pharm Pharmacol. 2010;62(11):1569–79.

    Article  PubMed  CAS  Google Scholar 

  10. Kesisoglou F, Panmai S, Wu Y. Application of nanoparticles in oral delivery of immediate release formulations. Current Nanoscience. 2007;3(2):183–90.

    Article  CAS  Google Scholar 

  11. Liu F, Park J-Y, Zhang Y, Conwell C, Liu Y, Bathula SR, et al. Targeted Cancer Therapy With Novel High Drug-Loading Nanocrystals. J Pharm Sci. 2010;99(8):3542–51.

    Article  PubMed  CAS  Google Scholar 

  12. Yeo Y, Ito T, Bellas E, Highley CB, Marini R, Kohane DS. In situ cross-linkable hyaluronan hydrogels containing polymeric nanoparticles for preventing postsurgical adhesions. Ann Surg. 2007;245(5):819–24.

    Article  PubMed  Google Scholar 

  13. Bouquet W, Ceelen W, Adriaens E, Almeida A, Quinten T, De Vos F, et al. In vivo Toxicity and Bioavailability of Taxol (R) and a Paclitaxel/beta-Cyclodextrin Formulation in a Rat Model During HIPEC. Ann Surg Oncol. 2010;17(9):2510–7.

    Article  PubMed  CAS  Google Scholar 

  14. Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm Res. 2006;23(12):2709–28.

    Article  PubMed  CAS  Google Scholar 

  15. Kabanov AV, Batrakova EV, Alakhov VY. Pluronic((R)) block copolymers for overcoming drug resistance in cancer. Adv Drug Deliv Rev. 2002;54(5):759–79.

    Article  PubMed  CAS  Google Scholar 

  16. Batrakova EV, Li S, Brynskikh AM, Sharma AK, Li YL, Boska M, et al. Effects of pluronic and doxorubicin on drug uptake, cellular metabolism, apoptosis and tumor inhibition in animal models of MDR cancers. J Control Release. 2010;143(3):290–301.

    Article  PubMed  CAS  Google Scholar 

  17. Merisko-Liversidge E, Liversidge GG. Nanosizing for oral and parenteral drug delivery: A perspective on formulating poorly-water soluble compounds using wet media milling technology. Adv Drug Deliv Rev. 2011;63(6):427–40.

    Article  PubMed  CAS  Google Scholar 

  18. Ghosh I, Bose S, Vippagunta R, Harmon F. Nanosuspension for improving the bioavailability of a poorly soluble drug and screening of stabilizing agents to inhibit crystal growth. Int J Pharm. 2011;409(1–2):260–8.

    Article  PubMed  CAS  Google Scholar 

  19. Debree E, Rosing H, Filis D, Romanos J, Melisssourgaki M, Daskalakis M, et al. Cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy with paclitaxel: A clinical and pharmacokinetic study. Ann Surg Oncol. 2008;15(4):1183–92.

    Article  Google Scholar 

  20. Bajaj G, Yeo Y. Drug delivery systems for intraperitoneal therapy. Pharm Res. 2010;27(5):735–8.

    Article  PubMed  CAS  Google Scholar 

  21. Liu P, Rong XY, Laru J, van Veen B, Kiesvaara J, Hirvonen J, et al. Nanosuspensions of poorly soluble drugs: Preparation and development by wet milling. Int J Pharm. 2011;411(1–2):215–22.

    Article  PubMed  CAS  Google Scholar 

  22. Tannock IF, Lee CM, Tunggal JK, Cowan DSM, Egorin MJ. Limited penetration of anticancer drugs through tumor tissue: A potential cause of resistance of solid tumors to chemotherapy. Clin Cancer Res. 2002;8(3):878–84.

    PubMed  CAS  Google Scholar 

  23. Fujiwara K, Armstrong D, Morgan M, Markman M. Principles and practice of intraperitoneal chemotherapy for ovarian cancer. Int J Gynecol Cancer. 2007;17(1):1–20.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chris Vervaet.

Rights and permissions

Reprints and permissions

About this article

Cite this article

De Smet, L., Colin, P., Ceelen, W. et al. Development of a Nanocrystalline Paclitaxel Formulation for Hipec Treatment. Pharm Res 29, 2398–2406 (2012). https://doi.org/10.1007/s11095-012-0765-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-012-0765-x

Key Words

Navigation