Skip to main content

Advertisement

SpringerLink
Log in

Paclitaxel-Loaded Poly(n-butylcyanoacrylate) Nanoparticle Delivery System to Overcome Multidrug Resistance in Ovarian Cancer

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

ABSTRACT

Purpose

The aim of this study was to test the ability of paclitaxel-loaded poly(butylcyanoacrylate) (PBCA) nanoparticles to overcome multidrug resistance (MDR) in human ovarian resistant cells (A2780/T) and investigate its possible mechanism.

Methods

We prepared paclitaxel-loaded PBCA nanoparticles by interfacial polymerization method. The physicochemistry of the nanoparticles was characterized. The cytotoxicity of paclitaxel-loaded PBCA nanoparticles was measured by MTT assay. Calcein-AM assay was used to analyze the P-glycoprotein (P-gp) function, and the expression of MDR-1 mRNA in A2780/T cells treated with drug-loaded nanoparticles was defined by QRT-PCR.

Results

The nanoparticles were approximately spherical in shape with an average diameter of 224.5 ± 5.7 nm. The encapsulation efficiency was 99.23%. The in vitro drug release profile exhibited a biphasic pattern. The drug formulated in PBCA nanoparticles showed a greater cytotoxicity than paclitaxel against A2780/T cells. Paclitaxel-loaded PBCA as well as blank PBCA nanoparticles decreased P-gp function in a dose-dependent manner, suggesting the efficacy of the drug-loaded nanoparticle system on overcoming MDR. There was no significant effect on inhibition to the expression of MDR1 mRNA.

Conclusions

Paclitaxel-loaded PBCA nanoparticles can enhance cytotoxicity and overcome MDR through a mechanism of the inhibition of P-gp function caused by the nanoparticles system.

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

Access this article

Log in via an institution

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

REFERENCES

  1. Rogers BB. Taxol: a promising new drug of the ‘90s. Oncol Nurs Forum. 1993;20:1483–9.

    PubMed  CAS  Google Scholar 

  2. Singla AK, Garg A, Aggarwal D. Paclitaxel and its formulations. Int J Pharm. 2002;235:179–92.

    Article  PubMed  CAS  Google Scholar 

  3. Liggins RT, Hunter WL, Burt HM. Solid-state characterization of paclitaxel. J Pharm Sci. 1997;86:1458–63.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Yusuf RZ, Duan Z, Lamendola DE, Penson RT, Seiden MV. Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation. Curr Cancer Drug Targets. 2003;3(1):1–19.

    Article  PubMed  CAS  Google Scholar 

  6. Calderwood SK, Khaleque MA, Sawyer DB, Ciocca DR. Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci. 2006;31:164–72.

    Article  PubMed  CAS  Google Scholar 

  7. Kirkin V, Joos S, Zörnig M. The role of Bcl-2 family members in tumorigenesis. Biochim Biophys Acta. 2004;1644:229–49.

    Article  PubMed  CAS  Google Scholar 

  8. Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5:219–34.

    Article  PubMed  Google Scholar 

  9. O’Connor R. The pharmacology of cancer resistance. Anticancer Res. 2007;27:1267–72.

    PubMed  Google Scholar 

  10. Stein WD, Bates SE, Fojo T. Intractable cancers: the many faces of multidrug resistance and the many targets it presents for therapeutic attack. Curr Drug Targets. 2004;5:333–46.

    Article  PubMed  CAS  Google Scholar 

  11. Cuvier C, Roblot-Treupel L, Millot JM, Lizard G, Chevillard S, Manfait M, et al. Doxorubicin-loaded nanospheres bypass tumor cell multidrug resistance. Biochem Pharmacol. 1992;44:509–17.

    Article  PubMed  CAS  Google Scholar 

  12. Soma CE, Dubernet C, Barratt G, Ne´mati F, Appel M, Benita S, et al. Ability of doxorubicin-loaded nanoparticles to overcome multi-drug resistance of tumor cells after their capture by macrophages. Pharm Res. 1999;16:1710–6.

    Article  PubMed  CAS  Google Scholar 

  13. Önyüksel H, Jeon E, Rubinstein I. Nanomicellar paclitaxel increases cytotoxicity of multidrug resistant breast cancer cells. Cancer Letters. 2009;274:327–30.

    Article  PubMed  Google Scholar 

  14. Minko T, Kopeckova P, Pozharov V, Kopecek J. HPMA copolymer bound adriamycin overcomes MDR1 gene encoded resistance in a human ovarian carcinoma cell line. J Control Release. 1998;54:223–33.

    Article  PubMed  CAS  Google Scholar 

  15. Huang CY, Chen CM, Lee YD. Synthesis of high loading and encapsulation efficient paclitaxel-loaded poly(n-butyl cyanoacrylate) nanoparticles via miniemulsion. Int J Pharm. 2007;338:267–75.

    Article  PubMed  CAS  Google Scholar 

  16. Couvreur P, Kante B, Lenaerts V, Scailteur V, Roland M, Speiser P. Tissue distribution of antitumor drugs associated with polyalkylcyanoacrylate nanoparticles. J Pharm Sci. 1980;69:199–202.

    Article  PubMed  CAS  Google Scholar 

  17. Couvreur P, Fattal E, Alphandary H, Puisieux F, Andremont A. Intracellular targeting of antibiotics by means of biodegradable nanoparticles. J Control Release. 1992;19:259–67.

    Article  CAS  Google Scholar 

  18. Damge C, Michel C, Aprahamian M, Couvreur P, Devissaguet JP. Nanocapsules as carriers for oral peptide delivery. J Control Release. 1990;13:233–39.

    Article  CAS  Google Scholar 

  19. Tasset Ch, Barette N, Thysman S, Ketelslegers JM, Lemoine D, Preat V. Polyisobutylcyanoacrylate nanoparticles as sustained release system for calcitonin. J Control Release. 1995;33:23–30.

    Article  CAS  Google Scholar 

  20. Li Y, Ogris M, Wagner E, Pelisek J, Rüffer M. Nanoparticles bearing polyethyleneglycol-coupled transferrin as gene carriers: preparation and in vitro evaluation. Int J Pharm. 2003;259:93–101.

    Article  PubMed  CAS  Google Scholar 

  21. Ne´mati F, Dubernet C, de Verdière AC, Pouponb MF, Treupel-Acarc L, Puisieux F, et al. Some parameters influencing cytotoxicity of free doxorubicin and doxorubiicn-loaded nanoparticles in sensitive and multidrug resistant leucemic murine cells: incubation time, number of nanoparticles per cell. Int J Pharm. 1994;102:55–62.

    Article  Google Scholar 

  22. de Verdière AC, Dubernet C, Némati F, Soma E, Appel M, Ferté J, et al. Reversion of multidrug resistance with polyalkylcyanoacrylate nanoparticles: towards a mechanism of action. Br J Cancer. 1997;76:198–205.

    Article  PubMed  Google Scholar 

  23. Dong X, Mattingly CA, Tseng MT, Cho MJ, Liu Y, Adams VR, et al. Doxorubicin and paclitaxel-loaded lipid-based nanoparticles overcome multidrug resistance by inhibiting P-glycoprotein and depleting ATP. Cancer Res. 2009;69:3918–26.

    Article  PubMed  CAS  Google Scholar 

  24. Zhang Y, Tang L, Sun L, Bao J, Song C, Huang L, et al. A novel paclitaxel-loaded poly(epsilon-caprolactone)/Poloxamer 188 blend nanoparticle overcoming multidrug resistance for cancer treatment. Acta Biomater. 2010;6:2045–52.

    Article  PubMed  CAS  Google Scholar 

  25. Ravindran J, Nair HB, Sung B, Prasad S, Tekmal RR, Aggarwal BB. Thymoquinone poly (lactide-co-glycolide) nanoparticles exhibit enhanced anti-proliferative, anti-inflammatory, and chemosensitization potential. Biochem Pharmacol. 2010;79:1640–7.

    Article  PubMed  CAS  Google Scholar 

  26. Wong HL, Rauth AM, Bendayan R, Manias JL, Ramaswamy M, Liu Z, et al. A new polymer-lipid hybrid nanoparticle system increases cytotoxicity of doxorubicin against multidrug-resistant human breast cancer cells. Pharm Res. 2006;23:1574–85.

    Article  PubMed  CAS  Google Scholar 

  27. Wong HL, Bendayan R, Rauth AM, Xue HY, Babakhanian K, Wu XY. A mechanistic study of enhanced doxorubicin uptake and retention in multi-drug resistant breast cancer cells using a polymer-lipid hybrid nanoparticle system. J Pharmacol Exp Ther. 2006;317:1372–81.

    Article  PubMed  CAS  Google Scholar 

  28. Chavanpatil MD, Patil Y, Panyam J. Susceptibility of nanoparticle-encapsulated paclitaxel to P-glycoprotein-mediated drug efflux. Int J Pharm. 2006;320:150–6.

    Article  PubMed  CAS  Google Scholar 

  29. Hekmatara T, Gelperina S, Vogel V, Yang SR, Kreuter J. Encapsulation of water-insoluble drugs in poly(butyl cyanoacrylate) nanoparticles. J Nanosci Nanotechnol. 2009;9:5091–8.

    Article  PubMed  CAS  Google Scholar 

  30. Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, et al. Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001;299:620–8.

    PubMed  CAS  Google Scholar 

  31. Susa M, Iyer AK, Ryu K, Hornicek FJ, Mankin H, Amiji MM, et al. Doxorubicin loaded polymeric nanoparticulate delivery system to overcome drug resistance in osteosarcoma. BMC Cancer. 2009;9:399.

    Article  PubMed  Google Scholar 

  32. Mitra A, Lin S. Effect of surfactant on fabrication and characterization of paclitaxel-loaded polybutylcyanoacrylate nanoparticulate delivery systems. J Pharm Pharmacol. 2003;55:895–902.

    Article  PubMed  CAS  Google Scholar 

  33. Mu L, Feng SS. Fabrication, characterization and in vitro release of paclitaxel (Taxol) loaded poly (lactic-co-glycolic acid) microspheres prepared by spray drying technique with lipid/cholesterol emulsifiers. J Control Release. 2001;76:239–54.

    Article  PubMed  CAS  Google Scholar 

  34. Slichenmyer WJ, Von Hoff DD. Taxol: a new and effective anti-cancer drug. Anticancer Drugs. 1991;2:519–30.

    Article  PubMed  CAS  Google Scholar 

  35. Dordunoo SK, Burt HM. Solubility and stability of taxol: effects of buffers and cyclodextrins. Int J Pharm. 1996;133:191–201.

    Article  CAS  Google Scholar 

  36. He M, Zhao Z, Yin L, Tang C, Yin C. Hyaluronic acid coated poly(butyl cyanoacrylate) nanoparticles as anticancer drug carriers. Int J Pharm. 2009;373:165–73.

    Article  PubMed  CAS  Google Scholar 

  37. Brigger I, Dubernet C, Couvreur P. Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliv Rev. 2002;54(5):631–51.

    Article  PubMed  CAS  Google Scholar 

  38. Larsen AK, Escargueil AE, Skladanowski A. Resistance mechanisms associated with altered intracellular distribution of anticancer agents. Pharmacol Ther. 2000;85(3):217–29.

    Article  PubMed  CAS  Google Scholar 

  39. Bogman K, Erne-Brand F, Alsenz J, Drewe J. The role of surfactants in the reversal of active transport mediated by multidrug resistance proteins. J Pharm Sci. 2003;92:1250–61.

    Article  PubMed  CAS  Google Scholar 

  40. Lo YL. Phospholipids as multidrug resistance modulators of the transport of epirubicin in human intestinal epithelial Caco-2 cell layers and everted gut sacs of rats. Biochem Pharmacol. 2000;60:1381–90.

    Article  PubMed  CAS  Google Scholar 

  41. Bauer B, Miller DS, Fricker G. Compound profiling for P-glycoprotein at the blood-brain barrier using a microplate screening system. Pharm Res. 2003;20:1170–6.

    Article  PubMed  CAS  Google Scholar 

  42. Mitsunaga Y, Takanaga H, Matsuo H, Naito M, Tsuruo T, Ohtani H, et al. Effect of bioflavonoids on vincristine transport across blood-brain barrier. Eur J Pharmacol. 2000;395:193–201.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS

This work was supported by a grant from the National Natural Science Foundations of China (No30572361). The authors would like to thank Dr. XM Chen (Department of Occupational Hygiene, Southern Medical University) and Dr. XC Bai (Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University) for technical assistance.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Fei Ren, Ruda Chen, Yabin Sun & Guofeng Li

  2. Institute of Cancer Research,, Southern Medical University, Guangzhou, 510515, China

    Ying Wang

  3. Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Yaodong Jiang

Authors
  1. Fei Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruda Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yabin Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yaodong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guofeng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guofeng Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ren, F., Chen, R., Wang, Y. et al. Paclitaxel-Loaded Poly(n-butylcyanoacrylate) Nanoparticle Delivery System to Overcome Multidrug Resistance in Ovarian Cancer. Pharm Res 28, 897–906 (2011). https://doi.org/10.1007/s11095-010-0346-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-010-0346-9

KEY WORDS

Search

Navigation