Skip to main content

Advertisement

SpringerLink
Log in

Paclitaxel- and lapatinib-loaded lipopolymer micelles overcome multidrug resistance in prostate cancer

  • Research Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Paclitaxel is a potent chemotherapeutic agent for treating refractory prostate cancer. However, its prolonged treatment develops multidrug resistance. Since lapatinib interacts with and inhibits P-gp activity, our objective was to determine whether the combination therapy of these two drugs can synergistically treat resistant prostate cancer. Our recently synthesized lipopolymer, poly(ethylene glycol)-block-poly(2-methyl-2-carboxylpropylene carbonate-graft-dodecanol) (PEG–PCD), was used to efficiently load both drugs into PEG–PCD micelles since they are hydrophobic. Lapatinib inhibited P-gp function but not its expression. Co-treatment of DU145-TXR cells with 0.5 μM paclitaxel and 5 μM lapatinib resulted in up to 138-fold reversal compared to paclitaxel alone. These formulations killed almost 70% and 80% of DU145-TXR cells when 0.5 μM paclitaxel was combined with lapatinib at a dose of 1 and 5 μM, respectively, while monotherapy had no effect. Combination therapy induced apoptosis and cell cycle arrest at mitotic phase. Xenograft tumor growth in athymic nude mice was significantly regressed when PEG–PCD micelles carrying lapatinib and paclitaxel were given intravenously twice a week. Furthermore, this combination therapy synergistically decreased antiangiogenic activity compared to the control or their monotherapy. In conclusion, lipopolymeric micelles carrying lapatinib and paclitaxel have the potential to treat resistant prostate cancer and can successfully deliver drugs to tumors while minimizing toxic effects associated with solubilizing agents.

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
Fig. 8

Similar content being viewed by others

References

  1. Theyer G, Schirmbock M, Thalhammer T, Sherwood ER, Baumgartner G, Hamilton G. Role of the MDR-1-encoded multiple drug resistance phenotype in prostate cancer cell lines. J Urol. 1993;150(5 Pt 1):1544–7.

    PubMed  CAS  Google Scholar 

  2. van Brussel JP, Mickisch GH. Multidrug resistance in prostate cancer. Onkologie. 2003;26(2):175–81. doi:10.1159/000071510.

    Article  PubMed  Google Scholar 

  3. Sanchez C, Mendoza P, Contreras HR, Vergara J, McCubrey JA, Huidobro C, et al. Expression of multidrug resistance proteins in prostate cancer is related with cell sensitivity to chemotherapeutic drugs. Prostate. 2009;69(13):1448–59. doi:10.1002/pros.20991.

    Article  PubMed  CAS  Google Scholar 

  4. Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5(3):219–34. doi:10.1038/nrd1984.

    Article  PubMed  CAS  Google Scholar 

  5. Danquah MK, Zhang XA, Mahato RI. Extravasation of polymeric nanomedicines across tumor vasculature. Adv Drug Deliv Rev. 2011;63(8):623–39. doi:10.1016/j.addr.2010.11.005.

    Article  PubMed  Google Scholar 

  6. Li F, Lu Y, Li W, Miller DD, Mahato RI. Synthesis, formulation and in vitro evaluation of a novel microtubule destabilizer, SMART-100. J Control Release. 2010;143(1):151–8. doi:10.1016/j.jconrel.2009.12.028.

    Article  PubMed  CAS  Google Scholar 

  7. Rahman A, Husain SR, Siddiqui J, Verma M, Agresti M, Center M, et al. Liposome-mediated modulation of multidrug resistance in human HL-60 leukemia cells. J Natl Cancer Inst. 1992;84(24):1909–15.

    Article  PubMed  CAS  Google Scholar 

  8. 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(9):3918–26. doi:10.1158/0008-5472.CAN-08-2747.

    Article  PubMed  CAS  Google Scholar 

  9. 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(2):223–33.

    Article  PubMed  CAS  Google Scholar 

  10. Carcaboso AM, Elmeliegy MA, Shen J, Juel SJ, Zhang ZM, Calabrese C, et al. Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas. Cancer Res. 2010;70(11):4499–508. doi:10.1158/0008-5472.CAN-09-4264.

    Article  PubMed  CAS  Google Scholar 

  11. Medina PJ, Goodin S. Lapatinib: a dual inhibitor of human epidermal growth factor receptor tyrosine kinases. Clin Ther. 2008;30(8):1426–47. doi:10.1016/j.clinthera.2008.08.008.

    Article  PubMed  CAS  Google Scholar 

  12. Dai CL, Tiwari AK, Wu CP, Su XD, Wang SR, Liu DG, et al. Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res. 2008;68(19):7905–14. doi:10.1158/0008-5472.CAN-08-0499.

    Article  PubMed  CAS  Google Scholar 

  13. Kuang YH, Shen T, Chen X, Sodani K, Hopper-Borge E, Tiwari AK, et al. Lapatinib and erlotinib are potent reversal agents for MRP7 (ABCC10)-mediated multidrug resistance. Biochem Pharmacol. 2010;79(2):154–61. doi:10.1016/j.bcp.2009.08.021.

    Article  PubMed  CAS  Google Scholar 

  14. Collins DM, Crown J, O’Donovan N, Devery A, O’Sullivan F, O’Driscoll L, et al. Tyrosine kinase inhibitors potentiate the cytotoxicity of MDR-substrate anticancer agents independent of growth factor receptor status in lung cancer cell lines. Investig New Drugs. 2010;28(4):433–44. doi:10.1007/s10637-009-9266-0.

    Article  CAS  Google Scholar 

  15. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672–9. doi:10.1093/jnci/djn123.

    Article  PubMed  CAS  Google Scholar 

  16. Liu Y, Majumder S, McCall W, Sartor CI, Mohler JL, Gregory CW, et al. Inhibition of HER-2/neu kinase impairs androgen receptor recruitment to the androgen responsive enhancer. Cancer Res. 2005;65(8):3404–9. doi:10.1158/0008-5472.CAN-04-4292.

    PubMed  CAS  Google Scholar 

  17. Shaw G, Prowse DM. Inhibition of androgen-independent prostate cancer cell growth is enhanced by combination therapy targeting Hedgehog and ErbB signalling. Cancer Cell Int. 2008;8:3. doi:10.1186/1475-2867-8-3.

    Article  PubMed  Google Scholar 

  18. Sridhar SS, Hotte SJ, Chin JL, Hudes GR, Gregg R, Trachtenberg J, et al. A multicenter phase II clinical trial of lapatinib (GW572016) in hormonally untreated advanced prostate cancer. Am J Clin Oncol. 2010;33(6):609–13. doi:10.1097/COC.0b013e3181beac33.

    Article  PubMed  CAS  Google Scholar 

  19. Di Leo A, Gomez HL, Aziz Z, Zvirbule Z, Bines J, Arbushites MC, et al. Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol. 2008;26(34):5544–52. doi:10.1200/JCO.2008.16.2578.

    Article  PubMed  Google Scholar 

  20. Yamamoto T, Yokoyama M, Opanasopit P, Hayama A, Kawano K, Maitani Y. What are determining factors for stable drug incorporation into polymeric micelle carriers? Consideration on physical and chemical characters of the micelle inner core. J Control Release. 2007;123(1):11–8.

    Article  PubMed  CAS  Google Scholar 

  21. Leung SY, Jackson J, Miyake H, Burt H, Gleave ME. Polymeric micellar paclitaxel phosphorylates Bcl-2 and induces apoptotic regression of androgen-independent LNCaP prostate tumors. Prostate. 2000;44(2):156–63.

    Article  PubMed  CAS  Google Scholar 

  22. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000;65(1–2):271–84.

    Article  PubMed  CAS  Google Scholar 

  23. Greish K, Nagamitsu A, Fang J, Maeda H. Copoly(styrene-maleic acid)-pirarubicin micelles: high tumor-targeting efficiency with little toxicity. Bioconjugate Chem. 2005;16(1):230–6.

    Article  CAS  Google Scholar 

  24. Li F, Danquah M, Mahato RI. Synthesis and characterization of amphiphilic lipopolymers for micellar drug delivery. Biomacromolecules. 2010;11(10):2610–20. doi:10.1021/bm100561v.

    Article  PubMed  CAS  Google Scholar 

  25. Wang TH, Wang HS, Soong YK. Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. Cancer. 2000;88(11):2619–28. doi:10.1002/1097-0142(20000601)88:11.

    Article  PubMed  CAS  Google Scholar 

  26. Dunne G, Breen L, Collins DM, Roche S, Clynes M, O’Connor R. Modulation of P-gp expression by lapatinib. Investig New Drugs. 2010. doi:10.1007/s10637-010-9482-7.

  27. Coley HM, Shotton CF, Ajose-Adeogun A, Modjtahedi H, Thomas H. Receptor tyrosine kinase (RTK) inhibition is effective in chemosensitising EGFR-expressing drug resistant human ovarian cancer cell lines when used in combination with cytotoxic agents. Biochem Pharmacol. 2006;72(8):941–8. doi:10.1016/j.bcp.2006.07.022.

    Article  PubMed  CAS  Google Scholar 

  28. Erlichman C, Boerner SA, Hallgren CG, Spieker R, Wang XY, James CD, et al. The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux. Cancer Res. 2001;61(2):739–48.

    PubMed  CAS  Google Scholar 

  29. Belotti D, Vergani V, Drudis T, Borsotti P, Pitelli MR, Viale G, et al. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res. 1996;2(11):1843–9.

    PubMed  CAS  Google Scholar 

  30. Steeghs N, Nortier JW, Gelderblom H. Small molecule tyrosine kinase inhibitors in the treatment of solid tumors: an update of recent developments. Ann Surg Oncol. 2007;14(2):942–53. doi:10.1245/s10434-006-9227-1.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work is supported by an Idea Award (W81XWH-10-1-0969) from the Department of Defense Prostate Cancer Research Program.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 19 S Manassas, CRB 224, Memphis, TN, 38103-3308, USA

    Feng Li, Michael Danquah, Saurabh Singh, Hao Wu & Ram I. Mahato

Authors
  1. Feng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Danquah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Saurabh Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ram I. Mahato
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ram I. Mahato.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, F., Danquah, M., Singh, S. et al. Paclitaxel- and lapatinib-loaded lipopolymer micelles overcome multidrug resistance in prostate cancer. Drug Deliv. and Transl. Res. 1, 420–428 (2011). https://doi.org/10.1007/s13346-011-0042-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-011-0042-2

Keywords

Search

Navigation