Investigational New Drugs

, Volume 36, Issue 2, pp 206–216 | Cite as

Antitumor activity of raloxifene-targeted poly(styrene maleic acid)-poly (amide-ether-ester-imide) co-polymeric nanomicelles loaded with docetaxel in breast cancer-bearing mice

  • Saeede Enteshari
  • Jaleh Varshosaz
  • Mohsen Minayian
  • Farshid Hassanzadeh
PRECLINICAL STUDIES

Summary

Purpose Raloxifene (RA) receptors have over-expressed GPER-positive breast cancer tumors. The purpose of this work was to evaluate the antitumor activity and pharmacokinetic behavior of docetaxel (DTX), loaded in RA-targeted nanomicelles, which were designed to overcome a lack of specific distribution and inadequate DTX concentration in tumor tissues, as well as its cytotoxicity and damage to normal tissues. Methods DTX-loaded RA-targeted poly(styrene maleic acid) (SMA)- poly(amide-ether-esterimide)-poly(ethylene glycol) (PAEEI-PEG) nanomicelles were prepared; then, their antitumor activity and survival rate were studied in MC4-L2 tumors induced in BALB/c mice. The pharmacokinetics of DTX-loaded SMA-PAEEI-PEG-RA micelles was also investigated in comparison with free DTX. Results DTX-loaded SMA-PAEEI-PEG-RA micelles inhibited tumor growth considerably and increased animal survival as compared to free DTX and non-targeted micelles. SMA-PAEEIPEG-RA micelles enhanced significantly the area under the curve (AUC0-∞) 1.3 times as compared to free DTX and reduced clearance (CL) from 410.43 ml/kg.h (for free DTX) to 308.8 ml/kg.h (for SMA-PAEEI-PEG-RA micelles). Volume of distribution (Vdss) was also reduced 1.4 times as compared to free DTX. RA-targeted micelles increased tumor inhibition rate (TIR) 1.3 times and median survival time (MST) >1.5 times compared to free DTX. Percentage increase in life span (%ILS) was also enhanced significantly from 41.66% to >83.33% in MC4-L2 tumor-bearing BALB/c mice. Discussion All studies in this work showed the potential of DTX-loaded SMA-PAEEI-PEG-RA micelles in the treatment of GPER-positive receptor breast cancer tumors.

Keywords

Poly(styrene maleic acid) poly(amide-ether-ester-imide)-poly(ethylene glycol) targeted micelles raloxifene docetaxel 

Notes

Acknowledgments

Financial support of the project by the Research Vice Chancellery of Isfahan University of Medical Sciences is appreciated. The authors gratefully appreciate the technical assistance of Dr. Mohajeri and MS Mahmoodi in doing immunohistochemical tests.

Compliance with ethical standards

Conflict of interest

Saeede Enteshari declares that she has no conflict of interest. Jaleh Varshosaz declares that she has no conflict of interest. Mohsen Minayian declares that he has no conflict of interest. Farshid Hassanzadeh declares that he has no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

References

  1. 1.
    Jain V, Jain S, Mahajan S (2014) Nanomedicines based drug delivery systems for anti-cancer targeting and treatment. Curr Drug Deliv 12(2):177–191CrossRefGoogle Scholar
  2. 2.
    Liang X-J, Chen C, Zhao Y, Wang PC (2010) Circumventing Tumor Resistance to Chemotherapy by Nanotechnology. Methods Mol Biol 596:467–488CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Byrne J, Betancourt T, Brannon-Peppas L (2008) Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv Drug Deliv Rev 60(15):1615–1626CrossRefPubMedGoogle Scholar
  4. 4.
    Minko T, Rodriguez-Rodriguez L, Pozharov V (2013) Nanotechnology approaches for personalized treatment of multidrug resistant cancers. Adv Drug Deliv Rev 65(13):1880–1895CrossRefPubMedGoogle Scholar
  5. 5.
    Gemignani ML, Armstrong DK (2014) Breast cancer. Gynecol Oncol 132(2):264–267CrossRefPubMedGoogle Scholar
  6. 6.
    Liu B, Yang M, Li R, Ding Y, Qian X, Yu L, Jiang X (2008) The antitumor effect of novel docetaxel-loaded thermosensitive micelles. Eur J Pharm Biopharm 69(2):527–534CrossRefPubMedGoogle Scholar
  7. 7.
    Pazdur R, Cortes JE (1995) Docetaxel. J Clin Oncol 13(10):2643–2655CrossRefPubMedGoogle Scholar
  8. 8.
    Bharali DJ, Khalil M, Gurbuz M, Simone TM, Mousa SA (2009) Nanoparticles and cancer therapy: a concise review with emphasis on dendrimers. Int J Nanomedicine 4(1):1–7CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Liu J, Zeng F, Allen C (2007) In vivo fate of unimers and micelles of a poly(ethylene glycol)-block-poly(caprolactone) copolymer in mice following intravenous administration. Eur J Pharm Biopharm 65(3):309–319CrossRefPubMedGoogle Scholar
  10. 10.
    Qu G, Yao Z, Zhang C, Wu X, Ping Q (2009) PEG conjugated N-octyl-O-sulfate chitosan micelles for delivery of paclitaxel: in vitro characterization and in vivo evaluation. Eur J Pharm Sci 37(2):98–105CrossRefPubMedGoogle Scholar
  11. 11.
    Alexis F, Pridgen E, Molnar LK, Farokhzad OC (2000) Factors affecting the clearance and biodistribution of polymeric nanoparticles. Biotechnology 18:412–420Google Scholar
  12. 12.
    Manchun S, Dass CR, Sriamornsak P (2012) Targeted therapy for cancer using pH-responsive nanocarrier systems. Life Sci 90(11):381–387CrossRefPubMedGoogle Scholar
  13. 13.
    Ganta S, Devalapally H, Shahiwala A, Amiji M (2008) A review of stimuli-responsive nanocarriers for drug and gene delivery. J Control Release 126(3):187–204CrossRefPubMedGoogle Scholar
  14. 14.
    Yang C, Ebrahim Attia AB, Tan JPK, Ke X, Gao S, Hedrick JL, Yang Y-Y (2012) The role of non-covalent interactions in anticancer drug loading and kinetic stability of polymeric micelles. Biomaterials 33(10):2971–2979CrossRefPubMedGoogle Scholar
  15. 15.
    Lappano R, Pisano A, Maggiolini M (2014) GPER function in breast cancer: an overview. Front Endocrinol 5:66CrossRefGoogle Scholar
  16. 16.
    Cheng S-B, Graeber CT, Quinn JA, Filardo EJ (2011) Retrograde transport of the transmembrane estrogen receptor, G-protein-coupled-receptor-30 (GPR30/GPER) from the plasma membrane towards the nucleus. Steroids 76(9):892–896PubMedGoogle Scholar
  17. 17.
    Thomas P, Pang Y, Filardo E, Dong J (2005) Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology 146(2):624–632CrossRefPubMedGoogle Scholar
  18. 18.
    Prossnitz ER, Sklar LA, Oprea TI, Arterburn JB (2008) GPR30: a novel therapeutic target in estrogen-related disease. Trends Pharmacol Sci 29(3):116–123CrossRefPubMedGoogle Scholar
  19. 19.
    Carmeci C, Thompson DA, Ring HZ, Francke U, Weigel RJ (1997) Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer. Genomics 45(3):607–617CrossRefPubMedGoogle Scholar
  20. 20.
    Hol T, Cox MB, Bryant HU, Draper MW (1997) Selective estrogen receptor modulators and postmenopausal women's health. J Women's Health 6(5):523–531CrossRefGoogle Scholar
  21. 21.
    Sporn MB, Dowsett SA, Mershon J, Bryant HU (2004) Role of raloxifene in breast cancer prevention in postmenopausal women: Clinical evidence and potential mechanisms of action. Clin Ther 26(6):830–840CrossRefPubMedGoogle Scholar
  22. 22.
    Varshosaz J, Enteshari S, Hassanzadeh F, Hashemi Bani B (2017) Synthesis of novel polystyrene-poly(amide-ether-ester-imide)-poly(ethylene glycol) co-polymeric micelles loaded with docetaxel: Physicochemical evaluation and cytotoxic effects on breast cancer cell lines. Mater Sci Mater Med (in press)Google Scholar
  23. 23.
    Varshosaz J, Enteshari S, Hassanzadeh F, Hashemi Bani B (2017) Raloxifene targeted styrene maleic acid (SMA)-poly ether ester imide–poly ethylene glycol (PAEEI-PEG) copolymeric micelles for the targeted delivery of docetaxel: Physicochemical evaluation and cytotoxic effects on breast cancer cell lines. Polos One (in press)Google Scholar
  24. 24.
    Lanari C, Lüthy I, Lamb CA, Fabris V, Pagano E, Helguero LA, Sanjuan N, Merani S, Molinolo AA (2001) Five novel hormone-responsive cell lines derived from murine mammary ductal carcinomas: in vivo and in vitro effects of estrogens and progestins. Cancer Res 61(1):293–302PubMedGoogle Scholar
  25. 25.
    Taymouri S, Varshosaz J, Hassanzadeh F, Javanmard SH, Mahzouni P (2016) Pharmacokinetics, organ toxicity and antitumor activity of docetaxel loaded in folate targeted cholesterol based micelles. Curr Drug Deliv 13(4):545–556CrossRefPubMedGoogle Scholar
  26. 26.
    Taheri A, Dinarvand R, Nouri FS, Khorramizadeh MR, Borougeni AT, Mansoori P, Atyabi F (2011) Use of biotin targeted methotrexate-human serum albumin conjugated nanoparticles to enhance methotrexate antitumor efficacy. Int J Nanomedicine 6:1863–1874PubMedPubMedCentralGoogle Scholar
  27. 27.
    Zhao M, Su M, Lin X, Luo Y, He H, Cai C, Tang X (2010) Evaluation of docetaxel-loaded intravenous lipid emulsion: pharmacokinetics, tissue distribution, antitumor activity, safety and toxicity. Pharm Res 27(8):1687–1702CrossRefPubMedGoogle Scholar
  28. 28.
    Ernsting MJ, Tang W-L, MacCallum NW, Li S-D (2012) Preclinical pharmacokinetic, biodistribution, and anti-cancer efficacy studies of a docetaxel-carboxymethylcellulose nanoparticle in mouse models. Biomaterials 33(5):1445–1454CrossRefPubMedGoogle Scholar
  29. 29.
    Wang X, Li J, Wang Y, Cho KJ, Kim G, Gjyrezi A, Koenig L, Giannakakou P, Shin HJC, Tighiouart M (2009) HFT-T, a targeting nanoparticle, enhances specific delivery of paclitaxel to folate receptor-positive tumors. ACS Nano 3(10):3165–3174CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Deng C, Jiang Y, Cheng R, Meng F, Zhong Z (2012) Biodegradable polymeric micelles for targeted and controlled anticancer drug delivery: promises, progress and prospects. Nano Today 7(5):467–480CrossRefGoogle Scholar
  31. 31.
    Zhao L, Y-m W, X-d Z, Liang Y, X-m Z, Li W, B-b L, Wang Y, Yu Y (2009) PK and tissue distribution of docetaxel in rabbits after i.v. administration of liposomal and injectable formulations. J Pharm Biomed Anal 49(4):989–996CrossRefPubMedGoogle Scholar
  32. 32.
    Fang J, Nakamura H, Maeda H (2011) The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 63(3):136–151CrossRefPubMedGoogle Scholar
  33. 33.
    Rezazadeh M, Emami J, Hasanzadeh F, Sadeghi H, Minaiyan M, Mostafavi A, Rostami M, Lavasanifar A (2016) In vivo pharmacokinetics, biodistribution and anti-tumor effect of paclitaxel-loaded targeted chitosan-based polymeric micelle. Drug Deliv 23(5):1707–1717Google Scholar
  34. 34.
    Hu F-Q, Meng P, Dai Y-Q, Du Y-Z, You J, Wei X-H, Yuan H (2008) PEGylated chitosan-based polymer micelle as an intracellular delivery carrier for anti-tumor targeting therapy. Eur J Pharm Biopharm 70(3):749–757CrossRefPubMedGoogle Scholar
  35. 35.
    Sausville EA, Burger AM (2006) Contributions of human tumor xenografts to anticancer drug development. Cancer Res 66(7):3351–3354CrossRefPubMedGoogle Scholar
  36. 36.
    Song Y, Tian Q, Huang Z, Fan D, She Z, Liu X, Cheng X, Yu B, Deng Y (2014) Self-assembled micelles of novel amphiphilic copolymer cholesterol-coupled F68 containing cabazitaxel as a drug delivery system. Int J Nanomedicine 9:2307PubMedPubMedCentralGoogle Scholar
  37. 37.
    Farokhzad OC, Cheng J, Teply BA, Sherifi I, Jon S, Kantoff PW, Richie JP, Langer R (2006) Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci U S A 103(16):6315–6320CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Pharmaceutics, School of Pharmacy and Novel Drug Delivery Systems Research CentreIsfahan University of Medical SciencesIsfahanIran
  2. 2.Department of Pharmacology, School of PharmacyIsfahan University of Medical SciencesIsfahanIran
  3. 3.Department of Pharmaceutical Chemistry, School of PharmacyIsfahan University of Medical SciencesIsfahanIran

Personalised recommendations