Skip to main content

Advertisement

Log in

Nanoparticles coated with the tumor-penetrating peptide iRGD reduce experimental breast cancer metastasis in the brain

Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Metastasis is the main killer in cancer; consequently, there is great interest in novel approaches to prevent and treat metastatic disease. Brain metastases are particularly deadly, as the protection of the blood-brain barrier obstructs the passage of common anticancer drugs. This study used magnetic resonance imaging (MRI) to investigate the therapeutic effects of nanoparticles coated with a tumor-penetrating peptide (iRGD) against a preclinical model of breast cancer brain metastasis. Single doses of iRGD nanoparticle were administered intravenously, and the effect on tumor growth was observed over time. iRGD nanoparticles, when applied in the early stages of metastasis development, strongly inhibited tumor progression. Overall, this study demonstrated for the first time that a single dose of iRGD nanoparticle can have a significant effect on metastatic tumor progression and nonproliferative cancer cell retention when applied early in course of tumor development. These data suggest that iRGD nanoparticles may be useful in preventatively reducing metastasis after a cancer diagnosis has been established.

Key messages

  • bSSFP MRI can be used to track nonproliferative iron-labeled cells and tumor development over time.

  • iRGD-NW, when applied early, has a significant effect on metastatic tumor progression.

  • Retained signal voids represent a subpopulation of nonproliferating tumor cells.

  • Reduced cell retention and tumor burden show a role for iRGD-NW in metastasis prevention.

  • iRGD target is universally expressed; thus, iRGD-NW should be clinically translatable.

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

References

  1. Lin NU (2013) Breast cancer brain metastases: new directions in systemic therapy. Ecancermedicalscience 7:307

    PubMed Central  PubMed  Google Scholar 

  2. Niikura N, Hayaski N, Masuda N, Takashima S, Nakamura R, Watanabe K, Kanbayashi C, Ishida M, Hozumi Y, Tsuneizumi M et al (2014) Treatment outcomes and prognostic factors for patients with brain metastases from breast cancer of each subtype: a multicenter retrospective analysis. Breast Cancer Res Treat 147:103–112

    Article  PubMed  Google Scholar 

  3. Arvold ND, Oh KS, Niemierko A, Taghian AG, Lin NU, Abi-Raad RF, Sreedhara M, Harris JR, Alexander BM (2012) Brain metastases after breast-conserving therapy and systemic therapy: incidence and characteristics by biologic subtype. Breast Cancer Res Treat 136:153–160

    Article  PubMed  Google Scholar 

  4. Brooks PC, Clark RA, Cheresh DA (1994) Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science (New York, N Y) 264:569–571

    Article  CAS  Google Scholar 

  5. Lorger M, Krueger JS, O’Neal M, Staflin K, Felding-Habermann B (2009) Activation of tumor cell integrin alphavbeta3 controls angiogenesis and metastatic growth in the brain. Proc Natl Acad Sci U S A 106:10666–10671

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Ruoslahti E (2002) Specialization of tumour vasculature. Nat Rev Cancer 2:83–90

    Article  PubMed  Google Scholar 

  7. Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Girard OM, Hanahan D, Mattrey RF, Ruoslahti E (2009) Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 16:510–520

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Ruoslahti E, Pierschbacher MD (1986) Arg-Gly-Asp: a versatile cell recognition signal. Cell 44:517–518

    Article  CAS  PubMed  Google Scholar 

  9. Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Greenwald DR, Ruoslahti E (2010) Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328:1031–1035

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Teesalu T, Sugahara KN, Ruoslahti E (2013) Tumor-penetrating peptides. Front Oncol 3:216

    Article  PubMed Central  PubMed  Google Scholar 

  11. Agemy L, Friedmann-Morvinski D, Kotamraju VR, Roth L, Sugahara KN, Girard OM, Mattrey RF, Verma IM, Ruoslahti E (2011) Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma. Proc Natl Acad Sci U S A 108:17450–17455

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Yu KF, Zhang WQ, Luo LM, Song P, Li D, Du R, Ren W, Huang D, Lu WL, Zhang X et al (2013) The antitumor activity of a doxorubicin loaded, iRGD-modified sterically-stabilized liposome on B16-F10 melanoma cells: in vitro and in vivo evaluation. Int J Nanomedicine 8:2473–2485

    PubMed Central  PubMed  Google Scholar 

  13. Sugahara K, Braun GB, de Mendoza TH, Kotamraju VR, French RP, Lowy AM, Teesalu T, Ruoslahti E (2014) A tumor-specific tissue-penetrating peptide inhibits metastasis. AACR Anual Meeting LB-102

  14. Murrell D, Foster PJ, Chambers AF (2014) Brain metastases from breast cancer: lessons from experimental magnetic resonance imaging studies and clinical implications. J Mol Med (Berl) 92:5–12

    Article  Google Scholar 

  15. Heyn C, Ronald JA, Ramadan SS, Snir JA, Barry AM, MacKenzie LT, Mikulis DJ, Palmieri D, Bronder JL, Steeg PS et al (2006) In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain. Magn Reson Med 56:1001–1010

    Article  PubMed  Google Scholar 

  16. Agemy L, Sugahara KN, Kotamraju VR, Gujraty K, Girard OM, Kono Y, Mattrey RF, Park JH, Sailor MJ, Jimenez AI et al (2010) Nanoparticle-induced vascular blockade in human prostate cancer. Blood 116:2847–2856

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Percy DB, Ribot EJ, Chen Y, McFadden C, Simedrea C, Steeg PS, Chambers AF, Foster PJ (2011) In vivo characterization of changing blood-tumor barrier permeability in a mouse model of breast cancer metastasis: a complementary magnetic resonance imaging approach. Invest Radiol 46:718–725

    PubMed  Google Scholar 

  18. Heyn C, Ronald JA, Mackenzie LT, MacDonald IC, Chambers AF, Rutt BK, Foster PJ (2006) In vivo magnetic resonance imaging of single cells in mouse brain with optical validation. Magn Reson Med 55:23–29

    Article  PubMed  Google Scholar 

  19. Park JH, von Maltzahn G, Zhang L, Schwartz MP, Ruoslahti E, Bhatia SN, Sailor MJ (2008) Magnetic iron oxide nanoworms for tumor targeting and imaging. Adv Mater 20:1630–1635

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Lockman PR, Mittapalli RK, Taskar KS, Rudraraju V, Gril B, Bohn KA, Adkins CE, Roberts A, Thorsheim HR, Gaasch JA, Huang S, Palmieri D, Steeg PS, Smith QR (2010) Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res 16(23):5664–5678

  21. Ribot EJ, Martinez-Santiesteban FM, Simedrea C, Steeg PS, Chambers AF, Rutt BK, Foster PJ (2011) In vivo single scan detection of both iron-labeled cells and breast cancer metastases in the mouse brain using balanced steady-state free precession imaging at 1.5 T. J Magn Reson Imaging 34:231–238

    Article  PubMed Central  PubMed  Google Scholar 

  22. Perera M, Ribot EJ, Percy DB, McFadden C, Simedrea C, Palmieri D, Chambers AF, Foster PJ (2012) In vivo magnetic resonance imaging for investigating the development and distribution of experimental brain metastases due to breast cancer. Transl Oncol 5:217–225

    Article  PubMed Central  PubMed  Google Scholar 

  23. Naumov GN, MacDonald IC, Weinmeister PM, Kerkvliet N, Nadkarni KV, Wilson SM, Morris VL, Groom AC, Chambers AF (2002) Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res 62:2162–2168

    CAS  PubMed  Google Scholar 

  24. Fitzgerald DP, Emerson DL, Qian Y, Anwar T, Liewehr DJ, Steinberg SM, Silberman S, Palmieri D, Steeg PS (2012) TPI-287, a new taxane family member, reduces the brain metastatic colonization of breast cancer cells. Mol Cancer Ther 11:1959–1967

    Article  CAS  PubMed  Google Scholar 

  25. Vellon L, Menendez JA, Liu H, Lupu R (2007) Up-regulation of alphavbeta3 integrin expression is a novel molecular response to chemotherapy-induced cell damage in a heregulin-dependent manner. Differentiation 75:819–830

    Article  CAS  PubMed  Google Scholar 

  26. Levkau B, Kenagy RD, Karsan A, Weitkamp B, Clowes AW, Ross R, Raines EW (2002) Activation of metalloproteinases and their association with integrins: an auxiliary apoptotic pathway in human endothelial cells. Cell Death Differ 9:1360–1367

    Article  CAS  PubMed  Google Scholar 

  27. Stupack DG, Puente XS, Boutsaboualoy S, Storgard CM, Cheresh DA (2001) Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J Cell Biol 155:459–470

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Kurozumi K, Ichikawa T, Onishi M, Fujii K, Date I (2012) Cilengitide treatment for malignant glioma: current status and future direction. Neurol Med Chir (Tokyo) 52:539–547

    Article  Google Scholar 

  29. Ruegg C, Dormond O, Mariotti A (2004) Endothelial cell integrins and COX-2: mediators and therapeutic targets of tumor angiogenesis. Biochim Biophys Acta 1654:51–67

    CAS  PubMed  Google Scholar 

  30. Grandclement C, Borg C (2011) Neuropilins: a new target for cancer therapy. Cancers (Basel) 3:1899–1928

    Article  CAS  Google Scholar 

  31. Starzec A, Vassy R, Martin A, Lecouvey M, Di Benedetto M, Crepin M, Perret GY (2006) Antiangiogenic and antitumor activities of peptide inhibiting the vascular endothelial growth factor binding to neuropilin-1. Life Sci 79:2370–2381

    Article  CAS  PubMed  Google Scholar 

  32. Castro-Rivera E, Ran S, Brekken RA, Minna JD (2008) Semaphorin 3B inhibits the phosphatidylinositol 3-kinase/Akt pathway through neuropilin-1 in lung and breast cancer cells. Cancer Res 68:8295–8303

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Nasarre C, Roth M, Jacob L, Roth L, Koncina E, Thien A, Labourdette G, Poulet P, Hubert P, Cremel G et al (2010) Peptide-based interference of the transmembrane domain of neuropilin-1 inhibits glioma growth in vivo. Oncogene 29:2381–2392

    Article  CAS  PubMed  Google Scholar 

  34. Zhang L, Parry GC, Levin EG (2013) Inhibition of tumor cell migration by LD22-4, an N-terminal fragment of 24-kDa FGF2, is mediated by Neuropilin 1. Cancer Res 73:3316–3325

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Pilch J, Habermann R, Felding-Habermann B (2002) Unique ability of integrin alpha(v)beta 3 to support tumor cell arrest under dynamic flow conditions. J Biol Chem 277:21930–21938

    Article  CAS  PubMed  Google Scholar 

  36. Saha RN, Vasanthakumar S, Bende G, Snehalatha M (2010) Nanoparticulate drug delivery systems for cancer chemotherapy. Mol Membr Biol 27:215–231

    Article  CAS  PubMed  Google Scholar 

  37. Peng XH, Qian X, Mao H, Wang AY, Chen ZG, Nie S, Shin DM (2008) Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy. Int J Nanomedicine 3:311–321

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Min KH, Lee HJ, Kim K, Kwon IC, Jeong SY, Lee SC (2012) The tumor accumulation and therapeutic efficacy of doxorubicin carried in calcium phosphate-reinforced polymer nanoparticles. Biomaterials 33:5788–5797

    Article  CAS  PubMed  Google Scholar 

  39. Ruoslahti E (2012) Peptides as targeting elements and tissue penetration devices for nanoparticles. Adv Mater 24:3747–3756

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the following: Cancer Center Support grant CA30199, and the Center for Cancer Nanotechnology Excellence and Translation U54 CA119367.

Conflict of interest

K.N.S., V.R.K., and E.R. have ownership interest (including patents) in CendR Therapeutics Inc., and E.R. is a founder, chairman of the board, and consultant/advisory board member of the company. ER is also a consultant/advisory board member and shareholder of EnduRx Pharmaceuticals Inc. and has ownership interest (including patents) in the same. No other authors have conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Amanda M. Hamilton.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hamilton, A.M., Aidoudi-Ahmed, S., Sharma, S. et al. Nanoparticles coated with the tumor-penetrating peptide iRGD reduce experimental breast cancer metastasis in the brain. J Mol Med 93, 991–1001 (2015). https://doi.org/10.1007/s00109-015-1279-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-015-1279-x

Keywords

Navigation