Skip to main content

Advertisement

SpringerLink
Log in

On-Command Drug Release from Nanochains Inhibits Growth of Breast Tumors

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

ABSTRACT

Purpose

To evaluate the ability of radiofrequency (RF)-triggered drug release from a multicomponent chain-shaped nanoparticle to inhibit the growth of an aggressive breast tumor.

Methods

A two-step solid phase chemistry was employed to synthesize doxorubicin-loaded nanochains, which were composed of three iron oxide nanospheres and one doxorubicin-loaded liposome assembled in a 100-nm-long linear nanochain. The nanochains were tested in the 4T1-Luc-GFP orthotopic mouse model, which is a highly aggressive breast cancer model. The 4T1-Luc-GFP cell line stably expresses firefly luciferase, which allowed the non-invasive in vivo imaging of tumor response to the treatment using bioluminescence imaging (BLI).

Results

Longitudinal BLI imaging showed that a single nanochain treatment followed by application of RF resulted in an at least 100-fold lower BLI signal compared to the groups treated with nanochains (without RF) or free doxorubicin followed by RF. A statistically significant increase in survival time of the nanochain-treated animals followed by RF (64.3 days) was observed when compared to the nanochain-treated group without RF (35.7 days), free doxorubicin-treated group followed by RF (38.5 days), and the untreated group (30.5 days; n = 5 animals per group).

Conclusions

These studies showed that the combination of RF and nanochains has the potential to effectively treat highly aggressive cancers and prolong survival.

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

Similar content being viewed by others

References

  1. Ferrari M. Cancer nanotechnology: opportunities and challenges. Nat Rev Cancer. 2005;5:161–71.

    Article  CAS  PubMed  Google Scholar 

  2. Lasic DD. Doxorubicin in sterically stabilized liposomes. Nature. 1996;380:561–2.

    Article  CAS  PubMed  Google Scholar 

  3. Dreher MR, Liu W, Michelich CR, Dewhirst MW, Yuan F, Chilkoti A. Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Nat Cancer Inst. 2006;98:335–44.

    Article  CAS  PubMed  Google Scholar 

  4. Yuan F. Transvascular drug delivery in solid tumors. Semin Radiat Oncol. 1998;8:164–75.

    Article  CAS  PubMed  Google Scholar 

  5. Laginha KM, Verwoert S, Charrois GJ, Allen TM. Determination of doxorubicin levels in whole tumor and tumor nuclei in murine breast cancer tumors. Clin Cancer Res. 2005;11:6944–9.

    Article  CAS  PubMed  Google Scholar 

  6. Gabizon A, Goren D, Horowitz AT, Tzemach D, Lossos A, Siegal T. Long-circulating liposomes for drug delivery in cancer therapy: a review of biodistribution studies in tumor-bearing animals. Adv Drug Deliv Rev. 1997;24:337–44.

    Article  CAS  Google Scholar 

  7. Peiris PM, Bauer L, Toy R, Tran E, Pansky J, Doolittle E, et al. Enhanced delivery of chemotherapy to tumors using a multicomponent nanochain with radio-frequency-tunable drug release. ACS Nano. 2012;6:4157–68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Peiris PM, Toy R, Doolittle E, Pansky J, Abramowski A, Tam M, et al. Imaging metastasis using an integrin-targeting chain-shaped nanoparticle. ACS Nano. 2012;6:8783–95.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Peiris PM, Schmidt E, Calabrese M, Karathanasis E. Assembly of linear nano-chains from iron oxide nanospheres with asymmetric surface chemistry. PLoS One. 2011;6:e15927.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Park JH, von Maltzahn G, Zhang LL, Schwartz MP, Ruoslahti E, Bhatia SN, et al. Magnetic iron oxide nanoworms for tumor targeting and imaging. Adv Mater. 2008;20:1630–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Gossuin Y, Disch S, Vuong QL, Gillis P, Hermann RP, Park JH, et al. NMR relaxation and magnetic properties of superparamagnetic nanoworms. Contrast Media Mol Imaging. 2010. doi:10.1002/cmmi.387.

    Google Scholar 

  12. Lu J, Ma S, Sun J, Xia C, Liu C, Wang Z, et al. Manganese ferrite nanoparticle micellar nanocomposites as MRI contrast agent for liver imaging. Biomaterials. 2009;30:2919–28.

    Article  CAS  PubMed  Google Scholar 

  13. Ai H, Flask C, Weinberg B, Shuai X, Pagel MD, Farrel D, et al. Magnetite-loaded polymeric micelles as ultrasensitive magnetic-resonance probes. Adv Mater. 2005;17:1949–52.

    Article  CAS  Google Scholar 

  14. Buzdar AU. Preoperative chemotherapy treatment of breast cancer—a review. Cancer. 2007;110:2394–407.

    Article  CAS  PubMed  Google Scholar 

  15. Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr. 2001;30:96–102.

    Google Scholar 

  16. Tao K, Fang M, Alroy J, Sahagian GG. Imagable 4T1 model for the study of late stage breast cancer. BMC Cancer. 2008;8:228.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Dykxhoorn DM, Wu Y, Xie H, Yu F, Lal A, Petrocca F, et al. miR-200 enhances mouse breast cancer cell colonization to form distant metastases. PLoS One. 2009;4:e7181.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Yori JL, Seachrist DD, Johnson E, Lozada KL, Abdul-Karim FW, Chodosh LA, et al. Kruppel-like factor 4 inhibits tumorigenic progression and metastasis in a mouse model of breast cancer. Neoplasia. 2011;13:601–10.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Bolotin E, Cohen R, Bar L, Emanuel N, Ninio S, Lasic D, et al. Ammonium sulfate gradients for efficient and stable remote loading of amphipathic weak bases into liposomes and ligandoliposomes. J Liposome Res. 1994;4:455–79.

    Article  Google Scholar 

  20. Lelekakis M, Moseley JM, Martin TJ, Hards D, Williams E, Ho P, et al. A novel orthotopic model of breast cancer metastasis to bone. Clin Exp Metastasis. 1999;17:163–70.

    Article  CAS  PubMed  Google Scholar 

  21. Aslaksonand CJ, Miller FR. Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res. 1992;52:1399–405.

    Google Scholar 

  22. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52.

    Article  CAS  PubMed  Google Scholar 

  23. Bertucci F, Finetti P, Birnbaum D. Basal breast cancer: a complex and deadly molecular subtype. Curr Mol Med. 2012;12:96–110.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Perreard L, Fan C, Quackenbush JF, Mullins M, Gauthier NP, Nelson E, et al. Classification and risk stratification of invasive breast carcinomas using a real-time quantitative RT-PCR assay. Breast Cancer Res. 2006;8:R23.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Bertucci F, Finetti P, Cervera N, Charafe-Jauffret E, Buttarelli M, Jacquemier J, et al. How different are luminal A and basal breast cancers? Int J Cancer. 2009;124:1338–48.

    Article  CAS  PubMed  Google Scholar 

  26. Taketo MM. Reflections on the spread of metastasis to cancer prevention. Cancer Prev Res. 2011;4:324–8.

    Article  CAS  Google Scholar 

  27. Gao ZG, Tian L, Hu J, Park IS, Bae YH. Prevention of metastasis in a 4T1 murine breast cancer model by doxorubicin carried by folate conjugated pH sensitive polymeric micelles. J Control Release. 2011;152:84–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Wang Z, Yu Y, Dai W, Lu J, Cui J, Wu H, et al. The use of a tumor metastasis targeting peptide to deliver doxorubicin-containing liposomes to highly metastatic cancer. Biomaterials. 2012;33:8451–60.

    Article  CAS  PubMed  Google Scholar 

  29. Pulaskiand BA, Ostrand-Rosenberg S. Mouse 4T1 breast tumor model. Curr Protoc Immunol. 2001 Chapter 20:Unit 20 22.

  30. Gao ZG, Tian L, Hu J, Park IS, Bae YH. Prevention of metastasis in a 4T1 murine breast cancer model by doxorubicin carried by folate conjugated pH sensitive polymeric micelles. J Control Release. 2011;152:84–89.

    Google Scholar 

  31. Wendt MK, Molter J, Flask CA, Schiemann WP. In vivo dual substrate bioluminescent imaging. J Vis Exp. 2011;56:3245.

    Google Scholar 

  32. Yori JL, Seachrist DD, Johnson E, Lozada KL, Abdul-Karim FW, Chodosh LA, et al. Kruppel-like factor 4 inhibits tumorigenic progression and metastasis in a mouse model of breast cancer. Neoplasia. 2011;13:601–610.

    Google Scholar 

  33. Rose PG. Pegylated liposomal doxorubicin: optimizing the dosing schedule in ovarian cancer. Oncologist. 2005;10:205–14.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

We thank Kristen Lozada for help with the 4T1 tumor model. This work was partially supported by a grant from the American Cancer Society IRG-91-022-18 (EK) and a pilot grant from the Case Comprehensive Cancer Center P30 CA043703 (EK). L.B and R.T. were supported by a fellowship from the NIH Interdisciplinary Biomedical Imaging Training Program (5T32EB007509).

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, USA

    Pubudu M. Peiris, Morgan Tam, Peter Vicente, Aaron Abramowski, Randall Toy, Aaron Mayer, Jenna Pansky, Elizabeth Doolittle, Samantha Tucci, Erik Schmidt, Christopher Shoup, Swetha Rao, Kaitlyn Murray, James P. Basilion & Efstathios Karathanasis

  2. Department of Radiology, Case Western Reserve University, Cleveland, Ohio, USA

    Pubudu M. Peiris, Ramamurthy Gopalakrishnan, James P. Basilion, Mark A. Griswold & Efstathios Karathanasis

  3. Case Center for Imaging Research, Case Western Reserve University, Cleveland, Ohio, USA

    Pubudu M. Peiris, Morgan Tam, Peter Vicente, Aaron Abramowski, Randall Toy, Lisa Bauer, Aaron Mayer, Jenna Pansky, Elizabeth Doolittle, Samantha Tucci, Erik Schmidt, Christopher Shoup, Swetha Rao, Kaitlyn Murray, Ramamurthy Gopalakrishnan, James P. Basilion, Mark A. Griswold & Efstathios Karathanasis

  4. Department of Physics, Case Western Reserve University, Cleveland, Ohio, USA

    Lisa Bauer

  5. Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA

    Ruth A. Keri

  6. Case Comprehensive Cancer Center, Case Western Reserve University, Wickenden Bldg. MS 7207, 10900 Euclid Ave., Cleveland, Ohio, 44106, USA

    Ruth A. Keri, James P. Basilion & Efstathios Karathanasis

Authors
  1. Pubudu M. Peiris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Morgan Tam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Vicente
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aaron Abramowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Randall Toy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lisa Bauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aaron Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jenna Pansky
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Elizabeth Doolittle
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Samantha Tucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Erik Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Christopher Shoup
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Swetha Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kaitlyn Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ramamurthy Gopalakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ruth A. Keri
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. James P. Basilion
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Mark A. Griswold
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Efstathios Karathanasis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Efstathios Karathanasis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peiris, P.M., Tam, M., Vicente, P. et al. On-Command Drug Release from Nanochains Inhibits Growth of Breast Tumors. Pharm Res 31, 1460–1468 (2014). https://doi.org/10.1007/s11095-013-1102-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-013-1102-8

KEY WORDS

Search

Navigation