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Molecular Imaging and Biology

, Volume 16, Issue 5, pp 680–689 | Cite as

Combination Treatment with Theranostic Nanoparticles for Glioblastoma Sensitization to TMZ

  • Byunghee Yoo
  • Marytheresa A. Ifediba
  • Subrata Ghosh
  • Zdravka Medarova
  • Anna Moore
Research Article

Abstract

Purpose

Tumor resistance to chemotherapeutic drugs is one of the major obstacles in the treatment of glioblastoma multiforme (GBM). In this study, we attempted to modulate tumor response to chemotherapy by combination treatment that included experimental (small interference RNA (siRNA), chlorotoxin) and conventional (temozolomide, TMZ) therapeutics.

Procedures

siRNA therapy was used to silence O6-methylguanine methyltransferase (MGMT), a key factor in brain tumor resistance to TMZ. For targeting of tumor cells, we used chlorotoxin (CTX), a peptide with antitumoral properties. siRNA and CTX were conjugated to iron oxide nanoparticles (NP) that served as the drug carrier and allowed the means to monitor the changes in tumor volume by magnetic resonance imaging (MRI).

Results

Theranostic nanoparticles (termed CTX-NP-siMGMT) were internalized by T98G glioblastoma cells in vitro leading to enhancement of TMZ toxicity. Combination treatment of mice bearing orthotopic tumors with CTX-NP-siMGMT and TMZ led to significant retardation of tumor growth, which was monitored by MRI.

Conclusions

While our results demonstrate that siRNA delivery by targeted nanoparticles resulted in modulating tumor response to chemotherapy in GBM, they also point to a significant contribution of CTX to tumor cell death.

Key words

Theranostic Nanoparticle Glioblastoma multiforme siRNA MRI Chlorotoxin Targeting Temozolomide 

Notes

Acknowledgments

This work was supported in part by T32CA009502 (PI Anna Moore).

Conflict of Interest Statement

Authors declare no potential conflicts of interest relevant to this publication.

Supplementary material

11307_2014_734_MOESM1_ESM.pdf (1.4 mb)
ESM 1 (PDF 1,433 kb)

References

  1. 1.
    Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRefGoogle Scholar
  3. 3.
    Friedman HS, Kerby T, Calvert H (2000) Temozolomide and treatment of malignant glioma. Clin Cancer Res 6:2585–2597PubMedGoogle Scholar
  4. 4.
    Hegi ME, Diserens AC, Godard S et al (2004) Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 10:1871–1874PubMedCrossRefGoogle Scholar
  5. 5.
    Hegi ME, Diserens AC, Gorlia T et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003PubMedCrossRefGoogle Scholar
  6. 6.
    Pegg AE (1990) Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res 50:6119–6129PubMedGoogle Scholar
  7. 7.
    Dumenco LL, Allay E, Norton K, Gerson SL (1993) The prevention of thymic lymphomas in transgenic mice by human O6-alkylguanine-DNA alkyltransferase. Science 259:219–222PubMedCrossRefGoogle Scholar
  8. 8.
    Kaina B, Fritz G, Mitra S, Coquerelle T (1991) Transfection and expression of human O6-methylguanine-DNA methyltransferase (MGMT) cDNA in Chinese hamster cells: the role of MGMT in protection against the genotoxic effects of alkylating agents. Carcinogenesis 12:1857–1867PubMedCrossRefGoogle Scholar
  9. 9.
    Pistollato F, Abbadi S, Rampazzo E et al (2010) Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma. Stem Cells 28:851–862PubMedCrossRefGoogle Scholar
  10. 10.
    Hegi ME, Liu L, Herman JG et al (2008) Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol 26:4189–4199PubMedCrossRefGoogle Scholar
  11. 11.
    Paz MF, Yaya-Tur R, Rojas-Marcos I et al (2004) CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clin Cancer Res 10:4933–4938PubMedCrossRefGoogle Scholar
  12. 12.
    Weller M, Stupp R, Reifenberger G et al (2010) MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 6:39–51PubMedCrossRefGoogle Scholar
  13. 13.
    Yoshino A, Ogino A, Yachi K et al (2010) Gene expression profiling predicts response to temozolomide in malignant gliomas. Int J Oncol 36:1367–1377PubMedCrossRefGoogle Scholar
  14. 14.
    Chinnasamy N, Rafferty JA, Hickson I et al (1997) O6-benzylguanine potentiates the in vivo toxicity and clastogenicity of temozolomide and BCNU in mouse bone marrow. Blood 89:1566–1573PubMedGoogle Scholar
  15. 15.
    Fairbairn LJ, Watson AJ, Rafferty JA et al (1995) O6-benzylguanine increases the sensitivity of human primary bone marrow cells to the cytotoxic effects of temozolomide. Exp Hematol 23:112–116PubMedGoogle Scholar
  16. 16.
    Kato T, Natsume A, Toda H et al (2010) Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells. Gene Ther 17:1363–1371PubMedCrossRefGoogle Scholar
  17. 17.
    Kumar M, Yigit M, Dai G et al (2010) Image-guided breast tumor therapy using a small interfering RNA nanodrug. Cancer Res 70:7553–7561PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Medarova Z, Pham W, Farrar C et al (2007) In vivo imaging of siRNA delivery and silencing in tumors. Nat Med 13:372–377PubMedCrossRefGoogle Scholar
  19. 19.
    Kumar M, Medarova Z, Pantazopoulos P et al (2010) Novel membrane-permeable contrast agent for brain tumor detection by MRI. Magn Reson Med 63:617–624PubMedCrossRefGoogle Scholar
  20. 20.
    DeBin JA, Strichartz GR (1991) Chloride channel inhibition by the venom of the scorpion Leiurus quinquestriatus. Toxicon 29:1403–1408PubMedCrossRefGoogle Scholar
  21. 21.
    Lyons SA, O'Neal J, Sontheimer H (2002) Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin. Glia 39:162–173PubMedCrossRefGoogle Scholar
  22. 22.
    Deshane J, Garner CC, Sontheimer H (2003) Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. J Biol Chem 278:4135–4144PubMedCrossRefGoogle Scholar
  23. 23.
    Veiseh M, Gabikian P, Bahrami SB et al (2007) Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci. Cancer Res 67:6882–6888PubMedCrossRefGoogle Scholar
  24. 24.
    Mamelak AN, Rosenfeld S, Bucholz R et al (2006) Phase I single-dose study of intracavitary-administered iodine-131-TM-601 in adults with recurrent high-grade glioma. J Clin Oncol 24:3644–3650PubMedCrossRefGoogle Scholar
  25. 25.
    Shen S, Khazaeli MB, Gillespie GY, Alvarez VL (2005) Radiation dosimetry of 131I-chlorotoxin for targeted radiotherapy in glioma-bearing mice. J Neurooncol 71:113–119PubMedCrossRefGoogle Scholar
  26. 26.
    Soroceanu L, Gillespie Y, Khazaeli MB, Sontheimer H (1998) Use of chlorotoxin for targeting of primary brain tumors. Cancer Res 58:4871–4879PubMedGoogle Scholar
  27. 27.
    Kievit FM, Veiseh O, Fang C et al (2010) Chlorotoxin labeled magnetic nanovectors for targeted gene delivery to glioma. ACS Nano 4:4587–4594PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Lee MJ, Veiseh O, Bhattarai N et al (2010) Rapid pharmacokinetic and biodistribution studies using cholorotoxin-conjugated iron oxide nanoparticles: a novel non-radioactive method. PLoS One 5:e9536PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Sun C, Fang C, Stephen Z et al (2008) Tumor-targeted drug delivery and MRI contrast enhancement by chlorotoxin-conjugated iron oxide nanoparticles. Nanomedicine 3:495–505PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Veiseh O, Kievit FM, Fang C et al (2010) Chlorotoxin bound magnetic nanovector tailored for cancer cell targeting, imaging, and siRNA delivery. Biomaterials 31:8032–8042PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Veiseh O, Sun C, Fang C et al (2009) Specific targeting of brain tumors with an optical/magnetic resonance imaging nanoprobe across the blood–brain barrier. Cancer Res 69:6200–6207PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Veiseh O, Sun C, Gunn J et al (2005) Optical and MRI multifunctional nanoprobe for targeting gliomas. Nano Lett 5:1003–1008PubMedCrossRefGoogle Scholar
  33. 33.
    Fu YJ, Yin LT, Liang AH et al (2007) Therapeutic potential of chlorotoxin-like neurotoxin from the Chinese scorpion for human gliomas. Neurosci Lett 412:62–67PubMedCrossRefGoogle Scholar
  34. 34.
    McFerrin MB, Sontheimer H (2006) A role for ion channels in glioma cell invasion. Neuron Glia Biol 2:39–49PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Watson AJ, Margison GP (1999) O (6)-Alkylguanine-DNA Alkyltransferase Assay. Methods Mol Med 28:167–178PubMedGoogle Scholar
  36. 36.
    Carlson BL, Pokorny JL, Schroeder MA, Sarkaria JN (2011) Establishment, maintenance and in vitro and in vivo applications of primary human glioblastoma multiforme (GBM) xenograft models for translational biology studies and drug discovery. Curr Protoc Pharmacol Chapter 14:Unit 14 16.Google Scholar
  37. 37.
    Akinc A, Thomas M, Klibanov A, Lanfer R (2005) Exploring polyethylenimine-mediated DNA transfection and the proton sponge hypothesis. J Gene Med 7:657–663PubMedCrossRefGoogle Scholar
  38. 38.
    Wang P, Yigit MV, Ran C et al (2012) A theranostic small interfering RNA nanoprobe protects pancreatic islet grafts from adoptively transferred immune rejection. Diabetes 61:3247–3254PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Wang P, Yigit M, Medarova Z et al (2011) Combined small interfering RNA therapy and in vivo magnetic resonance imaging in islet transplantation. Diabetes 60:565–571PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Hobbs SK, Monsky WL, Yuan F et al (1998) Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci U S A 95:4607–4612PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Chahal M, Xu Y, Lesniak D et al (2010) MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib. Neuro Oncol 12:822–833PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Cordier D, Forrer F, Kneifel S et al (2010) Neoadjuvant targeting of glioblastoma multiforme with radiolabeled DOTAGA-substance P—results from a phase I study. J Neurooncol 100:129–136PubMedCrossRefGoogle Scholar
  43. 43.
    Jenkinson MD, Smith TS, Haylock B et al (2010) Phase II trial of intratumoral BCNU injection and radiotherapy on untreated adult malignant glioma. J Neurooncol 99:103–113PubMedCrossRefGoogle Scholar
  44. 44.
    Oshiro S, Tsugu H, Komatsu F et al (2006) Evaluation of intratumoral administration of tumor necrosis factor-alpha in patients with malignant glioma. Anticancer Res 26:4027–4032PubMedGoogle Scholar
  45. 45.
    Moore A, Marecos E, Bogdanov A Jr, Weissleder R (2000) Tumoral distribution of long-circulating dextran-coated iron oxide nanoparticles in a rodent model. Radiology 214:568–574PubMedCrossRefGoogle Scholar
  46. 46.
    Bartlett DW, Davis ME (2006) Insights into the kinetics of siRNA-mediated gene silencing from live-cell and live-animal bioluminescent imaging. Nucleic Acids Res 34:322–333PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Stein GH (1979) T98G: an anchorage-independent human tumor cell line that exhibits stationary phase G1 arrest in vitro. J Cell Physiol 99:43–54PubMedCrossRefGoogle Scholar
  48. 48.
    Yin D, Xie D, Hofmann WK et al (2003) DNA repair gene O6-methylguanine-DNA methyltransferase: promoter hypermethylation associated with decreased expression and G:C to A:T mutations of p53 in brain tumors. Mol Carcinog 36:23–31PubMedCrossRefGoogle Scholar
  49. 49.
    Kesavan K, Ratliff J, Johnson EW et al (2010) Annexin A2 is a molecular target for TM601, a peptide with tumor-targeting and anti-angiogenic effects. J Biol Chem 285:4366–4374PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© World Molecular Imaging Society 2014

Authors and Affiliations

  • Byunghee Yoo
    • 1
  • Marytheresa A. Ifediba
    • 1
    • 2
  • Subrata Ghosh
    • 1
  • Zdravka Medarova
    • 1
  • Anna Moore
    • 1
  1. 1.Molecular Imaging Laboratory, MGH/HST Athinoula A. Martinos Center for Biomedical Imaging, Department of RadiologyMassachusetts General Hospital/Harvard Medical SchoolCharlestownUSA
  2. 2.Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA

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