Hyaluronan-mediated ferric oxide nanoparticles causes apoptosis of CD44 expressing head and neck squamous cell carcinoma cells

Ranjeeta Thapa, Jason Gorski, Anthony Bogedin, Michael Maywood, Christopher Clement, Seyedmehdi Hossaini Nasr, Darrin Hanna, Xuefei Huang, Bradley J Roth, Gerard Madlambayan, George D Wilson


Purpose: To eliminate CD44, a putative cancer stem cell (CSC) marker, overexpressing  head and neck squamous cell carcinoma (HNSCC) cells by using hyaluronan-conjugated, dextran-coated super paramagnetic iron oxide nanoparticles (HA-DESPIONs), in conjunction with induced heat produced by exposure to an alternating magnetic field (AMF).

Methods: An AMF generator was constructed by means of a solenoid coil and an impedance circuit driven by a power amplifier. A signal generator produced a small sinusoidal signal of 130 kHz that was then amplified to 9 A (peak to peak value) to generate an AMF of approximately 10 kA/m (12.6 mT) at the center of a coil. The heat generating effect of the AMF generator was tested via several kinetic and dose-dependent bulk heating experiments by exposing readily available magnetic nanoparticles to AMF. For elimination of CD44 population, UT-SCC-14 cells were exposed to either targeted HA-DESPIONs or non-targeted DESPIONs at a concentration 200 μg/ml and exposed to AMF for 30 minutes. Cells were processed after 24 hours for flow cytometry based analysis of apoptosis.

Results: Magnetic nanoparticles caused a concentration-dependent bulk heating effect in response to AMF resulting in a significant temperature rise. Following the exposure to AMF, non-conjugated DESPIONs were unable to induce targeted hyperthermia and hence had no effect on CD44 cell death in HNSCC cells. However, there was a significant cell death in the CD44 population treated with HA-DESPIONs and exposed to AMF. This effect was only obeserved when the magnetic field was turned on.

Conclusion: Bulk heating experiments concluded that a simple AMF generator was able to activate magnetic nanoparticles and flow cytometry demonstrated that HA- DESPIONs were able to cause apoptosis in UT-SCC-14 cells that express CD44.This may be a promising strategy to specifically target cancer stem cells (CSCs) for the treatment of HNSCC.


HNSCC, CD44, HA-DESPIONs, CSCs, AMF generator, magnetic hyperthermia

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Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357(17):1695-704.

Pignon JP, le Maître A, Maillard E, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009 Jul;92(1):4-14.

Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-11.

Prince ME, Sivanandan R, Kaczorowski A, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A. 2007;104(3):973-8.

Wang SJ, Wong G, de Heer AM, et al. CD44 Variant isoforms in head and neck squamous cell carcinoma progression. Laryngoscope. 2009;119(8):1518-30.

Toole BP, Slomiany MG. Hyaluronan, CD44 and Emmprin: partners in cancer cell chemoresistance. Drug Resist Updat. 2008;11(3):110-21.

Laurent TC, Laurent UB, Fraser JR. The structure and function of hyaluronan: An overview. Immunol Cell Biol. 1996;74(2):A1-7.

Bartolazzi A, Peach R, Aruffo A, Stamenkovic I. Interaction betwenn CD44 and hyaluronate is directly implicated in the regulation of tumor-development. J Exp Med. 1994;180(1):53-66.

Liu W, Frank JA. Detection and quantification of magnetically labeled cells by cellular MRI. Eur J Radiol. 2009;70(2):258-64.

Dixon WT, Blezek DJ, Lowery LA, et al. Estimating amounts of iron oxide from gradient echo images. Magn Reson Med. 2009;61(5):1132-6.

Ang KK, Andratschke NH, Milas L. Epidermal growth factor receptor and response of head-and-neck carcinoma to therapy. Int J Radiat Oncol Biol Phys. 2004;58(3):959-65.

Zhao Q, Wang LN, Cheng R, et al. Magnetic nanoparticle-based hyperthermia for head & neck cancer in mouse models. Theranostics. 2012;2(1):113-21.

Drake P, Cho H-J, Shih P-S, Kao C-H, Lee K-F, Kuo C-H, et al. Gd-doped iron-oxide nanoparticles for tumour therapy via magnetic field hyperthermia. J Mater Chem. 2007;17(46):4914-8.

Smolkova IS, Kazantseva NE, Babayan V, Smolka P, Parmar H, Vilcakova J, et al. Alternating magnetic field energy absorption in the dispersion of iron oxide nanoparticles in a viscous medium. J Magn Magn Mater. 2015;374:508-15.

Thomas LA, Dekker L, Kallumadil M, Southern P, Wilson M, Nair SP, et al. Carboxylic acid-stabilised iron oxide nanoparticles for use in magnetic hyperthermia. J Mater Chem. 2009;19(36):6529-35.

Muller S. Magnetic fluid hyperthermia therapy for malignant brain tumors-an ethical discussion. Nanomedicine. 2009;5(4):387-93.

Provenzale JM, Silva GA. Uses of Nanoparticles for Central Nervous System Imaging and Therapy. AJNR Am J Neuroradiol. 2009;30(7):1293-301.

Thapa R, Galoforo S, Kandel SM, El-dakdouki MH, Wilson TG, Huang X, et al. Radiosensitizing and hyperthermic properties of hyaluronan conjugated, dextran-coated ferric oxide nanoparticles: Implications for cancer stem cell therapy. J Nanomater. 2015; 2015:840594.

El-Dakdouki MH, Zhu DC, El-Boubbou K, et al. Development of multifunctional hyaluronan-coated nanoparticles for imaging and drug delivery to cancer cells. Biomacromolecules. 2012;13(4):1144-51.

El-Dakdouki MH, El-Boubbou K, Kamat M, et al. CD44 Targeting magnetic glyconanoparticles for atherosclerotic plaque imaging. Pharm Res. 2014;31(6):1426-37.

Wilson GD, Marples B, Galoforo S, et al. Isolation and genomic characterization of stem cells in head and neck cancer. Head Neck. 2013;35(11):1573-82.

Kamat M, El-Boubbou K, Zhu DC, Lansdell T, Lu X, Li W, et al. Hyaluronic acid immobilized magnetic nanoparticles for active targeting and imaging of macrophages. Bioconjug Chem. 2010;21(11):2128-35.

El-Boubbou K, Zhu DC, Vasileiou C, Borhan B, Prosperi D, Li W, et al. Magnetic glyco-nanoparticles: a tool to detect, differentiate, and unlock the glyco-codes of cancer via magnetic resonance imaging. J Am Chem Soc. 2010;132(12):4490-9.

El-Dakdouki MH, El-Boubbou K, Zhu DC, Huang X. A simple method for the synthesis of hyaluronic acid coated magnetic nanoparticles for highly efficient cell labelling and in vivo imaging. Rsc Adv. 2011;1(8):1449-52.

Thapa R, Wilson GD. Head and neck cancer: Current treatment options and associated challenges. Sch J App Med Sci. 2016;4(2D):590-600.

Thapa R, Wilson GD. The importance of CD44 as a stem cell biomarker and therapeutic target in cancer. Stem Cells Int. 2016;2016:2087204.

Thomas RG, Moon MJ, Lee H, et al. Hyaluronic acid conjugated superparamagnetic iron oxide nanoparticle for cancer diagnosis and hyperthermia therapy. Carbohydr Polym. 2015;131:439-46.

Singh N, Jenkins GJS, Asadi R, Doak SH. Potential toxicity of superparamagnetic iron oxide nanoparticles (SPION). Nano Rev. 2010;1.

Wabler M, Zhu W, Hedayati M, et al. Magnetic resonance imaging contrast of iron oxide nanoparticles developed for hyperthermia is dominated by iron content. Int J Hyperthermia. 2014;30(3):192-200.

Wilson GD, Thibodeau BJ, Fortier LE, et al. Cancer Stem Cell Signaling during Repopulation in Head and Neck Cancer. Stem Cells Int. 2016;2016:1894782.

Yee S, Ionascu D, Thapa R, Wilson GD. An exploratory RF pulse sequence technique used to induce differential heating in tissues containing iron oxide nanoparticles for a possible hyperthermic adjuvant effect to radiotherapy. Med Phys. 2014;41:356.

DOI: http://dx.doi.org/10.14319/ijcto.42.4

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