Combining ultrasmall gadolinium-based nanoparticles with photon irradiation overcomes radioresistance of head and neck squamous cell carcinoma

doi:10.1016/j.nano.2014.06.013

Nanomedicine: Nanotechnology, Biology and Medicine

Volume 11, Issue 1, January 2015, Pages 247-257

https://doi.org/10.1016/j.nano.2014.06.013 Get rights and content

Abstract

Gadolinium based nanoparticles (GBNs, diameter 2.9 ± 0.2 nm), have promising biodistribution properties for theranostic use in-vivo. We aimed at demonstrating the radiosensitizing effect of these GBNs in experimental radioresistant human head and neck squamous cell carcinoma (SQ20B, FaDu and Cal33 cell lines). Combining 0.6 mM GBNs with 250 kV photon irradiation significantly decreased SQ20B cell survival, associated with an increase in non-reparable DNA double-strand breaks, the shortening of G2/M phase blockage, and the inhibition of cell proliferation, each contributing to the commitment of late apoptosis. Similarly, radiation resistance was overcome for SQ20B stem-like cells, as well as for FaDu and Cal33 cell lines. Using a SQ20B tumor-bearing mouse model, combination of GBNs with 10 Gy irradiation significantly delayed tumor growth with an increase in late apoptosis and a decrease in cell proliferation. These results suggest that GBNs could be envisioned as adjuvant to radiotherapy for HNSCC tumors.

From the Clinical Editor

Gadolinium-based nanoparticles are studied as radiosensitizing theranostic agents to address head and neck squamous cell carcinoma in this novel study, demonstrating a promising adjuvant to radiotherapy for these often treatment resistant tumors.

Graphical Abstract

Gadolinium based nanoparticles (GBNs), less than 5 nm in diameter, combined with radiotherapy increase irreversible DNA double-strand breaks and mitotic catastrophe, leading to late apoptosis and therefore cell death. This radiosensitizing effect of GBNs is demonstrated in vitro in three radioresistant human head and neck squamous cell carcinoma (HNSCC) cell lines, and in vivo in mice bearing human SQ20B HNSCC tumor.

Section snippets

Gadolinium-based nanoparticles

GBNs consist of a polysiloxane core surrounded by gadolinium chelates (DTPA) covalently grafted to the inorganic matrix (Figure S1 in Supplementary Materials). GBNs were synthesized as described previously.¹⁷ For confocal and intra-tumor distribution studies, cyanine 5.5 (Cy5.5)-labeled GBNs were used.

Cell lines and culture conditions

The HNSCC SQ20B cell line, established from a patient with recurrence of a squamous cell carcinoma of the larynx after radiation therapy,¹⁹ was cultured as described previously.²⁰ A SQ20B/SP/CD44⁺

Cellular uptake of GBNs and cell viability

Nanoparticle internalization was followed by confocal microscopy analysis after 1 h incubation of SQ20B cells at 37 °C with different concentrations of Cy5.5-labeled GBNs (Figure 1, A). At concentrations of 0.2, 0.4, and 0.6 mM, GBNs were distributed throughout the cytoplasm without colocalization with DAPI nuclear dye. Large aggregates were observed outside the cell at the vicinity of the plasma for a GBN concentration of 0.8 mM or higher. For subsequent in vitro experiments, we used 0.4 and 0.6 mM

Discussion

In the present study, we demonstrated that small size nanoparticles, radiosensitized in vitro SQ20B cells and their corresponding stem cells, as well as 2 other HNSCC radioresistant tumor cell lines, showing a synergistic effect of GBNs combined with a 250 kV energy irradiation. We also demonstrated that cell death induced in response to the combined treatment was characteristic of mitotic catastrophe followed by late apoptosis, secondary to massive production of ROS and alteration of

Acknowledgments

We acknowledge M. Benchaib for providing assistance with biostatistical analysis, P. Bonazza for technical assistance, G. Alphonse for irradiation support. We would also like to acknowledge the flow cytometry platform of UFR BioSciences Gerland-Lyon-Sud (UMS3444/ US8) for their contribution. English correction was performed by Online English.

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: This work has been presented in part at WMIC2012 and AACR 2013.

: This project was funded and conducted under the framework of LANTHARAD (PDC019 CLARA) and LABEX PRIMES (ANR-11LABX-0063).

: Disclosure of potential conflict of interest: No potential conflicts of interest were disclosed.

¹: Should be considered as first co-author.

²: Should be considered as co-director.

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Original ArticleCombining ultrasmall gadolinium-based nanoparticles with photon irradiation overcomes radioresistance of head and neck squamous cell carcinoma

Abstract

From the Clinical Editor

Graphical Abstract

Section snippets

Gadolinium-based nanoparticles

Cell lines and culture conditions

Cellular uptake of GBNs and cell viability

Discussion

Acknowledgments

Adv Drug Deliv Rev

Nanomedicine: NBM

Biomaterials

Eur J Cancer Clin Oncol

Biochem Pharmacol

Int J Radiat Oncol Biol Phys

Mol Ther

Int J Radiat Oncol Biol Phys

Semin Radiat Oncol

Intensity modulating and other radiation therapy devices for dose painting

J Clin Oncol

New use of metals as nanosized radioenhancers

Anticancer Res

Renal clearance of quantum dots

Nat Biotechnol

Radiotherapy enhancement with gold nanoparticles

J Pharm Pharmacol

The use of gold nanoparticles to enhance radiotherapy in mice

Phys Med Biol

Gold nanoparticles enhance the radiation therapy of a murine squamous cell carcinoma

Phys Med Biol

Evaluation of cytotoxicity and radiation enhancement using 1.9 nm gold particles: potential application for cancer therapy

Nanotechnology

Preferential tumour accumulation of gold nanoparticles, visualized by magnetic resonance imaging: radiosensitization studies in vivo and in vitro

Int J Radiat Biol

Hybrid gadolinium oxide nanoparticles: multinodal contrast agents for in vivo imaging

J Am Chem Soc

Ultrasmall rigid particles as multimodal probes for medical applications

Angew Chem Int Ed Engl

Hybrid gadolinium oxide nanoparticles combining imaging and therapy

J Mater Chem

Biodistribution study of nanometric hybrid gadolinium oxide particles as a multimodal SPECT/MR/optical imaging and theragnostic agent

Bioconjug Chem

Biodistribution of ultra-small gadolinium-based nanoparticles as theranostic agent: application to brain tumors

J Biomater Appl

Towards an image-guided microbeam radiation therapy using gadolinium-based nanoparticles

ACS Nano

Original Article
Combining ultrasmall gadolinium-based nanoparticles with photon irradiation overcomes radioresistance of head and neck squamous cell carcinoma