Molecular Targeting of Ultrasonographic Contrast Agent for Detection of Head and Neck Squamous Cell Carcinoma | Head and Neck Cancer | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Ang KK, Trotti A, Brown BW,  et al.  Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer.  Int J Radiat Oncol Biol Phys. 2001;51(3):571-57811597795PubMedGoogle ScholarCrossref
Sanki A, Uren RF, Moncrieff M,  et al.  Targeted high-resolution ultrasound is not an effective substitute for sentinel lymph node biopsy in patients with primary cutaneous melanoma.  J Clin Oncol. 2009;27(33):5614-561919786669PubMedGoogle ScholarCrossref
Holtel MR. Emerging technology in head and neck ultrasonography.  Otolaryngol Clin North Am. 2010;43(6):1267-1274, vii21044741PubMedGoogle ScholarCrossref
Cosgrove D. Why do we need contrast agents for ultrasound?  Clin Radiol. 1996;51:(suppl 1)  1-48605763PubMedGoogle ScholarCrossref
Blomley MJ, Cooke JC, Unger EC, Monaghan MJ, Cosgrove DO. Microbubble contrast agents: a new era in ultrasound.  BMJ. 2001;322(7296):1222-122511358777PubMedGoogle ScholarCrossref
Cosgrove D. Ultrasound contrast agents: an overview.  Eur J Radiol. 2006;60(3):324-33016938418PubMedGoogle ScholarCrossref
Calliada F, Pallavicini D, Pasamonti M,  et al.  Topical role and future perspectives of sonographic contrast agents in the differential diagnosis of solid thyroid lesions.  Rays. 2000;25(2):191-19711370537PubMedGoogle Scholar
Weihua Z, Tsan R, Huang WC,  et al.  Survival of cancer cells is maintained by EGFR independent of its kinase activity.  Cancer Cell. 2008;13(5):385-39318455122PubMedGoogle ScholarCrossref
Rosenthal EL, Shreenivas S, Peters GE, Grizzle WE, Desmond R, Gladson CL. Expression of extracellular matrix metalloprotease inducer in laryngeal squamous cell carcinoma.  Laryngoscope. 2003;113(8):1406-141012897567PubMedGoogle ScholarCrossref
Amin DN, Hida K, Bielenberg DR, Klagsbrun M. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors.  Cancer Res. 2006;66(4):2173-218016489018PubMedGoogle ScholarCrossref
Newman JR, Bohannon IA, Zhang W, Skipper JB, Grizzle WE, Rosenthal EL. Modulation of tumor cell growth in vivo by extracellular matrix metalloprotease inducer.  Arch Otolaryngol Head Neck Surg. 2008;134(11):1218-122419015455PubMedGoogle ScholarCrossref
Dean NR, Knowles JA, Helman EE,  et al.  Anti-EMMPRIN antibody treatment of head and neck squamous cell carcinoma in an ex-vivo model.  Anticancer Drugs. 2010;21(9):861-86720700044PubMedGoogle ScholarCrossref
Abràmoff MD, Magalhaes PJ, Ram SJ. Image processing with ImageJ.  Biophotonics Intl. 2004;11(7):36-4215084075PubMedGoogle Scholar
Hoyt K, Sorace AG, Saini R. Quantitative mapping of tumor vascularity using volumetric contrast-enhanced ultrasound.  Invest Radiol. 2012;47(3):167-17419854966PubMedGoogle Scholar
Guibal A, Taillade L, Mulé S,  et al.  Noninvasive contrast-enhanced US quantitative assessment of tumor microcirculation in a murine model: effect of discontinuing anti-VEGF therapy.  Radiology. 2010;254(2):420-42920093514PubMedGoogle ScholarCrossref
Carraro R, Molinari F, Deandrea M, Garberoglio R, Suri JS. Characterization of thyroid nodules by 3-D contrast-enhanced ultrasound imaging.  Conf Proc IEEE Eng Med Biol Soc. 2008;2008:2229-223219163142PubMedGoogle Scholar
Deshpande N, Pysz MA, Willmann JK. Molecular ultrasound assessment of tumor angiogenesis.  Angiogenesis. 2010;13(2):175-18820549555PubMedGoogle ScholarCrossref
Willmann JK, Paulmurugan R, Chen K,  et al.  US imaging of tumor angiogenesis with microbubbles targeted to vascular endothelial growth factor receptor type 2 in mice.  Radiology. 2008;246(2):508-51818180339PubMedGoogle ScholarCrossref
Curry JM, Bloedon E, Malloy KM,  et al.  Ultrasound-guided contrast-enhanced sentinel node biopsy of the head and neck in a porcine model.  Otolaryngol Head Neck Surg. 2007;137(5):735-74117967637PubMedGoogle ScholarCrossref
Newman JR, Gleysteen JP, Barañano CF,  et al.  Stereomicroscopic fluorescence imaging of head and neck cancer xenografts targeting CD147.  Cancer Biol Ther. 2008;7(7):1063-107018431087PubMedGoogle ScholarCrossref
Gleysteen JP, Newman JR, Chhieng D, Frost A, Zinn KR, Rosenthal EL. Fluorescent labeled anti-EGFR antibody for identification of regional and distant metastasis in a preclinical xenograft model.  Head Neck. 2008;30(6):782-78918228526PubMedGoogle ScholarCrossref
Stramare R, Scagliori E, Mannucci M, Beltrame V, Rubaltelli L. The role of contrast-enhanced gray-scale ultrasonography in the differential diagnosis of superficial lymph nodes.  Ultrasound Q. 2010;26(1):45-5120216194PubMedGoogle ScholarCrossref
Liao C, Sun Q, Liang B, Shen J, Shuai X. Targeting EGFR-overexpressing tumor cells using Cetuximab-immunomicelles loaded with doxorubicin and superparamagnetic iron oxide.  Eur J Radiol. 2011;80(3):699-70520810233PubMedGoogle Scholar
Zhu ZB, Mathis JM, Makhija SK,  et al.  Targeting of a conditionally replicative adenovirus agent to human squamous cell carcinomas of the head and neck.  Int J Oncol. 2007;31(5):1213-122217912450PubMedGoogle Scholar
Original Article
July 2012

Molecular Targeting of Ultrasonographic Contrast Agent for Detection of Head and Neck Squamous Cell Carcinoma

Author Affiliations

Author Affiliations: Departments of Surgery (Drs Knowles, Heath, and Rosenthal), Biomedical Engineering (Mr Saini and Dr Hoyt), Radiology (Drs Umphrey and Hoyt and Mr Warram), and Pathology (Mr Warram), University of Alabama at Birmingham.

Arch Otolaryngol Head Neck Surg. 2012;138(7):662-668. doi:10.1001/archoto.2012.1081

Objective To investigate the feasibility of ultrasonographic (US) imaging of head and neck cancer with targeted contrast agents both in vitro and in vivo. We hypothesize that conjugation of microbubble contrast agent to tumor-specific antibodies may improve US detection of head and neck squamous cell carcinoma (HNSCC).

Design Preclinical blinded assessment of anti-EGFR and anti-CD147 microbubble contrast agents for US imaging of HNSCC.

Setting Animal study.

Subjects Immunodeficient mice.

Intervention Injection of targeted microbubbles.

Main Outcome Measure Microbubble uptake in tumors as detected by US.

Results In vitro assessment of anti–epidermal growth factor receptor (EGFR) and anti-CD147–targeted microbubbles in 6 head and neck cancer cell lines yielded a 6-fold improvement over normal dermal fibroblasts (P < .001). Binding of targeted agents had a positive correlation to both epidermal growth factor receptor (EGFR) (R2 = 0.81) and CD147 (R2 = 0.72) expression among all cell lines. In vivo imaging of flank tumors in nude mice (N = 8) yielded enhanced resolution of anti-EGFR–and anti-CD147–targeted microbubble agents over IgG control (P < .001), while dual-targeted contrast agents offered enhanced imaging over single-targeted contrast agents (P = .02 and P = .05, respectively). In a blinded in vivo assessment, targeted contrast agents increased intratumoral enhancement of flank tumors over controls. Targeted US contrast agents to both EGFR and CD147 were 100% sensitive and 87% specific in the detection of flank tumors.

Conclusion This preclinical study demonstrates feasibility of using molecular US to target HNSCC for contrast-enhanced imaging of HNSCC tumor in vivo.