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Oral Oncol. 2017 Aug;71:156-162. doi: 10.1016/j.oraloncology.2017.06.009. Epub 2017 Jun 27.

Early detection of squamous cell carcinoma in carcinogen induced oral cancer rodent model by ratiometric activatable cell penetrating peptides.

Author information

1
Division of Otolaryngology, Head and Neck Surgery, University of California, San Diego, La Jolla, CA, USA.
2
Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, USA.
3
Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
4
Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
5
Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA, USA.
6
Division of Otolaryngology, Head and Neck Surgery, University of California, San Diego, La Jolla, CA, USA; Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. Electronic address: q1nguyen@ucsd.edu.

Abstract

OBJECTIVES:

Ratiometric cell-penetrating-peptides (RACPP) are hairpin-shaped molecules that undergo cleavage by tumor-associated proteases resulting in measurable Cy5:Cy7 fluorescence ratiometric change to label cancer in vivo. We evaluated an MMP cleavable RACPP for use in the early detection of malignant lesions in a carcinogen-induced rodent tumor model.

METHODS:

Wild-type immune-competent mice were given 4-nitroquinoline-oxide (4NQO) for 16weeks. Oral cavities from live mice that had been intravenously administered MMP cleavable PLGC(Me)AG-RACPP were serially imaged from week 11 through week 21 using white-light reflectance and Cy5:Cy7 ratiometric fluorescence.

RESULTS:

In an initial study we found that at week 21 nearly all mice (13/14) had oral cavity lesions, of which 90% were high-grade dysplasia or invasive carcinoma. These high-grade lesions were identifiable with white light reflectance and RACPP Cy5:Cy7 ratiometric fluorescence with similar detectability, Area Under Curve (AUC) for RACPP detection was 0.97 (95% Confidence interval (CI)=0.92-1.02, p<0.001), sensitivity=89%, specificity=100%. In a follow up study, oral cavity lesions generated by 4NQO were imaged and histologically analyzed at weeks 16, 18 and 21. In this study we showed that RACPP-fluorescence detection positively identified 15 squamous cell carcinomas (in 6 separate mice) that were poorly visible or undetectable by white light reflectance.

CONCLUSIONS:

RACPP ratiometric fluorescence can be used to accurately detect carcinogen-induced carcinoma in immunocompetent mice that are poorly visible or undetectable by white light reflectance.

KEYWORDS:

Carcinogen-induced head and neck squamous cell carcinoma; Enzyme responsive; In vivo; Matrix metalloproteinase; Ratiometricfluorescence imaging

[Indexed for MEDLINE]
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