Detection of Non-Melanoma Skin Cancer by in vivo Fluorescence Imaging with Fluorocoxib A

Abstract

Non-melanoma skin cancer (NMSC) is the most common form of cancer in the US and its incidence is increasing. The current standard of care is visual inspection by physicians and/or dermatologists, followed by skin biopsy and pathologic confirmation. We have investigated the use of in vivo fluorescence imaging using fluorocoxib A as a molecular probe for early detection and assessment of skin tumors in mouse models of NMSC. Fluorocoxib A targets the cyclooxygenase-2 (COX-2) enzyme that is preferentially expressed by inflamed and tumor tissue, and therefore has potential to be an effective broadly active molecular biomarker for cancer detection. We tested the sensitivity of fluorocoxib A in a BCC allograft SCID hairless mouse model using a wide-field fluorescence imaging system. Subcutaneous allografts comprised of 1000 BCC cells were detectable above background. These BCC allograft mice were imaged over time and a linear correlation (R2 = 0.8) between tumor volume and fluorocoxib A signal levels was observed. We also tested fluorocoxib A in a genetically engineered spontaneous BCC mouse model (Ptch1+/− K14-Cre-ER2 p53fl/fl), where sequential imaging of the same animals over time demonstrated that early, microscopic lesions (100 μm size) developed into visible macroscopic tumor masses over 11 to 17 days. Overall, for macroscopic tumors, the sensitivity was 88% and the specificity was 100%. For microscopic tumors, the sensitivity was 85% and specificity was 56%. These results demonstrate the potential of fluorocoxib A as an in vivo imaging agent for early detection, margin delineation and guided biopsies of NMSCs.

Fluorocoxib A loaded nanoparticles enable targeted visualization of cyclooxygenase-2 in inflammation and cancer

“…More recently, nanoparticle-based molecular imaging technologies have shown great promise by rationally designing agents with multi-functionality [47, 48] and high signal-to-noise [49, 50] in pathological tissue. Though the first clinically-used, fluorescent COX-2 imaging reagent is likely to be based on near infrared (NIR) fluorophores rather than rhodamine, FA was chosen as the probe of choice in these studies because it has been most rigorously validated as a molecular imaging agent for visualizing overexpression of COX-2 in inflammation [7], HNSCC tumor xenografts [7], spontaneous murine colorectal carcinomas [7], spontaneous canine colorectal carcinoma [8], canine transitional cell carcinoma xenografts [9], and non-melanoma basal cell carcinoma allografts and spontaneous basal cell carcinomas [10]. Importantly, fluoroxocibs that enable imaging in the near infrared (NIR) region are in earlier stages of development [51], and we anticipate that our delivery approach will translate seamlessly to these new compounds and yield even better SNR, potentially visualizing COX-2 at doses up to 100× lower than those safely administered to mice within the present studies (0.2 vs. 20 mg/kg).…”

“…Clinical translation of FA has the potential to address the significant, unmet need for techniques that enable earlier detection of cancers of the skin, colon, esophagus, bladder, and oropharynx [7–10]. For example, five year survival for colorectal cancer is 90% if diagnosed while it is still localized, but falls to 68% for regional disease, and just 10% for disease with distant metastases [11].…”

A Bright Future for Precision Medicine: Advances in Fluorescent Chemical Probe Design and Their Clinical Application

“…For instance, the red fluorophore 5-ROX conferred COX-2 selectivity but was only potent when the ethylenediamide linker was increased from 2 to 4 carbons, illustrating the significant effects that the chemical properties of the dyes and linkers have on overall probe performance (Uddin, et al, 2013). This COX-2 probe, termed fluorocoxib A (Figure 3F), has been used to image colon cancer polyps (Uddin, et al, 2010) as well as non-melanoma skin cancer using non-invasive detection methods (Ra, et al, 2015), however use of the 5-ROX fluorophore (λ ex = 580 nm, λ em = 605 nm) may limit its clinical translatability to human patients.…”

Chemomodulatory Potential of Bartogenic Acid Against DMBA/Croton Oil Induced Two-Step Skin Carcinogenesis in Mice

“…The cause of majority of the cancers are genetic predisposition and exposure to the environmental pollutants such as excessive tobacco or alcohol, exposure to harmful chemicals and radiations 2, which leads to either internal factors such as spontaneous mutations, hormones and nutrient metabolism in the body or by external stimulators 3. Among different types of cancers, skin cancer is one of the most common forms of human cancer 4. Every year almost around 1.2 million new skin cancer cases are diagnosed in the United States 5.…”