Abstract
Head and neck squamous cell carcinoma (HNSCC) survival rates have not improved in a decade, with a 63% 5-year recurrence rate after surgery, making HNSCC a compelling indication for optical surgical navigation (OSN). A promising peptide, HN1, targeted and internalized in human HNSCC cells in multiple laboratories, but was slow (24 h) to accumulate. We modified HN1 and explored structural variables to improve the uptake kinetics and create IRdye800 adducts useful for OSN. Eleven new molecules were synthesized and characterized chemically, in human HNSCC cells (Cal 27), and in HNSCC xenograft mice. Cal 27 flank xenografts in Balb/c nude mice were imaged for 3–48 h after 40 nmol intravenous doses of IR800-labeled molecules. Cell uptake kinetics in the 1–2 h window incubated at 1–10 μM were independent of the dye label (FITC, Cy5, or IR800), but increased markedly with additional N-terminal lipophilic substitution, and after resequencing the peptide to separate polar amino acids and move the lysine-dye more centrally. Microscopy confirmed the strong Cal 27 cell binding and demonstrated primarily cytosolic and membrane localization of the fastest peptide, 4Iphf-HN17. 4Iph-HN17-IR800 showed 26-fold greater rate of uptake in cells than HN1-IR800, and far stronger OSN imaging intensity and tumor to background contrast in mice, suggesting that the new peptide is a promising candidate for OSN of HNSCC.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy in the United States
Three groups of molecules were studied: the original HN1 sequence, a second sequence based on the original negative control “jumbled” peptide, HNJ, wherein the seven polar amino acids are clustered adjacent at the N-terminus, and a new group made with a novel sequence of the same amino acids, HN17
We retained the original names of the HN1 and HNJ derived peptides, adding the conjugated fluorescent dye as a suffix, e.g., HN1-FITC, and abbreviated additional moieties at the N-terminus as: f for Fmoc and
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy in the United States. Despite advances in diagnosis and therapy, there has been no significant improvement in its 5-year relative survival rate for more than a decade [1]. Surgery is the primary treatment modality for HNSCC [2]. Chance of local regional recurrence within 5 years [3,4], and recurrence can be as high as 90% if the margin is positive [4], which it is in ~25% of patients [5]. While pre-surgical radiological imaging and experience aid the surgical planning, intraoperative margin decisions are made primarily by vision and palpation, with disfigurement as a primary side effect of surgery. Any practical method that improves the accuracy of intraoperative detection of tumor tissue along the margin is likely to reduce recurrence risk, increase survival, and minimize disfigurement caused by excessive normal tissue removal
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