Advancing theranostics with tumor-targeting peptides for precision otolaryngology

Abstract

Worldwide, about 600,000 head and neck squamous cell carcinoma (HNSCC) are detected annually, many of which involve high risk human papilloma virus (HPV). Surgery is the primary and desired first treatment option. Following surgery, the existence of cancer cells at the surgical margin is strongly associated with eventual recurrence of cancer and a poor outcome. Despite improved surgical methods (robotics, microsurgery, endoscopic/laparoscopic, and external imaging), surgeons rely only on their vision and touch to locate tumors during surgery. Diagnostic imaging systems like computed tomography (CT), magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and positron-emission tomography (PET) are too large, slow and costly to use efficiently during most surgeries and, ultrasound imaging, while fast and portable, is not cancer specific. This purpose of this article is to review the fundamental technologies that will radically advance Precision Otolaryngology practices to the benefit of patients with HNSCC. In particular, this article will address the potential for tumor-targeting peptides to enable more precise diagnostic imaging while simultaneously advancing new therapeutic paradigms for next generation image-guided surgery, tumor-specific chemotherapeutic delivery and tumor-selective targeted radiotherapy (i.e., theranostic).

Keywords: Diagnostic imaging; Optical surgical navigation; Peptide; Squamous cell carcinoma; Theranostic.

Fig. 1

Cerenkov luminescence imaging of the PET radioisotope ⁶⁸Ga in vitro. The positron-emitter ⁶⁸Ga was eluted from a generator (Eckert & Ziegler, Berlin, Germany) and its activity was measured using a calibrated dose calibrator (Capintec CRC 212). The manufacturer specified setting and calibration factor for ⁶⁸Ga was used for all measurements. Clear Eppendorf tubes containing various activity concentrations of ⁶⁸Ga were placed within the imaging chamber of a commercial bioluminescence imaging system (IVIS 100; Perkin Elmer, Waltham, MA). The IVIS system consists of a cryogenically-cooled charged couple device (CCD) camera, operating at −90 °C, and a temperature controlled, light-tight imaging chamber. Two sets of images were collected; a white-light image and a luminescence image that captured photon output due to Cerenkov luminescence. Photon flux was quantified by means of proprietary software (Living Image version 2.5) using custom regions of interest based on the outlines of the Eppendorf tube caps visible on the white-light image. A. CLI image of 89 kBq of ⁶⁸Ga. B. ROI analysis of photon flux demonstrated 1136,500 p/sec/cm²/sr. C. There is a positive linear relationship between the ⁶⁸Ga activity and measured luminescence (R² = 0.9996). The ⁶⁸Ga activities ranged from 19 to 1689 kBq and were imaged in triplicate using the IVIS 100 high resolution (4) setting, FOV15, f1, open filter for 30 s (Courtesy of CLW, MVK and MFT).

Fig. 2

Precision Otolaryngology for HNSCC. The HN-1 peptide as a the ranostic agent (i.e., demonstrates both therapeutic and diagnostic attributes). HN-1 (center) can potentially be conjugated with NIR fluorescence dyes, PET radioisotopes and non-PET diagnostic radioisotopes for tumor-specific diagnostic imaging applications. In terms of therapeutics, HN-1 can potentially be conjugated with various types of chemotherapeutic agents like peptides, toxins and siRNA or therapeutic radioisotopes for PRRT mediated via alpha or beta particle emissions. In fact, HN-1 has already demonstrated its potential for labeling with multiple diagnostic and therapeutic moieties. Dual-labeling of HN-1 with fluorescent dyes and chemotherapeutic agents has already been described in the literature and evaluated in vitro and, to some extent, in vivo. There is potential for dual-labeling HN-1 with both fluorescent dyes and diagnostic radioisotopes to enable more precise image-guided surgery or fluorescence-augmented radioguided surgery. There is also potential for dual-labeling HN-1 with diagnostic radioisotopes and chemotherapeutic agents to precisely localize and quantify the delivery of the theranostic agent to the target lesions. Dual-labeled HN-1 with therapeutic radioisotopes and chemotherapeutic radiosensitizers is another approach to precisely deliver a high-yield chemoradiotherapy payload to target tumor lesions.