First-in-Human Assessment of cRGD-ZW800-1, a Zwitterionic, Integrin-Targeted, Near-Infrared Fluorescent Peptide in Colon Carcinoma

Abstract

Purpose: Incomplete oncologic resections and damage to vital structures during colorectal cancer surgery increases morbidity and mortality. Moreover, neoadjuvant chemoradiotherapy has become the standard treatment modality for locally advanced rectal cancer, where subsequent downstaging can make identification of the primary tumor more challenging during surgery. Near-infrared (NIR) fluorescence imaging can aid surgeons by providing realtime visualization of tumors and vital structures during surgery.Experimental Design: We present the first-in-human clinical experience of a novel NIR fluorescent peptide, cRGD-ZW800-1, for the detection of colon cancer. cRGD-ZW800-1 was engineered to have an overall zwitterionic chemical structure and neutral charge to lower nonspecific uptake and thus background fluorescent signal. We performed a phase I study in 11 healthy volunteer as well as a phase II feasibility study in 12 patients undergoing an elective colon resection, assessing 0.005, 0.015, and 0.05 mg/kg cRGD-ZW800-1 for the intraoperative visualization of colon cancer.Results: cRGD-ZW800-1 appears safe, and exhibited rapid elimination into urine after a single low intravenous dose. Minimal invasive intraoperative visualization of colon cancer through fullthickness bowel wall was possible after an intravenous bolus injection of 0.05 mg/kg at least 2 hours prior to surgery. Longer intervals between injection and imaging improved the tumor-tobackground ratio.Conclusions: cRGD-ZW800-1 enabled fluorescence imaging of colon cancer in both open and minimal invasive surgeries. Further development of cRGD-ZW800-1 for widespread use in cancer surgery may be warranted given the ubiquitous overexpression of various integrins on different types of tumors and their vasculature.

RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field

“…The RGD-based pentapeptide cyclo[RGDyK] was conjugated to a near infrared dye to generate “cRGD-ZW800-1”. The probe presented suitable in vivo imaging properties in preclinical studies in various tumor models [ 445 ] and was translated to first-in-human imaging in colon carcinoma, where the investigators were able to visualize colorectal tumors over normal mucosa and reported no safety concerns of the procedure [ 446 ]. Although the authors describe their approach as αvβ6-targeted, we would like to point the reader to studies showing that cyclo[RGDyK] exhibits high affinity to αvβ3 (IC 50 : 3.8 nM), and lower affinity to αvβ6 (IC 50 : 86 nM) [ 318 ], suggesting that tumor uptake of cRGD-ZW800-1 cannot be primarily be mediated via αvβ6 integrin.…”

Receptor-Targeted Fluorescence-Guided Surgery With Low Molecular Weight Agents

“…The establishment of neoadjuvant chemoradiotherapy as the standard for locally advanced rectal cancer further complicates eventual surgical resection with MIS due to obscuring of critical visual information. To overcome these challenges, de Valk et al (54) evaluated the utility of cRGD-ZW800-1 to provide real time discrimination between tumor and normal tissues. The Phase I trial was a randomized, placebo-controlled, double-blinded, microdosing study to evaluate safety, tolerability and PK.…”

“…Ex vivo imaging, white-light with NIRF overlay (E) . Panels (B–E) are adapted from ( 54 ) with permission.…”

“…To overcome these challenges, de Valk et al. ( 54 ) evaluated the utility of cRGD-ZW800-1 to provide real time discrimination between tumor and normal tissues. The Phase I trial was a randomized, placebo-controlled, double-blinded, microdosing study to evaluate safety, tolerability and PK.…”

Clinical translation and implementation of optical imaging agents for precision image-guided cancer surgery

“…Only if the imaging agent, more specifically the fluorophore, is well matched with the clinical imaging system can standardized reporting really tell us something about the efficacy of the imaging agent itself (phase II study) and its potential for clinical use (phase III study). Standardized back-table pathology plays an important role in studying the biodistribution of an imaging agent in the tissue of interest [33], but lacks the majority of information about the potential clinical, intraoperative use. A suboptimal image is not necessarily caused by dysfunction of the imaging agent rather than a suboptimal combination of one of the elements in this "imaging cascade" (binding moiety, fluorophore, tissue type, dosing, imaging interval, camera system, camera use, post-processing, image interpretation).…”