Identification of a Folate Receptor-Targeted Near-Infrared Molecular Contrast Agent to Localize Pulmonary Adenocarcinomas

Abstract

Non-small cell lung cancer (NSCLC) is the number one cancer killer in the United States. Despite attempted curative surgical resection, nearly 40% of patients succumb to recurrent disease. High recurrence rates may be partially explained by data suggesting that 20% of NSCLC patients harbor synchronous disease that is missed during resection. In this report, we describe the use of a novel folate receptor-targeted near-infrared contrast agent (OTL38) to improve the intraoperative localization of NSCLC during pulmonary resection. Using optical phantoms, fluorescent imaging with OTL38 was associated with less autofluorescence and greater depth of detection compared to traditional optical contrast agents. Next, in in vitro and in vivo NSCLC models, OTL38 reliably localized NSCLC models in a folate receptor-dependent manner. Before testing intraoperative molecular imaging with OTL38 in humans, folate receptor-alpha expression was confirmed to be present in 86% of pulmonary adenocarcinomas upon histopathologic review of 100 human pulmonary resection specimens. Lastly, in a human feasibility study, intraoperative molecular imaging with OTL38 accurately identified 100% of pulmonary adenocarcinomas and allowed for identification of additional subcentimeter neoplastic processes in 30% of subjects. This technology may enhance the surgeon's ability to identify NSCLC during oncologic resection and potentially improve long-term outcomes.

A Targeted Folate Receptor-α Near-infrared Fluorescent Agent Used for in Vitro Diagnosis of Endometrial Cytology

“…Because previous reports have indicated an increased expression of FR-α in a large number of patients with uterine cancer and other solid tumours, a potential strategy should be to distinguish benign, precancerous and malignant lesions based on the expression of FR-α [14,17,31,32]. Consequently, the agent used in intraoperative imaging, FRα-targeting antibodydrugs and diagnosis of endometrial cancer, ovarian cancer and NSCLC were developed previously [14,[18][19][20][21][22]. Therefore, we synthesised the near-infrared targeting uorescent dye ZW-FA, performed its characterisation and explored its potential feasibility in vitro diagnosis of endometrial cancer in this study.…”

“…FR-α in normal tissues is restricted to apical surfaces of some organs such as the kidney, lung and choroid plexus [13]. Overexpression of FR-α has been reported in various solid tumours such as non-small cell endometrial cancer, cell lung adenocarcinoma, breast carcinoma, ovarian cancer and so on [14][15][16][17]. Based on the expression of FR-α, the agent used in intraoperative imaging, FRα-targeting antibody drugs and diagnosis of endometrial cancer, ovarian cancer and non-small cell lung cancer (NSCLC) were developed previously [14,[18][19][20][21][22].…”

Intraoperative Molecular Imaging in Lung Cancer: The State of the Art and the Future

“…3,4 More recently, targeted probes have been developed that utilize antibodies, aptamers, or peptides to bind to cancerous tissue more specifically and further enhance the tumor-to-background ratio (TBR). 5,6 In this issue of Molecular Therapy, Predina et al 7 report on their pilot clinical trial of a near-infrared smallmolecule probe targeting folate receptor-a (FRa) to sensitively detect pulmonary adenocarcinomas (PAs) during surgery. In line with previous clinical trials of FRa-targeted probes in ovarian and colorectal cancers and of fluorescently-labeled anti-EGFR antibodies, such as cetuximab-IRD800, in head and neck cancer, this trial lends further support to the clinical utility of intraoperative molecular imaging (IMI) in identifying lesions that might otherwise be missed.…”

“…18 A major advantage of small molecule probes, like OTL38 (1.4 kDa), over bulkier antibodybased probes is rapid plasma clearance, while still maintaining a long residence time in tumors, allowing administration shortly before surgery and providing the surgeon with a long detection window. 7 By contrast, antibody-based probes (150 kDa) must be administered days in advance for adequate washout time in order to obtain low background levels. While OTL38 is currently being tested in clinical trials of IMI in ovarian and renal cell carcinoma, the study by Predina et al 7 is among the first to demonstrate its use in PAs.…”

“…7 By contrast, antibody-based probes (150 kDa) must be administered days in advance for adequate washout time in order to obtain low background levels. While OTL38 is currently being tested in clinical trials of IMI in ovarian and renal cell carcinoma, the study by Predina et al 7 is among the first to demonstrate its use in PAs. The investigators found that OTL38 was detectable deeper in tissue than FITC (1 cm versus 1 mm) and that tissue autofluorescence was considerably lower in the NIR range.…”