A pH-Activatable Nanoprobe Labels Diverse Histologic Subtypes of Human Lung Cancer During Resection.

BACKGROUND: Intraoperative molecular imaging (IMI) uses tumor-targeted optical contrast agents to improve identification and clearance of cancer during surgery. Recently, pH-activatable contrast agents have been developed but none has been tested in lung cancer. Here, we report the successful clinical translation of pegsitacianine (ONM-100), a pH-activatable nanoprobe, for fluorescence-guided lung cancer resection. METHODS: We first characterized the pH setpoint for pegsitacianine fluorescence activation in vitro. We then optimized the specificity, dosing, and timing of pegsitacianine in murine flank xenograft models of lung adenocarcinoma and squamous cell carcinoma. Finally, we tested pegsitacianine in humans undergoing lung cancer surgery as part of an ongoing phase 2 trial. RESULTS: We found that the fluorescence activation of pegsitacianine occurred below physiologic pH in vitro. Using preclinical models of lung cancer, we found that the probe selectively labeled both adenocarcinoma and squamous cell carcinoma xenografts (mean tumor-to-background ratio [TBR] > 2.0 for all cell lines). In the human pilot study, we report cases in which pegsitacianine localized pulmonary adenocarcinoma and pulmonary squamous cell carcinoma (TBRs= 2.7 and 2.4) in real time to illustrate its successful clinical translation and potential to improve surgical management. CONCLUSIONS: This translational study demonstrates the feasibility of pegsitacianine as an IMI probe to label the two most common histologic subtypes of human lung cancer.

Intraoperative near-infrared imaging of mesothelioma.

Though difficult to achieve, complete resection of malignant pleural mesothelioma is paramount to improving patient survival. Surgeons have traditionally been limited to using visual inspection and manual palpation to locate and remove cancerous tissue. However, intraoperative molecular imaging (IMI) is a promising new technology in surgery. Molecular imaging utilizes a fluorescent tracer that selectively accumulates in cancer cells. An imaging device is then used to detect and augment the fluorescent signal emitted from the fluorescent cancer cells. Our group and others have demonstrated that molecular imaging with either indocyanine green (ICG) or a folate receptor alpha (FRα) targeted fluorophore can accurately identify a number of intrathoracic malignancies. Early studies of intraoperative imaging have suggested its efficacy for malignant pleural mesothelioma. In a murine model of mesothelioma, intraoperative imaging was found to have sensitivity of 87% and specificity of 83%. In a pilot human study, eight patients with biopsy-proven epithelial malignant pleural mesothelioma were administered 5 mg/kg of intravenous ICG injection 24 h prior to resection. The following day, a near-infrared (NIR) imaging device was used to detect tumor fluorescence intraoperatively. After what was believed to be complete tumor excision, the wound bed was re-imaged for residual fluorescence indicative of retained tumor. When residual fluorescence was detected, additional tissue was resected, if feasible, and specimens were sent for pathologic correlation. In all cases, intraoperative fluorescence localized to mesothelioma deposits which were confirmed on final pathology. Following resection, fluorescence was confirmed ex vivo with a mean tumor-to-background ratio (TBR) of 3.2 (IQR: 2.9-3.4). It is hoped that this technology will improve outcomes for mesothelioma patients by allowing for a more complete oncologic resection.