Development of Tumor-Targeted Near Infrared Probes for Fluorescence Guided Surgery

Abstract

Complete surgical resection of malignant disease is the only reliable method to cure cancer. Unfortunately, quantitative tumor resection is often limited by a surgeon's ability to locate all malignant disease and distinguish it from healthy tissue. Fluorescence-guided surgery has emerged as a tool to aid surgeons in the identification and removal of malignant lesions. While nontargeted fluorescent dyes have been shown to passively accumulate in some tumors, the resulting tumor-to-background ratios are often poor, and the boundaries between malignant and healthy tissues can be difficult to define. To circumvent these problems, our laboratory has developed high affinity tumor targeting ligands that bind to receptors that are overexpressed on cancer cells and deliver attached molecules selectively into these cells. In this study, we explore the use of two tumor-specific targeting ligands (i.e., folic acid that targets the folate receptor (FR) and DUPA that targets prostate specific membrane antigen (PSMA)) to deliver near-infrared (NIR) fluorescent dyes specifically to FR and PSMA expressing cancers, thereby rendering only the malignant cells highly fluorescent. We report here that all FR- and PSMA-targeted NIR probes examined bind cultured cancer cells in the low nanomolar range. Moreover, upon intravenous injection into tumor-bearing mice with metastatic disease, these same ligand-NIR dye conjugates render receptor-expressing tumor tissues fluorescent, enabling their facile resection with minimal contamination from healthy tissues.

Dual-Modality Image-Guided Surgery of Prostate Cancer with a Radiolabeled Fluorescent Anti-PSMA Monoclonal Antibody

“…First, cancerous tissue can be distinguished from benign structures visually on the basis of color, texture, and morphology. In addition, tactile palpation can aid the surgeon in detecting tumor tissue because of differences in elasticity or plasticity (6). However, the detection of tumor cells in resection margins and micrometastases remains extremely challenging.…”

Synthesis, Functionalization, and Design of Magnetic Nanoparticles for Theranostic Applications

“…accurately delimit tumor margin in a less harmful way which is crucial to preserve other important structures upon using intrasurgical imaging tools. [24,808] Performing the imaging procedure in exactly the same area for both techniques via MRI/ CT dual imaging agents also leads to better diagnosis. Furthermore, it reduces the total dose of contrast agents administered into the patient's body, which indeed results in less consequent side effects.…”

Dynamic optical projection of acquired luminescence for aiding oncologic surgery

“…ICG is the only approved NIR fluorescent reporter 4 although targeted agents are in various stages of the translational process. 12,14,15 As NIR fluorescent molecular probes become approved for diagnostic use in human medicine, fluorescence imaging will become an essential tool for oncologic surgery.…”