Potential of activatable FAP-targeting immunoliposomes in intraoperative imaging of spontaneous metastases

Abstract

Despite intensive research and medical advances met, metastatic disease remains the most common cause of death in cancer patients. This results from late diagnosis, poor therapeutic response and undetected micrometastases and tumor margins during surgery. One approach to overcome these challenges involves fluorescence imaging, which exploits the properties of fluorescent probes for diagnostic detection of molecular structures at the onset of transformation and for intraoperative detection of metastases and tumor margins in real time. Considering these benefits, many contrast agents suitable for fluorescence imaging have been reported. However, most reports only demonstrate the detection of primary tumors and not the detection of metastases or their application in models of image-guided surgery. In this work, we demonstrate the influence of fibroblast activation protein (FAP) on the metastatic potential of fibrosarcoma cells and elucidate the efficacy of activatable FAP-targeting immunoliposomes (FAP-IL) for image-guided detection of the spontaneous metastases in mice models. Furthermore, we characterized the biodistribution and cellular localization of the liposomal fluorescent components in mice organs and traced their excretion over time in urine and feces. Taken together, activatable FAP-IL enhances intraoperative imaging of metastases. Their high accumulation in metastases, subsequent localization in the bile canaliculi and liver kupffer cells and suitable excretion in feces substantiates their potency as contrast agents for intraoperative imaging.

Fluorescent contrast agents for tumor surgery (Review)

“…Several NIR fluorescent dyes have been developed and incorporated, for example with antibodies (86,87), nanoparticles (88) or encapsulated within nanomaterials (89,90), to be used as contrast agents for molecular imaging of different tumors (4). Researchers have identified that elevated levels of fibroblast activation protein (FAP) in stromal fibroblasts are associated with aggressive cancer types (91–95).…”

“…Tumor cells may spread to distant host tissues, leading to metastatic disease, a well-known cause of mortality in patients with cancer (4). Following treatment, high levels of metastasis and the recurrence of cancer may be observed due to incomplete removal of the edges of the primary tumor (4).…”

“…Tumor cells may spread to distant host tissues, leading to metastatic disease, a well-known cause of mortality in patients with cancer (4). Following treatment, high levels of metastasis and the recurrence of cancer may be observed due to incomplete removal of the edges of the primary tumor (4). Surgery holds different challenges, including identifying small lesions, locating metastases, as well as confirming complete tumor removal (5–9).…”

“…It describes the non-invasive use of near-infrared light to excite the contrast agent, after which the intensity of contrast agent fluorescence can be detected. Thus, the fluorescence represents the transformation of the molecular structure of the contrast agent, which is tissues in different diseases (4). NIRF guidance was introduced to improve the identification of lesions and guide the removal of these lesions (13).…”

Label-free optical imaging technologies for rapid translation and use during intraoperative surgical and tumor margin assessment

“…7,8 Aside from the required drug approvals for these probes, their use is challenged by the need for high site-specific targeting, low nonspecific binding to normal cells and tissues, often a darkened surgical suite to collect weak optical signals, and the pharmacokinetics for the administration, targeting, and clearance. 9,10 While these probe-or label-based methods continue to show promise, we believe there is significant merit in pursuing labelfree optical imaging methods to address this critical surgical need.…”