Tissue-Specific Near-Infrared Fluorescence Imaging

Abstract

CONSPECTUS Near-infrared (NIR) fluorescence light has been widely utilized in clinical imaging by providing surgeons highly specific images of target tissue. The “NIR window” from 650 to 900 nm is especially useful due to several special features such as minimal autofluorescence and absorption of biomolecules in tissue, as well as low light scattering. Compared with visible wavelengths, NIR fluorescence light is invisible, thus allowing highly sensitivity real-time image guidance in human surgery without changing the surgical field. The benefit of using NIR fluorescence light as a clinical imaging technology can be attributed to its molecular fluorescence as an exogenous contrast agent. Indeed, whole body preoperative imaging of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) remains important in diagnostic utility, but they lack the efficacy of innocuous and targeted NIR fluorophores to simultaneously facilitate the real-time delineation of diseased tissue while preserving vital tissues. Admittedly, NIR imaging technology has been slow to enter clinical use mostly due to the late-coming development of truly breakthrough contrast agents for use with current imaging systems. Therefore, clearly defining the physical margins of tumorous tissue remains of paramount importance in bioimaging and targeted therapy. An equally noteworthy yet less researched goal is the ability to outline healthy vital tissues that should be carefully navigated without transection during the intraoperative surgery. Both of these paths require optimizing a gauntlet of design considerations to obtain not only an effective imaging agent in the NIR window but also high molecular brightness, water solubility, biocompatibility, and tissue-specific targetability. The imaging community recognizes three strategic approaches which include (1) passive targeting via the EPR effect, (2) active targeting using the innate overall biodistribution of known molecules, and (3) activatable targeting through an internal stimulus, which turns on fluorescence from an off state. Recent advances in nanomedicine and bioimaging offer much needed promise toward fulfilling these stringent requirements as we develop a successful catalog of targeted contrast agents for illuminating both tumors and vital tissues in the same surgical space by employing spectrally distinct fluorophores in real time. These tissue-specific contrast agents can be versatile arsenals to physicians for real-time intraoperative navigation as well as image-guided targeted therapy. There is a versatile library of tissue-specific fluorophores available in the literature, with many discussed herein, which offers clinicians an array of possibilities that will undoubtedly improve intraoperative success and long-term postoperation prognosis.

PSMA-targeted contrast agents for intraoperative imaging of prostate cancer,

“…15 ZW fluorophores are designed to form balanced charges and biologically inherent surface after conjugation with targeting agents by preventing interactions with biological tissues and proteins, yet improving targeting efficiency. 17,18 …”

“…This result indicates that the conjugated fluorophore agitates the favorable pharmacokinetic property of targeted ligand. 17 To evaluate the influence of effector domain on the targeting efficiency of bioconjugates, in this study, a series of KUE-conjugated NIR fluorophores were synthesized and their PSMA-binding was tested in terms of net charges, spacer length, hydrophobicity, and polarity. Since the size of KUE is smaller than that of effector domain, we hypothesized that the targeting efficiency as well as biodistribution and clearance patterns of KUE conjugates would be strongly governed by the conjugated NIR fluorophores.…”

“…Since the size of KUE is smaller than that of effector domain, we hypothesized that the targeting efficiency as well as biodistribution and clearance patterns of KUE conjugates would be strongly governed by the conjugated NIR fluorophores. 17,23 To systematically compare the influence of physicochemical properties of fluorophores on PSMA targeting efficiency, as shown in Fig. 1, a serious of polymethine fluorophores were selected and conjugated with various length of polyethylene glycol (PEG): a pentamethine cyanine ( i.e.…”

“…17,18 Given the depth of the S1 pocket under the surface of PSMA, therefore, a suitable length of flexible linkers should be considered between a targeted ligand and a fluorophore. 5,27 To find the optimal length for PSMA-specific binding, we introduced a set of PEGs with varying EG repeating units from 2 to 24 (Fig.…”

NADPH as a potential intrinsic probe for tumour margin estimation

“…ICG has demonstrated potential in various oncological applications through combination with endoscopic-based techniques such as laparoscopy 6 , as well as demonstrating its potential use in breast cancer margin estimation 7,8 . Despite success with ICG, near-infrared imaging techniques have not readily entered into clinical use due to the lack of appropriate contrast agents that have been FDA approved with current imaging technologies 9 . The main problems with developing a contrast agent include the significant amount of time and money required to design a probe and bring it to market for human use.…”