Phosphonated Near‐Infrared Fluorophores for Biomedical Imaging of Bone

Abstract

The conventional method for creating targeted contrast agents is to conjugate separate targeting and fluorophore domains. In this study we report a new strategy based on incorporation of targeting moieties into the non-resonant structure of pentamethine and heptamethine indocyanines. Using the known affinity of phosphonates for bone minerals as a model system, we have synthesized two families of bifunctional molecules that target bone without the need for a traditional bisphosphonate. With peak fluorescence emission at ≈ 700 nm or ≈ 800 nm, these molecules can be used for FLARE dual-channel imaging. Longitudinal FLARE studies in mice demonstrate that phosphonated near-infrared fluorophores remain stable in bone for over 5 weeks, and histological analysis demonstrates incorporation into bone matrix. Taken together, we describe a new strategy for creating ultracompact, targeted, near-infrared fluorophores for various bioimaging applications.

Pre-Assembly of Near-Infrared Fluorescent Multivalent Molecular Probes for Biological Imaging

“…Inspection of the bone imaging literature indicates increasing community interest in using fluorescent probes for preclinical studies, 44–46 and there are also ongoing efforts to produce multimodality probes for clinical imaging. 47,48 Furthermore, researchers are beginning to develop bone-targeting systems for drug delivery and bone tissue engineering.…”

Site‐Specific In Vivo Bioorthogonal Ligation via Chemical Modulation

“…[10] Very recently, we have developed a novel concept of targeted contrast agents (i.e., structure-inherent targeting), where the inherent chemical structure governs the fate of an injected molecule and the ultimate targeting to specific organs such as thyroid/parathyroid glands, [10] bone, [11] and cartilage. [12] Using this concept, we could achieve significantly reduced background tissue retention and nonspecific uptake in the reticuloendothlial system (RES), and thus improve the signal-to-background ratio (SBR) of the target.…”

NIR Fluorescence Imaging Systems with Optical Packaging Technology

“…Since NIR fluorescent light is basically invisible to human eye, specially designed exogenous contrast agents are required to get the NIR fluorescent light within the surgical field to emit photons at the specific locations. When combined with an appropriate NIR fluorophore, these imaging systems enable real-time in vivo imaging to highlight the specific structures desired by the surgeon such as pan and sentinel lymph nodes, 14) peripheral nerves, 15) vasculature, 16,17) bone, 18) pancreas, 19) thyroid and parathyroid glands, 20) as well as many tumorous tissues. 6,21-23) The key to future success will be first-in-human trials of new technology, which in turn requires a comprehensive understanding of such design parameters discussed in this article.…”