Molecular Imaging Agents Specific for the Annulus Fibrosus of the Intervertebral Disk

Paradigm shifts in surgery arise when surgeons are empowered to perform surgery faster, better, and/or less expensively. Optical imaging that exploits invisible near-infrared fluorescent light has the potential to improve cancer surgery outcomes while minimizing anesthesia time and lowering healthcare costs. Because of this, the last few years have witnessed an explosion of proof-of-concept clinical trials in the field. In this review, we introduce the concept of near-infrared fluorescence imaging for cancer surgery, review the clinical trial literature to date, outline the key issues pertaining to imaging system and contrast agent optimization, discuss limitations and leverage, and provide a framework for making the technology available for the routine care of cancer patients in the near future.

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“…34 Optically-active nerve cell agents 35,36 have also been described, but are yet to achieve NIR wavelengths.…”

Section: Introductionmentioning

confidence: 99%

Image-guided cancer surgery using near-infrared fluorescence

et al. 2013

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“…The nerve-specific peptides are a targeting sequence that largely highlights the epineurium with some binding to the endoneurium [13]. The three classes of nerve-specific small molecule organic fluorophores include the stilbene derivatives [14], the distyrylbenzene (DSB) derivatives [14–17], and the styryl pyridinium (FM) fluorophores [18,19]. The FM dyes have been found to stain only the dorsal root and trigeminal ganglia when administered systemically [18].…”

Section: Introductionmentioning

confidence: 99%

Structure-Activity Relationship of Nerve-Highlighting Fluorophores

et al. 2013

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Nerve damage is a major morbidity associated with numerous surgical interventions. Yet, nerve visualization continues to challenge even the most experienced surgeons. A nerve-specific fluorescent contrast agent, especially one with near-infrared (NIR) absorption and emission, would be of immediate benefit to patients and surgeons. Currently, there are only three classes of small molecule organic fluorophores that penetrate the blood nerve barrier and bind to nerve tissue when administered systemically. Of these three classes, the distyrylbenzenes (DSBs) are particularly attractive for further study. Although not presently in the NIR range, DSB fluorophores highlight all nerve tissue in mice, rats, and pigs after intravenous administration. The purpose of the current study was to define the pharmacophore responsible for nerve-specific uptake and retention, which would enable future molecules to be optimized for NIR optical properties. Structural analogs of the DSB class of small molecules were synthesized using combinatorial solid phase synthesis and commercially available building blocks, which yielded more than 200 unique DSB fluorophores. The nerve-specific properties of all DSB analogs were quantified using an ex vivo nerve-specific fluorescence assay on pig and human sciatic nerve. Results were used to perform quantitative structure-activity relationship (QSAR) modeling and to define the nerve-specific pharmacophore. All DSB analogs with positive ex vivo fluorescence were tested for in vivo nerve specificity in mice to assess the effect of biodistribution and clearance on nerve fluorescence signal. Two new DSB fluorophores with the highest nerve to muscle ratio were tested in pigs to confirm scalability.

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“…NIR fluorescence microscopy for ex vivo nerve tissue slides was performed on a Nikon Eclipse TE300 microscope system as previously described 12,20,24. The microscope was equipped with a 100 W mercury light source, NIR-compatible optics, and a NIR-compatible 4X, 10x, and 20X Plan Fluor objective lens (Nikon, Melville, NY).…”

Section: Methodsmentioning

confidence: 99%

“…Among these agents, DSBs such as BMB, GE3082, and GE3111 have been investigated for image-guided nerve surgery 12-14. However, none of these compounds were optimal because of high adsorption and scattering in tissues from the ultraviolet and visible wavelengths required.…”

Section: Introductionmentioning

confidence: 99%

Prototype Nerve-Specific Near-Infrared Fluorophores

Park¹,

Hyun²,

Ashitate³

et al. 2014

Theranostics

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Nerve preservation is an important issue during most surgery because accidental transection or injury results in significant morbidity, including numbness, pain, weakness, or paralysis. Currently, nerves are still identified only by gross appearance and anatomical location during surgery, without intraoperative image guidance. Near-infrared (NIR) fluorescent light, in the wavelength range of 650-900 nm, has the potential to provide high-resolution, high-sensitivity, and real-time avoidance of nerve damage, but only if nerve-specific NIR fluorophores can be developed. In this study, we evaluated a series of Oxazine derivatives to highlight various peripheral nerve structures in small and large animals. Among the targeted fluorophores, Oxazine 4 has peak emission near into the NIR, which provided nerve-targeted signal in the brachial plexus and sciatic nerve for up to 12 h after a single intravenous injection. In addition, recurrent laryngeal nerves were successfully identified and highlighted in real time in swine, which could be preserved during the course of thyroid resection. Although optical properties of these agents are not yet optimal, chemical structure analysis provides a basis for improving these prototype nerve-specific NIR fluorophores even further.

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Molecular Imaging Agents Specific for the Annulus Fibrosus of the Intervertebral Disk

Cited by 25 publications

References 33 publications

Image-guided cancer surgery using near-infrared fluorescence

Image-guided cancer surgery using near-infrared fluorescence

Structure-Activity Relationship of Nerve-Highlighting Fluorophores

Prototype Nerve-Specific Near-Infrared Fluorophores

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