Nerve-Highlighting Fluorescent Contrast Agents for Image-Guided Surgery

Abstract

Nerve damage is the major morbidity of many surgeries, resulting in chronic pain, loss of function, or both. The sparing of nerves during surgical procedures is a vexing problem because surrounding tissue often obscures them. To date, systemically administered nerve-highlighting contrast agents that can be used for nerve-sparing image-guided surgery have not been reported. In the current study, physicochemical and optical properties of 4,4’-[(2-methoxy-1,4-phenylene)di-(1E)-2,1-ethenediyl]bis-benzenamine (BMB) and a newly synthesized, red-shifted derivative 4-[(1E)-2-[4-[(1E)-2-[4-aminophenyl]ethenyl]-3-methoxyphenyl]ethenyl]-benzonitrile (GE3082) were characterized in vitro and in vivo. Both agents crossed the blood-nerve barrier and blood-brain barrier, and rendered myelinated nerves fluorescent after a single systemic injection. Although both BMB and GE3082 also exhibited significant uptake in white adipose tissue, GE3082 underwent a hypsochromic shift in adipose tissue that provided a means to eliminate the unwanted signal using hyperspectral deconvolution. Dose and kinetic studies were performed in mice to determine the optimal dose and drug-imaging interval. Results were confirmed in rat and pig, with the latter used to demonstrate, for the first time, simultaneous fluorescence imaging of blood vessels and nerves during surgery using the FLARE™ (Fluorescence-Assisted Resection and Exploration) imaging system. These results lay the foundation for the development of ideal nerve-highlighting fluorophores for image-guided surgery.

Identification of the Protein Target of Myelin-Binding Ligands by Immunohistochemistry and Biochemical Analyses

“…Because of the lipophilic nature of BMB and GE3082, these agents were previously reported to partition nonspecifically to adipose tissue (Gibbs-Strauss et al 2011). The majority of fatty acid content of adipose tissue is composed of oleic, palmitic, and linoleic acids (Kokatnur et al 1979), similar to olive oil.…”

“…In vivo nerve imaging studies on BMB and GE3082 were described previously (Gibbs-Strauss et al 2011). Briefly, a dose of 14 mg/kg each of BMB and GE3082 was administered intravenously into mice.…”

“…The ideal in vivo imaging agent should exhibit selectivity to a component of myelin as well as be able to penetrate the blood-brain and blood-nerve barriers. Several such agents have now been reported, including small molecules such as GE3111 and GE3082 for visualizing nerves in real time during surgery (Gibbs-Strauss et al 2011;Cotero et al 2012;Gray et al 2012), as well as BMB and CIC for positron emission tomography imaging (Stankoff et al 2006;Wang et al 2009).…”

Mini-review: fluorescence imaging in cancer cells using dye-doped nanoparticles

“…[27][28][29][30][31][32][33][34] Imaging with far-red and near-infrared absorbing and emitting dyes such as cyanine, squaraine, thiazine, oxazine, porphyrins, and phthalocyanines, is commmonplace and most of them have been approved for clinical trials. [35][36][37][38][39][40][41][42][43][44][45][46][47] Recently, a new class of dyes, borondipyrromethane (BODIPY) derivatives, have emerged and gained popularity.…”

Visualization of prostatic nerves by polarization-sensitive optical coherence tomography

“…An electrophysiological testing method such as electromyographic (EMG) stimulation [11][12][13] and various imaging methods have been developed and are under investigation to provide better identification of CNs [14][15][16][17]. The imaging methods are transrectal ultrasound (TRUS) [18][19][20][21], dye-based fluorescence imaging [22][23][24][25][26][27][28][29][30], multiphoton microscopy (MPM) [31,32], coherent anti-Stokes Raman scattering (CARS) microscopy [33], and photoacoustic microscopy (PAM) [34,35]. However, these imaging methods have their own limitations as far as their use for the surgery.…”