Near-infrared (NIR) fluorescence has the potential to revolutionize image-guided surgery. However, ideal fluorophores for in vivo, and eventually clinical, use have not yet been described. Under an NIH Bioengineering Research Partnership (BRP) grant, the PI's laboratory has developed a surgical imaging system that simultaneously, and in real-time, acquires two independent wavelengths of NIR fluorescence emission images along with color video images. The imaging system has already been translated to the clinic, and is being formally evaluated in three NIH-funded clinical trials. Nevertheless, the fundamental limitation to the future success of this technology is the development of NIR fluorophores that perform optimally in the body, and which can be made widely available to other academic researchers. To be clinically viable, the ideal NIR fluorophore requires certain optical properties, including excitation and emission H800 nm, and both a high extinction coefficient (5) and quantum yield (QY) in serum. However, the reason why existing NIR fluorophores perform so poorly in vivo has more to do with biodistribution and clearance. After IV injection, the ideal NIR fluorophore would rapidly equilibrate between the intravascular and extra vascular spaces and would be cleared efficiently via renal filtration. To date, every NIR fluorophore described in the literature suffers from two fundamental flaws: 1) hepatic clearance, which results in NIR fluorescence signal throughout the GI tract that persists for hours, and/or 2) non-specific background uptake in normal tissues, which typically persists for hours and results in a low signal-to-background ratio (SBR). This grant builds upon an observation we made two years ago using NIR fluorescent quantum dots (Choi et al., Nature Biotechnol. 2007; 25: 1165-70). Unexpectedly, and for reasons only partially understood, zwitterionic organic coatings resulted in extremely low non-specific tissue uptake, rapid renal clearance, and no serum protein binding. However, purely anionic or cationic coatings gave the opposite results. Based on these data, we began collaborating with Drs. Patonay and Strekowski at Georgia State University, leaders in the field of NIR fluorophore chemistry, to synthesize zwitterionic heptamethine indocyanine NIR fluorophores. The preliminary results, described herein, demonstrate that both non-targeted and tumor-targeted zwitterionic NIR fluorophores have remarkable optical and in vivo properties, including 800 nm fluorescence, high 5 and QY, rapid renal clearance, absence of protein binding, and ultra-low non-specific tissue uptake (i.e., background).
The specific aims of this grant are focused on the synthesis of optimized zwitterionic NIR fluorophores for in vivo and surgical imaging, on validating their use as targeted diagnostic agents for prostate cancer, and for scale-up from analytical to preparative production. Completion of these aims will lay the foundation for future clinical testing during image-guided surgery. Importantly, we also present an intellectual property strategy that will permit free sharing of optimized NIR fluorophores within the academic community.
Near-infrared light is invisible to the human eye; but penetrates relatively deeplyinto living tissue. It is therefore ideal for image-guided surgery; because it provides surgeons with high-sensitivity; high-resolution detection of diseases; such as cancer; without changing the look of the surgicalfield. Although hardware systems that use near-infrared fluorescent light for image-guided surgery are alreadyavailable; optimized fluorophores; or ''light bulbs'' are not. The goal of this grant is to develop a new class ofideal near-infrared fluorophores that can be injected into the bloodstream. These fluorophores would ''stick'' totumors and other diseased tissue; but not to normal tissue.
|Inoue, Kazumasa; Gibbs, Summer L; Liu, Fangbing et al. (2014) Microscopic validation of macroscopic in vivo images enabled by same-slide optical and nuclear fusion. J Nucl Med 55:1899-904|
|Park, Min Ho; Hyun, Hoon; Ashitate, Yoshitomo et al. (2014) Prototype nerve-specific near-infrared fluorophores. Theranostics 4:823-33|
|Ashitate, Yoshitomo; Hyun, Hoon; Kim, Soon Hee et al. (2014) Simultaneous mapping of pan and sentinel lymph nodes for real-time image-guided surgery. Theranostics 4:693-700|
|Hyun, Hoon; Owens, Eric A; Narayana, Lakshminarayana et al. (2014) Central C-C Bonding Increases Optical and Chemical Stability of NIR Fluorophores. RSC Adv 4:58762-58768|
|Verbeek, Floris P R; van der Vorst, Joost R; Tummers, Quirijn R J G et al. (2014) Near-infrared fluorescence imaging of both colorectal cancer and ureters using a low-dose integrin targeted probe. Ann Surg Oncol 21 Suppl 4:S528-37|
|Choi, Hak Soo (2014) Nanoparticle assembly: building blocks for tumour delivery. Nat Nanotechnol 9:93-4|
|Hyun, Hoon; Wada, Hideyuki; Bao, Kai et al. (2014) Phosphonated near-infrared fluorophores for biomedical imaging of bone. Angew Chem Int Ed Engl 53:10668-72|
|Lee, Jeong Heon; Park, Sunny; Hyun, Hoon et al. (2013) High-throughput screening of small molecule ligands targeted to live bacteria surface. Anal Chem 85:3508-14|
|Choi, Hak Soo; Gibbs, Summer L; Lee, Jeong Heon et al. (2013) Targeted zwitterionic near-infrared fluorophores for improved optical imaging. Nat Biotechnol 31:148-53|
|Vahrmeijer, Alexander L; Hutteman, Merlijn; van der Vorst, Joost R et al. (2013) Image-guided cancer surgery using near-infrared fluorescence. Nat Rev Clin Oncol 10:507-18|
Showing the most recent 10 out of 18 publications