title: Design of Protease Activated Optical Contrast Agents That Exploit a Latent Lysosomotropic Effect for Use in Fluorescence-Guided Surgery.
abstract: There is a need for new molecular-guided contrast agents to enhance surgical procedures such as tumor resection that require a high degree of precision. Cysteine cathepsins are highly up-regulated in a wide variety of cancers, both in tumor cells and in the tumor-supporting cells of the surrounding stroma. Therefore, tools that can be used to dynamically monitor their activity in vivo could be used as imaging contrast agents for intraoperative fluorescence image guided surgery (FGS). Although multiple classes of cathepsin-targeted substrate probes have been reported, most suffer from overall fast clearance from sites of protease activation, leading to reduced signal intensity and duration in vivo. Here we describe the design and synthesis of a series of near-infrared fluorogenic probes that exploit a latent cationic lysosomotropic effect (LLE) to promote cellular retention upon protease activation. These probes show tumor-specific retention, fast activation kinetics, and rapid systemic distribution. We demonstrate that they are suitable for detection of diverse cancer types including breast, colon and lung tumors. Most importantly, the agents are compatible with the existing, FDA approved, da Vinci surgical system for fluorescence guided tumor resection. Therefore, our data suggest that the probes reported here can be used with existing clinical instrumentation to detect tumors and potentially other types of inflammatory lesions to guide surgical decision making in real time.
authors.forename: Leslie O
authors.initials: LO
authors.lastname: Ofori
authors.forename: Nimali P
authors.initials: NP
authors.lastname: Withana
authors.forename: Tyler R
authors.initials: TR
authors.lastname: Prestwood
authors.forename: Martijn
authors.initials: M
authors.lastname: Verdoes
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Brady
authors.forename: Monte M
authors.initials: MM
authors.lastname: Winslow
authors.affiliation: Intuitive Surgical Inc., 1020 Kifer Road, Sunnyvale, California 94086, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sorger
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000378:metabolism; D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D005453:Fluorescence; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000601:surgery*; D061848:Optical Imaging / Q000379:methods*; D025321:Surgery, Computer-Assisted / Q000379:methods*
chemical_list: D003287:Contrast Media; D005456:Fluorescent Dyes; D002403:Cathepsins