Heptamethine cyanines for use as fluorescent markers of the biliary and renal systems
Inventors
Schnermann, Martin John • Kim, Peter C. W. • CHA, Jaepyeong • Nani, Roger Rauhauser
Assignees
Childrens National Medical Center Inc • US Department of Health and Human Services
Publication Number
US-11787764-B2
Publication Date
2023-10-17
Expiration Date
2039-02-14
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Abstract
Heptamethine cyanines for use as fluorescent markers of the biliary and renal systems are disclosed. Certain heptamethine cyanines exhibit renal system specificity, while others exhibit biliary system specificity. The compounds may be used for diagnostic purposes and/or for visualization of renal or biliary systems during surgery.
Core Innovation
The invention discloses heptamethine cyanine compounds and methods for their use as fluorescent markers of the biliary and renal systems. Specific embodiments of these compounds exhibit either renal system specificity or biliary system specificity. These compounds can be used for diagnostic purposes and visualization during surgery by administering the compound to a subject and irradiating a targeted portion with light sufficient to produce fluorescence, thereby enabling real-time visualization of the targeted system.
The background highlights that despite progress in molecular medicine, surgical interventions rely mainly on memory recall and visual and tactile cues, which may be insufficient for the identification and preservation of critical structures. Unintended injuries during surgery cause complications and increased healthcare costs. Current fluorescence-guided surgical methods mainly use the FDA-approved indocyanine green, but a new generation of dyes is needed to address the specific challenges in surgical imaging, such as specificity and stability. The disclosed heptamethine cyanines address these needs by providing high specificity for either renal or biliary systems, good quantum yields, and stability, facilitating improved intraoperative visualization.
Claims Coverage
The independent claims focus on methods for in vivo visualization of the renal system using a pharmaceutical composition with a specific heptamethine cyanine compound, with further claims on surgical procedures using this visualization.
Method for in vivo visualization of renal system using compound of Formula IA
Administering to a subject a pharmaceutical composition comprising a fluorescence agent with a compound of Formula IA, in an amount sufficient for fluorescence detection upon irradiation with light in the range of 650 nm to 900 nm.
Pharmaceutical composition administration routes and formulation
Administering the pharmaceutical composition by oral, buccal, systemic, injection, transdermal, rectal, inhalation, or insufflation routes, where the composition can include physiologically acceptable fluids, excipients, wetting agents, emulsifying agents, preservatives, and pH buffering agents.
Fluorescence detection parameters
Maintaining a contrast-background ratio (CBR) of at least 1.5 for at least 30 minutes with light sources including lasers, LEDs, xenon lamps, halogen bulbs, or VSCEL, using light intensities about 0.1 to 1000 mW/cm2, and performing irradiation externally or internally using suitable light applicators or devices.
Surgical procedure employing fluorescence-guided visualization
Administering the compound UL-766 to a patient for accumulation in the ureter, irradiating abdominopelvic area with NIR light (600-850 nm), visualizing ureter fluorescence, and performing surgery within the area while visualizing the ureter.
The independent claims cover the administration of pharmaceutical compositions containing specific heptamethine cyanine compounds for fluorescence-guided visualization of the renal system, detailing administration routes, light irradiation parameters, and applications in surgical procedures, providing improved specificity and real-time visualization of the ureter.
Stated Advantages
Compounds exhibit high specificity for renal or biliary systems, enabling targeted and clear visualization.
The compounds have good quantum yields, ensuring bright fluorescence for real-time imaging.
Compounds are unreactive towards thiols and cellular proteomes, implying improved stability and reduced potential toxicity.
They enable rapid excretion and fluorescence visualization shortly after injection, providing timely intraoperative guidance.
Fluorescence-guided visualization reduces risk of iatrogenic injuries during abdominopelvic surgeries by facilitating real-time identification of structures such as the ureter and bile ducts.
The fluorescence signal maintains sufficiently long contrast-to-background ratios for effective surgical use.
Documented Applications
In vivo visualization of at least a portion of the renal system or biliary system of a subject, including real-time imaging during surgery.
Identifying ureteral obstruction or iatrogenic injury by fluorescence detection at the ureteropelvic junction.
Identifying bile leakage or iatrogenic injury in the biliary system during hepatobiliary surgery.
Visualizing the biliary tree, cystic ducts, Calot's triangle, gallbladder, and intrahepatic ducts during laparoscopic or open surgery.
Detecting hepatocellular carcinoma and colorectal liver metastasis in hepatic tissue by fluorescence with the disclosed compounds.
Use in fluorescence-guided surgical procedures within abdominopelvic area to minimize injury and improve surgical outcomes.
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