Surgical resection of malignant disease is one of the effective treatments for cancer. However, the inability of surgeons to distinguish diseased tissue from adjacent healthy tissue leads to incomplete tumor resection and tumor recurrence. Optical image-guided surgery is gaining traction, especially when near infrared (NIR) fluorophores are targeted to tumor tissues.  Thus, imaging in the NIR region (700-900 nm) avoids autofluorescence that primarily resides in the visible range and targeting to tumor tissues eliminates non-specific uptake by healthy tissues that resulting to higher signal-to-back ground ratio. While multiple NIR dyes are commercially available for conjugation to a tumor-targeting ligand, each of them displays major deficiencies related to conjugation efficiency, product stability, or fluorescence quantum yield. To obtain the optimal tumor-targeted NIR dye for eventual clinical use, we have conjugated pteroic acid to S0456 (a commercially available NIR dye) via amino acids that can undergo addition-elimination reaction with vinyl chloride moiety in S0456. Amino acids such as cysteine, tyrosine, lysine, serine, tyramine, amino proline, etc. were screened as possible candidates to improve binding affinity of pterioc acid to folate receptor as well as enhance fluorescence intensity of S0456. Of the multiple imaging agents considered, pteroyl-tyrosine-S0456 exhibits a quantum yield equal to the best NIR dyes available, but can be synthesized in just two steps at 90% overall yield in multi-gram quantities. Moreover, the conjugate displays high affinity and specificity for folate receptors (FR) and accumulates in FR+ expressing cancers in mice with FR+ tumors.  Finally, histopthathological analysis demonstrated that pteroyl-tyrosine-S0456 exhibits excellent safety profile in mice. Taken together, FR specific NIR probe demonstrates significant potential for use in fluorescent guided surgery by aiding in the complete resection of diseased tissue.

Evaluation of pteroyl-amino acid-NIR dye conjugates for tumor targeted fluorescence guided surgery

246th National Meeting (2013)

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