Heteroatom Substituted Porphyrazines as Optical Agents for Tumor Diagnosis and Therapy

Porphyrazines are a class of tetrapyrrole that have recently attracted attention for their intense electronic absorption and emission in the near infrared region. These optical properties allow a porphyrazine to be used as a fluorescent optical imaging agent for tumor detection. A relatively unstudied sub-class of porphyrazine with peripheral chiral bis-acetal moieties are especially promising.;A series of mixed benzo/bis-acetal porphyrazines have been synthesized and screened for application as near infrared optical probes. Of particular interest, one member of this class, porphyrazine 247, exhibits intense electronic absorption (lambdaabs = 702 nm; log epsilon = 4.12) and emission (lambdaem = 727 nm; phi f = 0.09), the latter of which can be observed from within tumor cells in vitro. Porphyrazine 247 also exhibits potential as a sensitizer for photodynamic therapy with near quantitative quantum yields of singlet oxygen generation when bound to model lipid vesicles. Porphyrazine 247 also exhibits remarkable preferential uptake into tumors in vivo by a mechanism mediated by low-density lipoprotein and over expressed low-density lipoprotein receptors.;The scope of the utility for this platform has been expanded by examination of mixed naphtho/bis-acetal porphyrazines. These porphyrazines have optical properties shifted far into the near infrared region (lambda abs = 875 nm; log epsilon = 4.53; lambdaem = 925 nm) highlighting our ability to tune the optical properties of a given porphyrazine. These porphyrazines also enter tumor cells where their fluorescence is clearly observed. Finally, an unsymmetrical benzo/bis-acetal porphyrazine has been synthesized with a design conducive to protein association responsible for tumor specificity. This porphyrazine enters cells by interaction with serum albumin where intense fluorescence is observed. Free alcohol groups at the porphyrazine periphery can be activated by arenesulfonation for conjugation to bioactive groups with the hope that these groups will be co-transported into cells.