Adduct of fluorescent dye and tumor avid tetrapyrrole
A compound having preferential localization in tumor tissue relative to normal tissue, a preferential electromagnetic absorption at a wavelength between about 660 and 900 nm, and a fluorescence at a wavelength shifted from the preferential absorption by at least +30 nm and preferably at least +50 nm. The compound further preferably destroys tumor tissue in which it is absorbed when exposed to light at its preferential absorption wavelength. In a preferred embodiment of the invention, the compound is a conjugate of a tumor avid tetrapyrrole compound with a fluorescent dye, and more preferably the fluorescent dye is an indocyanine dye such as indocyanine green. The tumor avid tetrapyrrole compound is preferably a porphyrin derivative selected from the group consisting of chlorins, bacteriochlorins, purpurins and derivatives thereof.
1. A compound having preferential localization in tumor tissue relative to normal tissue, a preferential electromagnetic absorption at a wavelength between about 660 and 900 nm, and a fluorescence at a wavelength shifted from the preferential absorption by at least +30 nm, said compound being a conjugate of a tumor avid tetrapyrrole compound with a fluorescent dye said compound having the formula:
where:
R 1 is, substituted or unsubstituted,—CH═CH 2 , —CHO, COOH, or
where R 9 =—OR 10 where R 10 is lower alkyl of 1 through 8 carbon atoms, or —(CH 2 —O) n CH 3 ;
R 2 , R 2a , R 3 , R 3a , R 4 , R 5 , R 5a , R 7 , and R 7a are independently hydrogen, lower alkyl, substituted lower alkyl, lower alkylene or substituted lower alkylene or two R 2 , R 2a , R 3 , R 3a , R 5 , R 5a , R 7 , and R 7a groups on adjacent carbon atoms may be taken together to form a covalent bond or two R 2 , R 2a , R 3 , R 3a , R 5 , R 5a , R 7 , and R 7a groups on the same carbon atom may form a double bond to a divalent pendant group; R 2 and R 3 may together form a 5 or 6 membered heterocyclic ring containing oxygen, nitrogen or sulfur; R 6 is —CH 2 —, —NR 11 —, where R 11 is, substituted or unsubstituted, lower alkyl, or lower alkylene; or a R 6 is a covalent bond; R 8 is —(CH 2 ) 2 CO 2 R 12 where R 12 is, substituted or unsubstituted, lower alkyl, lower alkylene or —NH 2 , wherein at least one of R 1 , R 2a , R 3 , R 3a , R 4 , R 5 , R 5a , R 7 , R 7a , R 8 , R 9 , R 10 , R 11 , or R 12 is substituted with a dye fluorescing at a peak emission wave length of from about 800 to about 900 nm and having a peak absorption at least 30 nm below its peak emission.
2. The compound of claim 1 wherein the shift is at least +50 nm.
3. The compound of claim 1 wherein the fluorescent dye is an indocyanine dye.
4. The compound of claim 1 wherein the tumor avid tetrapyrrole compound is selected from the group consisting of chlorins, bacteriochlorins and porphyrins.
5. The compound of claim 4 wherein the dye is an indocyanine dye.
6. The compound of claim 4 wherein the dye is indocyanine green.
7. The compound of claim 1 having the structural formula: