Synthesis, aggregation and cellular investigations of porphyrin-cobaltacarborane conjugates.
A new series of porphyrin-cobaltacarborane conjugates (1-5) that contain four to sixteen carborane clusters per porphyrin macrocycle, were prepared in excellent yields (90-97 %) by means of a ring-opening reaction of the zwitterionic cobaltacarborane [3,3'-Co(8-C(4)H(8)O(2-)-1,2-C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))]. The X-ray structure of one conjugate (3) is presented. The aggregation properties of these conjugates were investigated by using absorption and fluorescence spectrophotometry, and the stages of microcrystal formation were captured by using atomic force microscopy. All conjugates were found to aggregate in aqueous solutions, to form a broad dispersity of particle sizes. The cellular uptake, cytotoxicity, and preferential sites of subcellular localization of this series of conjugates were evaluated in human carcinoma HEp2 cells. The extent of conjugate cellular uptake depends on the number of cobaltacarborane units at the porphyrin periphery, their distribution, and the conjugate aggregation behavior. Conjugates 2 and 4, bearing either two adjacent or three 3,5-dicobaltacarboranephenyl groups, accumulated the most within HEp2 cells and are, therefore, the most promising boron neutron capture therapy agents. All conjugates showed very low dark- and photo-toxicity, probably due to their strong tendency for aggregation in aqueous solutions, and localized subcellularly within vesicles that correlated, to some extent, with the cell lysosomes.
Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA.
Erhong
E
Hao
Martha
M
Sibrian-Vazquez
Wilson
W
Serem
Jayne C
JC
Garno
Frank R
FR
Fronczek
M Graça H
MG
Vicente
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008027:Light; D008247:Lysosomes / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D010316:Particle Size; D011166:Porphyrins / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000528:radiation effects; D013329:Structure-Activity Relationship; D013997:Time Factors; D000098851:Carboranes
D011166:Porphyrins; C515487:cobaltacarborane; D000098851:Carboranes