Mitochondria targeting by guanidine- and biguanidine-porphyrin photosensitizers.
We report the syntheses of three new amphiphilic porphyrin derivatives, containing a guanidine, a biguanidine, or an MLS peptide, that were designed to target the cell mitochondria. The guanidine- and biguanidine-porphyrins are poorly soluble in water, forming J-type aggregates in aqueous solutions. On the other hand, the porphyrin-MLS peptide conjugate bearing a low molecular weight PEG spacer is highly water-soluble and does not aggregate in aqueous media. The fluorescence quantum yields determined for all porphyrins were higher at low pH (<6) and the porphyrin-peptide conjugate had the highest quantum yields in aqueous media. All porphyrins showed low dark toxicity toward human carcinoma HEp2 cells, and the guanidine-porphyrin was the most phototoxic (IC 50 = 4.8 microM at 1 J cm (-2)), followed by the biguanidine-porphyrin and the porphyrin-MLS (IC50 = 8.2 microM and 9.8 microM at 1 J cm (-2), respectively). The porphyrin-MLS peptide conjugate accumulated the most within cells of all porphyrins at all times investigated and the biguanidine-porphyrin accumulated the least. Both the guanidine- and biguanidine-porphyrins localized within cell mitochondria and, in addition, were found in the lysosomes and the ER (in the case of the guanidine-porphyrin). In contrast, the porphyrin-MLS peptide conjugate localized mainly within the cell lysosomes.
Sibrian-Vazquez
Martha
M
Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA.
Nesterova
Irina V
IV
Jensen
Timothy J
TJ
Vicente
M Graça H
MG
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002855:Chromatography, Thin Layer; D002942:Circular Dichroism; D019791:Guanidine / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D008247:Lysosomes / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects*; D010777:Photochemistry; D017319:Photosensitizing Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011166:Porphyrins / Q000737:chemistry / Q000378:metabolism*; D013056:Spectrophotometry, Ultraviolet; D013347:Subcellular Fractions
D007202:Indicators and Reagents; D017319:Photosensitizing Agents; D011166:Porphyrins; D019791:Guanidine