ABSTRACT
We discovered a rare phenomenon wherein a thieno-pyrrole fused BODIPY dye (SBDPiR690) generates singlet oxygen without heavy halogen atom substituents. SBDPiR690 generates both singlet oxygen and fluorescence. To our knowledge, this is the first example of such a finding. To establish a structure-photophysical property relationship, we prepared SBDPiR analogs with electron-withdrawing groups at the para-position of the phenyl groups. The electron-withdrawing groups increased the HOMO-LUMO energy gap and singlet oxygen generation. Among the analogs, SBDPiR688, a CF3 analog, had an excellent dual functionality of brightness (82290 m(-1) cm(-1) ) and phototoxic power (99170 m(-1) cm(-1) ) comparable to those of Pc 4, due to a high extinction coefficient (211 000 m(-1) cm(-1) ) and balanced decay (Φflu =0.39 and ΦΔ =0.47). The dual functionality of the lead compound SBDPiR690 was successfully applied to preclinical optical imaging and for PDT to effectively control a subcutaneous tumor.
Subject(s)
Boron Compounds/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Pyrroles/chemistry , Singlet Oxygen/metabolism , Animals , Apoptosis/drug effects , Boron Compounds/toxicity , Cell Line, Tumor , Crystallography, X-Ray , Drug Design , Fluorescent Dyes/chemistry , Halogens/chemistry , Heterocyclic Compounds, 4 or More Rings/toxicity , Humans , Lasers , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Conformation , Neoplasms/drug therapy , Photochemotherapy , Photosensitizing Agents/chemistry , Photosensitizing Agents/therapeutic use , Photosensitizing Agents/toxicity , Quantum Theory , Singlet Oxygen/chemistry , Spectroscopy, Near-Infrared , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Mitochondria-specific photosensitizers were designed by taking advantage of the preferential localization of delocalized lipophilic cations (DLCs) in mitochondria. Three DLC-porphyrin conjugates: CMP-Rh (a core modified porphyrin-rhodamine B cation), CMP-tPP (a core modified porphyrin-mono-triphenyl phosphonium cation), CMP-(tPP)(2) (a core modified porphyrin-di-tPP cation) were prepared. The conjugates were synthesized by conjugating a monohydroxy core modified porphyrin (CMP-OH) to rhodamine B (Rh B), or either one or two tPPs, respectively, via a saturated hydrocarbon linker. Their ability for delivering photosensitizers to mitochondria was evaluated using dual staining fluorescence microscopy. In addition, to evaluate the efficiency of the conjugates as photosensitizers, their photophysical properties and in vitro biological activities were studied in comparison to those of CMP-OH. Fluorescence imaging study suggested that CMP-Rh specifically localized in mitochondria. On the other hand, CMP-tPP and CMP-(tPP)(2) showed less significant mitochondrial localization. All conjugates were capable of generating singlet oxygen at rates comparable to CMP-OH. Interestingly, all cationic conjugates showed dramatic increase in cellular uptake and phototoxicity compared to CMP-OH. This improved photodynamic activity might be primarily due to an enhanced cellular uptake. Our study suggests that Rh B cationic group is better at least for CMP than tPP as a mitochondrial targeting vector.
