Synthesis And Photophysicochemical Properties Of Triphenylphosphine And Piperazinyl Substituted Silicon(?) Phthalocyanines

Photodynamic therapy(PDT)has been used in clinical treatment of tumor and non-tumor diseases.It could kill the cancer cells by the combination of photosensitizer,light and molecular oxygen to produce active oxygen.As second-generation photosensitizer,phthalocyanine and its derivatives have the advantages of large conjugated system,high extinction coefficient and high singlet oxygen quantum yield.However,phthalocyanines are prone to aggregation in aqueous solution which leading to lower their singlet oxygen yield.Furtheremore,the singlet oxygen diffusion distance and short lifetime greatly limit the therapeutic efficiency of photodynamic therapy.Therefore,the synthesis of phthalocyanine with lower aggration behavior and organelles targeting specificity are one of the most effective ways to improve the therapeutic effect of PDT.A series of triphenylphosphine and piperazine substituted silicon phthalocyanines have been designed and synthesized.The aim of molecular design is to endow photosensitizer with dual functions of cell organelles targeting and photodynamic therapic ability.Mitochondria are double membrane organelles,whose membrane potential ranges from-150 m V to-180 m V.Positive charges of cationic triphenylphosphine can interact with negatively charged mitochondria to achieve mitochondrial targeting.Lysosome are acdic organells in eukaryotic cells(p H=4.5-5.5).It is explained the basic groups with biofilm permeability(such as morpholine,dimethylamino and alkyl tertiary amine)can specifically target lysosomes.The dipolarity of the basic group piperazine is similar to that of morpholine and has stronger hydrophilicity than that of morpholine.And the positive charge of N-methyl piperazine group is expected to be the potential target group for mitochondria.Therefore,a series of triphenylphosphine and piperazine substituted silicon phthalocyanines have been synthesized by introducing triphenylphosphine,piperazine and N-methylpiperazine groups into the axial position of the silicon phthalocyanine.Their structures were characterized,their photophysical and photochemical properties were studied,and their uptake by ovarian and breast cancer cells were preliminarily studied.The details are as follows:(1)Triphenylphosphine with targeted mitochondria substituted silicon phthalocyanines:di-(6-triphenylphosphine hexanoate)phthalocyanines silicon(?)(PPh₃-Si Pc)was synthesized and their srcture were characterized by FT-IR,¹H NMR and MALDI-TOF-MS.In addition,the fluorescence quantum yields,fluorescence lifetime and singlet oxygen quantum yields of PPh₃-Si Pc in DMF were 0.33,0.47 and 6.83 ns,respectively.PPh₃-Si Pc could be taken up by HO-8910 ovarian cancer cells and exhibited bright fluorescence.PPh₃-Si Pc was found to be co-localized with Mito-tracker Green in HO-8910 cells(Pearson Correlation Coefficient Rr=0.81,Co-location Coefficient R=0.98)and had good phototoxicity(IC₅₀=0.5?M).Therefore,PPh₃-Si Pc is expected to be a potential mitochondrial targeted photosensitizer for using in fluorescence imaging-guided photodynamic therapy.(2)A series of piperazinyl axial substituted silicon phthalocyanine complexes have been synthesized.Di-(1-ethoxypiperazine)phthalocyanine silicon(IV)(PIP-Si Pc)was firstly prepared by directly introducing 1-ethoxypiperazine to the axial position of dichlorosilicphthalocyanine.The solubility,fluorescence quantum yield,fluorescence lifetime and singlet oxygen quantum yield of PIP-Si Pc were excellent in organic solvent and aqueous solution.Besides,it could be taken up by MCF-7 breast cancer cells and exhibited the strong red fluorescence observed under confocal laser scanning microscopy(CLSM).Therefore,PIP-Si Pc may be a promising photosensitizer for for imaging and treatment in PDT.Next,diphenylmethyl and fluoro-diphenylmethyl were further introduced into the PIP-Si Pc to prepare di-(4-(diphenylmethylpiperazinyl)-1-ethoxy)phthalocyanine silicon(IV)(2Ph-PIP-Si Pc)and di-(4-(4,4'-difluorophenylpiperazine)-1-ethoxy)phthalocyanine silicon(IV)(2F-PIP-Si Pc).Their structures were characterized by FT-IR,¹H NMR and MALDI-TOF-MS.Compared with PIP-Si Pc,the Q-band absorption and fluorescence emission peak of 2Ph-PIP-Si Pc and 2F-PIP-Si Pc were red-shift,but the fluorescence quantum yield and singlet oxygen quantum yield are obviously decreased.Unexpectedly,the fluorescence of 2Ph-PIP-Si Pc and 2F-PIP-Si Pc in DMF/H₂O system increased gradually with the increase of water content,showing aggregation-induced emission effect.By the way,2Ph-PIP-Si Pc and 2F-PIP-Si Pc could be directly taken up by the MCF-7 cells and exhited red fluorescence.(3)A series of N-methylated piperazinyl axial substituted silicon phthalocyanine complexes have been synthesized.They are di-(4-(4-cyanobenzyl)piperazine)-1-ethoxy)phthalocyanine silicon(IV)(PIP-CN-Si Pc),di-(4-(4-cyanobenzyl)-1-methyl-iodopiperazine)-1-ethoxy)phthalocyanine silicon(IV)(PIP-CN-Si Pc I₂),di-(4-(4-nitrobenzyl)piperazine)-1-ethoxy)phthalocyanine silicon(IV)(PIP-NO₂-SIP_C)and di-(4-(4-nitrobenzyl)-1-methyl-iodopiperazine)-1-ethoxy)phthalocyanine silicon(IV)(PIP-NO₂-Si Pc I₂).Their strcture were characterized by FT-IR,¹H NMR and MALDI-TOF-MS.The photophysical properties of PIP-CN-Si Pc,PIP-CN-Si Pc I₂,PIP-NO₂-Si Pc and PIP-NO₂-Si Pc I₂ were compared by UV–Vis and fluorescence spectra.The position of the Q-band absorption,the fluorescence intensity,the fluorescence lifetimes and the singlet oxygen quantum yields of piperazine phthalocyanines(PIP-CN-Si Pc and PIP-NO₂-Si Pc)were not significantly affected by the introduction of Cyanobenzyl and Nitrobenzyl groups.However,N-methylated piperazinyl axial substituted silicon phthalocyanines not only increased their solubility in organic solvents but also endowed them water solubility.In addition,the absorption and emission peaks of the N-methylated phthalocyanines(PIP-CN-Si Pc I₂ and PIP-NO₂-Si Pc I₂)were red-shifted,the fluorescence intensities,the fluorescence quantum yields,the fluorescence lifetimes,as well as singlet oxygen quantum yields were increased,and were prolonged,which was due to the disaggregation of phthalocyanine because of the charge repulsion of positive of methylated phthalocyanine.The methylated phthalocyanines(PIP-CN-Si Pc I₂ and PIP-NO₂-Si Pc I₂)were potential photosensitizer for PDT treatment.