Facile synthesis of pegylated zinc(ii) phthalocyanines via transesterification and their in vitro photodynamic activities

Treatment of 4,5-bis[4-(methoxycarbonyl)phenoxy]phthalonitrile and 4,5-bis[3,5-bis(methoxycarbonyl)phenoxy]phthalonitrile with an excess of 1,3-diiminoisoindoline in the presence of Zn(OAc) ₂·2H ₂O and 1,8-diazabicyclo[5.4.0]undec-7-ene in triethylene glycol monomethyl ether or polyethylene glycol monomethyl ether (with an average molecular weight of 550) led to "3 + 1" mixed cyclisation and transesterification in one pot, affording the corresponding di-β- substituted zinc(ii) phthalocyanines in 7-23% yield. As shown by absorption spectroscopy, these compounds were essentially non-aggregated in N,N-dimethylformamide and could generate singlet oxygen effectively. The singlet oxygen quantum yields (Φ _Δ = 0.53-0.57) were comparable with that of the unsubstituted zinc(ii) phthalocyanine (Φ _Δ = 0.56). These compounds in Cremophor EL emulsions also exhibited photocytotoxicity against HT29 human colorectal adenocarcinoma and HepG2 human hepatocarcinoma cells with IC ₅₀ values in the range of 0.25-3.72 μM. The analogue with four triethylene glycol chains was the most potent photosensitiser and localised preferentially in the mitochondria of HT29 cells. The bis(polyethylene glycol)-counterpart could form surfactant-free nanoparticles both in water and in the culture medium. The hydrodynamic radii, as determined by dynamic laser light scattering, ranged from 6.3 to 79.8 nm depending on the preparation methods and conditions. The photocytotoxicity of these nanoparticles (IC ₅₀ = 0.43-0.56 μM) was comparable with that of the Cremophor EL-formulated system (IC ₅₀ = 0.34 μM). © 2011 The Royal Society of Chemistry.