Pivotal Role\nof\nthe Intracellular Microenvironment\nin the High Photodynamic Activity of Cationic Phthalocyanines

To\ninvestigate the influence of phthalocyanine aggregation on their\nphotodynamic activity, a series of six cationic water-soluble zinc(II)\nphthalocyanines bearing from four to sixteen 4-((diethylmethylammonium)methyl)phenoxy\nsubstituents was synthesized. Depending on their structure, the phthalocyanines\nhave different aggregation behaviors in phosphate buffer solutions\nranging from fully assembled to monomeric states. Remarkably, independent\nof aggregation in buffer, very high photodynamic efficiencies against\nthe tumor cell lines MCF-7 and MDA-MB-231 in the nanomolar range were\nfound for all investigated phthalocyanine, and the IC<sub>50</sub>(light) varied from 27 to 358 nM (3.5 J/cm<sup>2</sup>, 660 nm) with\nIC<sub>50</sub>(dark)/IC<sub>50</sub>(light) ratios up to ∼3700.\nThis is due to the intracellular disassembly of aggregated phthalocyanines\nwith the formation of monomeric photoactive forms, as demonstrated\nby fluorescence microscopy. Indeed, the interaction of aggregated\nphthalocyanines with serum proteins in a buffer resulted in the disassembly\nof nonluminescent aggregate species with the release of photoactive\nmonomers bound to protein macromolecules.