pH-Responsive self-assembled polymer-photosensitizer conjugate for activable photodynamic therapy†

This paper reports synthesis, aqueous self-assembly and relevance of the pH-triggered activable photodynamic therapy of amphiphilic polyurethane (P1S) functionalized with a heavy-atom free organic photosensitizer. Condensation polymerization between 1,4-diisocyanatobutane and two different dihydroxy monomers (one having a pendant hydrophilic wedge and the other having 1,3-dihydroxypropan-2-one with a reactive carbonyl group) in the presence of a measured amount of (S)-2-methylbutan-1-ol (chain-stopper) and DABCO catalyst produces a reactive pre-polymer P1. Hydrazide-functionalized thionated-naphthalenemonoimide (NMIS), which acts as a photosensitizer, reacted with the carbonyl-functionality of P1 to obtain the desired polymer-photosensitizer conjugate P1S in which the dye was attached to the polymer backbone via an acid-labile hydrazone linker. In water, P1S adopted an intra-chain H-bonding stabilized folded structure, which further assembled to produce a polymersome structure (D_h ≈ 200 nm), in which the hydrophobic membrane consists of aggregated NMIS and trialkoxy-benzene chromophores, as evident from UV/vis, CD and small-angle X-ray diffraction studies. In the aggregated state, NMIS loses its reactive oxygen species (ROS) generation ability and remains in a dormant state. However, under acidic conditions (pH 5.5), the photosensitizer is detached (presumably because of the cleavage of the hydrazone linker) and regains its full ROS-generation activity under photoirradiation, as evidenced from the standard DCFH assay. To test the possibility of such pH-activable intra-cellular ROS generation, P1S was treated with HeLa cells, as it is known that cancer cells are more acidic than normal cells. Indeed, photoirradiation-induced intra-cellular ROS generation was evident by the DCFH assay, resulting in efficient cell killing.